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Sample records for carbon tetrachloride-induced hepatotoxicity

  1. Carbon tetrachloride-induced hepatotoxicity in pregnant and lactating rats.

    Science.gov (United States)

    Mochizuki, Masahiro; Shimizu, Satomi; Urasoko, Yoshinaka; Umeshita, Kazuhiko; Kamata, Takashi; Kitazawa, Takahiro; Nakamura, Daichi; Nishihata, Yoshito; Ohishi, Takumi; Edamoto, Hiroshi

    2009-04-01

    Carbon tetrachloride (CCl4) is well known to induce hepatotoxicity after being metabolized to trichloromethyl free radical ((.)CCl3) by CYP2E1. In the present study, the hepatotoxicity induced by a single oral dose (2,000 mg/kg) of CCl4 was compared between pregnant (gestation days (GD) 13 and 19) or postpartum (postpartum days (PPD) 1, 13 and 27) and non-pregnant rats. Hepatotoxicity in CCl4-treated pregnant rats evaluated by blood chemistry (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities) and histopathological finding (area of damaged hepatocytes) was minimal on GD19, being weaker than that in non-pregnant rats. CYP2E1 expression in non-treated pregnant rats decreased as pregnancy progressed and reached minimum level on GD19. Thus, the degree of CCl4-induced hepatotoxicity roughly corresponded to CYP2E1 levels during pregnancy. After delivery, hepatotoxicity in CCl4-treated lactating rats was maximal on PPD13, being stronger than that in non-pregnant rats, and then it decreased slightly on PPD27. The CYP2E1 level in the non-treated lactating rats tended to increase but remained at lower levels until PPD13 compared with that in non-pregnant rats. Thus, the degree of CCl4-induced hepatotoxicity did not correspond to CYP2E1 levels during lactation. This suggests that during lactation, there may be certain factors other than CYP2E1 expression responsible for the degree of CCl4-induced hepatotoxicity.

  2. Telmisartan ameliorates carbon tetrachloride-induced acute hepatotoxicity in rats.

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    Atawia, Reem T; Esmat, Ahmed; Elsherbiny, Doaa A; El-Demerdash, Ebtehal

    2017-02-01

    This study assessed the potential hepatoprotective effect of telmisartan (TLM), a selective angiotensin II type 1 (AT1 ) receptor blocker, on carbon tetrachloride (CCl4 )-induced acute hepatotoxity in rats. Intraperitoneal injection of male Wistar rats with CCl4 1 mL kg(-1) , 1:1 mixture with corn oil for 3 days increased serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities as well as total bilirubin, triglycerides and total cholesterol levels. This is in addition to the disrupted histological architecture in the CCl4 group. Rats receiving CCl4 and co-treated with TLM (3 and 10 mg kg(-1) , orally) showed ameliorated serum biochemical and histological changes almost to the control level. Nevertheless, rats treated with TLM (1 mg kg(-1) ) didn't show any significant changes compared to CCl4 intoxicated group. In addition, TLM rectified oxidative status disrupted by CCl4 intoxication. Interestingly, TLM protected against CCl4 -induced expressions of nuclear factor-κB, inducible nitric oxide synthase and cyclooxygenase-II, in a dose related manner. Moreover, TLM (3 and 10 mg kg(-1) ) significantly modified CCl4 -induced elevation in tumor necrosis factor-α and nitric oxide levels. Furthermore, TLM showed a marked decline in CD68+ cells stained areas and reduced activity of myeloperoxidase enzyme compared to CCl4 -intoxicated group. In conclusion, both doses of TLM (3 and 10 mg kg(-1) ) showed significant hepato-protective effects. However, TLM at a dose of 10 mg kg(-1) didn't show significant efficacy above 3 mg kg(-1) which is nearly equivalent to the human anti-hypertensive dose of 40 mg. Thus, may be effective in guarding against several hepatic complications due to its antioxidant and anti-inflammatory activities. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 359-370, 2017.

  3. Hepatoprotective effect ofAverrhoea carambolafruit extract on carbon tetrachloride induced hepatotoxicity in mice

    Institute of Scientific and Technical Information of China (English)

    AK Azeem; Molly Mathew; Chandramohan Nair DilipC

    2010-01-01

    Objective:To investigate the hepatoprotective activity ofAverroha carambola fruit extract against carbon tetrachloride induced hepatic injury.Methods:Hepatotoxicity was induced on albino mice by intraperitoneal administration ofCCl4, half an hour after the administration of the last dose of the extract ofAverroha carambola fruit. Aqueous extract of the fruit ofAverroha carambola was administered at a dose of 0.9 g/kg body weight once daily for seven days. The hepatic injury and its prevention was assessed by the estimation of serum activities of alanine aminotransferase (ALT), aspartate aminotransferase(AST), alkaline phosphates(ALP), glutathione level and histopathological studies of liver.Results: Pre-treatment of mice with the fruit extract ofAverrhoea carambola significantly reduced serum levels ofALT, AST andALP enzyme and significantly increased the liver reduced glutathione levels24 h after the administration of carbon tetrachloride. A marked improvement in the enzyme activities and the liver reduced glutathione level was observed in the pre-treated mice 4 days after the administration of carbon tetrachloride. Histopathological studies provided supportive evidence for the biochemical analysis. Conclusions:The aqueous extract of the fruit ofAverrhoea carambola has hepatoprotective effect against carbon tetrachloride induced liver damage in mice.

  4. Attenuation of Carbon Tetrachloride-Induced Hepatotoxicity by Cow Urine Distillate in Rats

    Institute of Scientific and Technical Information of China (English)

    M PGURURAJA; A B JOSHI; HIMANSHU JOSHI; D SATHYANARAYANA; E V S SUBRAHMANYAM; K S CHANDRASHEKHAR

    2009-01-01

    Objectives To study the carbon tetrachloride-induced hepatoprotective activity in cow urine. Methods Effect of cow urine distillate on liver function was studied in vivo in rats intoxicated with carbon tetrachloride (CCl4). Hepatotoxicity was induced by a 1:1 (v/v) mixture of CCl4 in olive oil (5 mL/kg i.p). Protective effect of cow urine distillate (in three dose levels) and standard drug Silymarin (100 mg/kg, p.o) on liver function were studied in intoxicated rats. Parameters in the study included liver function tests and histological observations. Results The cow urine distillate decreased the levels of SGOT, SGPT, ALP, GGT, and total bilirubin in a dose-dependent manner (P<0.05) as sylimarin. Conclusion The observed protective effects of cow urine distillate on liver function might be due to the presence of antioxidants in cow urine.

  5. HEPATOPROTECTIVE ACTIVITY OF ETHANOLIC EXTRACT OF ALTHAEA OFFICINALIS LINN AGAINST CARBON TETRACHLORIDE INDUCED HEPATOTOXICITY ON ALBINO WISTAR RATS

    OpenAIRE

    Jabbar Zoobi; Ali Mohd.

    2011-01-01

    In Indian traditional system of medicine, herbal remedies are prescribed for the treatment of various diseases including liver diseases. The present study was aimed to investigate the hepatoprotective activity of the ethanolic extract of Althaea officinalis against Carbon tetrachloride induced hepatotoxicity in rats. Liver function were assessed by the determination of SGPT and SGOT studies. The serum biochemical analysis results suggested that the use of ethanolic extract of Althaea officina...

  6. Hepatoprotective effect of Origanum vulgare in Wistar rats against carbon tetrachloride-induced hepatotoxicity.

    Science.gov (United States)

    Sikander, Mohammad; Malik, Shabnam; Parveen, Kehkashan; Ahmad, Maqsood; Yadav, Deepak; Hafeez, Zubair Bin; Bansal, Manish

    2013-04-01

    The effect of an aqueous extract of Origanum vulgare (OV) leaves extract on CCl4-induced hepatotoxicity was investigated in normal and hepatotoxic rats. To evaluate the hepatoprotective activity of OV, rats were divided into six groups: control group, O. vulgare group, carbon tetrachloride (CCl4; 2 ml/kg body weight) group, and three treatment groups that received CCl4 and OV at doses of 50, 100, 150 mg/kg body weight orally for 15 days. Alanine amino transferase (ALT), alkaline phosphatase (ALP), and aspartate amino transferase (AST) in serum, lipid peroxide (LPO), GST, CAT, SOD, GPx, GR, and GSH in liver tissue were estimated to assess liver function. CCl4 administration led to pathological and biochemical evidence of liver injury as compared to controls. OV administration led to significant protection against CCl4-induced hepatotoxicity in dose-dependent manner, maximum activity was found in CCl4 + OV3 (150 mg/kg body weight) groups and changes in the hepatocytes were confirmed through histopathological analysis of liver tissues. It was also associated with significantly lower serum ALT, ALP, and AST levels, higher GST, CAT, SOD, GPx, GR, and GSH level in liver tissue. The level of LPO also decreases significantly after the administration of OV leaves extract. The biochemical observations were supplemented with histopathological examination of rat liver sections. Thus, the study suggests O. vulgare showed protective activity against CCl4-induced hepatotoxicity in Wistar rats and might be beneficial for the liver toxicity.

  7. Amelioration of carbon tetrachloride induced hepatotoxicity in rats by standardized Feronia limonia. Linn leaf extracts

    OpenAIRE

    Devkar, Ranjitsinh V; Jadeja, Ravirajsinh N.; Jain, Mahendra; Kapadia, Rakhee; Mishra, S. H.; Menaka C. Thounaojam

    2012-01-01

    The hepatoprotective potential of standardized Feronia limonia (Family, Rutaceae) methanolic extract (FL-7) and chloroform soluble fraction (FL-9) were assessed against carbon tetrachloride (CCl4) induced oxidative stress and hepatotoxicity in rats. Rats treated with CCl4 recorded significant elevation in plasma markers of hepatic injury, alteration in hepatic antioxidant status and histopathological damages. However, rats pretreated with FL-7 (200 or 400 mg/kg, p.o.) and FL-9 (100 or 200 mg/...

  8. Role of the sympathetic nervous system in carbon tetrachloride-induced hepatotoxicity and systemic inflammation.

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    Jung-Chun Lin

    Full Text Available Carbon tetrachloride (CCl4 is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA in a mouse model of CCl4-induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL-1α, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2, and tumor necrosis factor-α (TNF-α], as well as decreased expression of granulocyte colony-stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1α, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-α were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response.

  9. HEPATOPROTECTIVE ACTIVITY OF ALSTONIA SCHOLARIS FRUITS AGAINST CARBON TETRACHLORIDE-INDUCED HEPATOTOXICITY IN RATS

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    K. RAVI SHANKAR, A. LAKSHMANA RAO, L. KALYANI

    2013-09-01

    Full Text Available The hepatoprotective activity of ethanolic extract of fruits of Alstonia scholaris was evaluated by carbon tetrachloride (CCL4-induced hepatotoxicity in rats. The toxicant CCL4 was used to induce hepatotoxicity at a dose of 2 ml/kg as 1:1 mixture with olive oil. The ethanolic extract of fruits of Alstonia scholaris was administered in the dose of 150 and 300 mg/kg/day orally for 5 days. Silymarin (50 mg/kg was used as standard drug. The hepatoprotective effect of the ethanolic extract was evaluated by the assessment of biochemical parameters such as SGOT, SGPT, SALKP, total bilirubin and histopathological studies of the liver. Treatment of animals with the ethanolic extract significantly reduced the liver damage and the symptoms of liver injury by restoration of architecture of liver as indicated by lower levels of serum bilirubin as compared with the normal and silymarin treated groups.

  10. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats.

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    Gang Tan

    Full Text Available BACKGROUND: Hydrogen sulfide (H(2S displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2S in carbon tetrachloride (CCl(4-induced hepatotoxicity, cirrhosis and portal hypertension. METHODS AND FINDINGS: Sodium hydrosulfide (NaHS, a donor of H(2S, and DL-propargylglycine (PAG, an irreversible inhibitor of cystathionine γ-lyase (CSE, were applied to the rats to investigate the effects of H(2S on CCl(4-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2S, hepatic H(2S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4 significantly reduced serum levels of H(2S, hepatic H(2S production and CSE expression. NaHS attenuated CCl(4-induced acute hepatotoxicity by supplementing exogenous H(2S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, hyaluronic acid (HA, albumin, tumor necrosis factor (TNF-α, interleukin (IL-1β, IL-6 and soluble intercellular adhesion molecule (ICAM-1, liver histology, hepatic hydroxyproline content and α-smooth muscle actin (SMA expression. PAG showed opposing effects to NaHS on most of the above parameters. CONCLUSIONS: Exogenous H(2S attenuates CCl(4-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H(2S may present a promising approach, particularly for its prophylactic effects, against liver

  11. Hepatoprotective effect of Rosa canina fruit extract against carbon tetrachloride induced hepatotoxicity in rat

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    Heibatollah Sadeghi

    2016-03-01

    Full Text Available Objective: The present study was conducted to investigate the hepatoprotective activity of hydro-ethanolic fruit extract of Rosa canina (R. canina against carbon tetrachloride (CCl4-induced hepatotoxicity in rats. Methods: Male Wistar albino rats were randomly divided into six groups of 8 animals of each, including control, toxic (CCl4, R. canina 250, 500, and 750 mg/kg + CCl4 and R. canina 750 mg/kg alone. R. canina (p.o., daily and CCl4 (1 ml/kg twice a week, 50% v/v in olive oil, i.p. were administered to animals for six weeks. Serum analysis was performed to assay the levels of aspartate aminotransferase (AST, alanine amino transaminase (ALT, alkaline phosphatase (ALP, albumin (ALB, total protein (TP and malondialdehyde (MDA. Biochemical observations were also supplemented with histopathological examination (haematoxylin and eosin staining of liver section.Results: Hepatotoxicity was evidenced by considerable increase in serum levels of AST, ALT, ALP, and lipid peroxidation (MDA and decrease in levels of ALB and TP. Injection of CCL4 also induced congestion in central vein, and lymphocyte infiltration. Treatment with hydro-alcoholic fruit extract of R. canina at doses of 500 and 750 mg/kg significantly reduced CCl4-elevated levels of ALT, AST, ALP and MDA (p

  12. The Aqueous Seed Extract Of Carica papaya Linn. Prevents Carbon Tetrachloride Induced Hepatotoxicity In Rats

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    A A Adeneye

    2009-06-01

    Full Text Available Summary: Carica papaya Linn. is known to have a versatile application in African folkloric medicine. In the current study, the dose-dependent (100 – 400 mg/kg/day/oral route and time-course protective effects of the 400 mg/kg/oral route of the aqueous seed extract of unripe and mature Carica papaya fruit (CPE were investigated in carbon tetrachloride (CCl4 hepatotoxic rats for 72 hours. Results showed the extract to cause significant (p<0.05, p<0.001, dose related attenuation in the elevation of serum liver enzyme markers of acute hepatocellular injury (ALT, AST, serum lipids (TG, TC, HDL-c, LDL-c and VLDL-c and serum proteins (TP and ALB. Maximum hepatoprotection was offered at an oral dose of 400 mg/kg/day of the extract. The biochemical results obtained were corroborated by improvements in the CCl4-induced hepatic histological changes. In addition, maximum hepatoprotection was offered at the 400 mg/kg of CPE for up to 3 hours post-CCl4 induction. In conclusion, the results obtained in the current study justify the folkloric application of CPE in the treatment of drug-related hepatic injury. Industrial relevance: Results of the current study provide some scientific information to develop safe and effective products such as food supplements, dietary supplements, etc. that could be useful in the clinical management of patients with drug related hepatic disorders.

  13. Carbon tetrachloride-induced hepatotoxicity in rat is reversed by treatment with riboflavin.

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    Al-Harbi, Naif O; Imam, Faisal; Nadeem, Ahmed; Al-Harbi, Mohammed M; Iqbal, Muzaffar; Ahmad, Sheikh Fayaz

    2014-08-01

    Liver is a vital organ for the detoxification of toxic substances present in the body and hepatic injury is associated with excessive exposure to toxicants. The present study was designed to evaluate the possible hepatoprotective effects of riboflavin against carbon tetrachloride (CCl4) induced hepatic injury in rats. Rats were divided into six groups. Hepatotoxicity was induced by the administration of a single intraperitoneal dose of CCl4 in experimental rats. Riboflavin was administered at 30 and 100mg/kg by oral gavage to test its protective effect on hepatic injury biochemically and histopathologically in the blood/liver and liver respectively. The administration of CCl4 resulted in marked alteration in serum hepatic enzymes (like AST, ALT and ALP), oxidant parameters (like GSH and MDA) and pro-inflammatory cytokine TNF-α release from blood leukocytes indicative of hepatic injury. Changes in serum hepatic enzymes, oxidant parameters and TNF-α production induced by CCl4 were reversed by riboflavin treatment in a dose dependent manner. Treatment with standard drug, silymarin also reversed CCl4 induced changes in biomarkers of liver function, oxidant parameters and inflammation. The biochemical observations were paralleled by histopathological findings in rat liver both in the case of CCl4 and treatment groups. In conclusion, riboflavin produced a protective effect against CCl4-induced liver damage. Our study suggests that riboflavin may be used as a hepato-protective agent against toxic effects caused by CCl4 and other chemical agents in the liver.

  14. D-Pinitol Protects Against Carbon Tetrachloride-Induced Hepatotoxicity in Rats.

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    Rengarajan, Thamaraiselvan; Rajendran, Peramaiyan; Nandakumar, Natarajan; Lokeshkumar, Boobathy; Balasubramanian, Maruthaiveeran Periyasamy

    2015-01-01

    The aim of the study was to evaluate the protective activity of D-Pinitol against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. The animals were divided into six groups, with each group consisting of six animals. Group I animals served as normal controls and received olive oil vehicle (1.0 ml/kg body weight intraperitoneally). Group II rats served as CCl4 controls, which received 30% CCl4 suspended in olive oil (3.0 ml/kg body weight intraperitoneally) twice a week for 4 weeks. Group III rats were treated with 30% CCl4 suspended in olive oil (3.0 ml/kg body weight intraperitoneally) twice a week for 4 weeks, followed by D-Pinitol (100 mg/kg body weight) given for 28 days intragastrically. Group IV rats received D-Pinitol alone at a concentration of 100 mg/kg body weight for 28 days intragastrically. At the end of the experimental period, serum marker enzymes and lipid peroxidation (LPO) levels were significantly increased in group II animals. On the other hand, D-Pinitol treatment significantly decreased marker enzymes and LPO levels and increased the antioxidant level. CYP expression was also investigated. Therefore, the present study revealed that D-Pinitol acts as a protective agent by decreasing metabolic activation of xenobiotics through its antioxidant nature.

  15. Antioxidant and hepatoprotective effects of flower extract of Millingtonia hortensis Linn. on carbon tetrachloride induced hepatotoxicity

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    S Babitha

    2012-01-01

    Full Text Available Objective: Millingtonia hortensis Linn is an abundant resource of flavonoids, which might be beneficial in protecting liver tissue from injury. The hepatoprotective and antioxidant potential of ethanolic extract of M. hortensis on carbon tetrachloride (CCl 4 induced hepatotoxicity and the possible mechanism involved therein were investigated in rats. Materials and Methods: Preliminary phytochemical studies were carried out to determine the total phenol and flavonoid contents. 30 adult Wistar rats were allocated into 5 groups. Control group received vehicle, group-2 received CCl 4 alone (1 ml/kg body weight, intraperitonially, groups 3 - 5 received the ethanolic flower extract in 2 dose levels (200 and 400 mg/kg and Curcumin (100 mg/kg as a standard for 8 days orally, followed by CCl 4 as a single dose on the 8 th day. 48 hours later, blood was withdrawn, serum was subjected to biochemical assessments, and liver homogenate was examined for lipid peroxides, glutathione, superoxide dismutase, catalase and total protein levels. Furthermore, hepatic tissues were subjected to histopatological studies. Results: CCl 4 treatment produced a profound increase in the levels of malondialdehyde, hepatic marker enzymes and bilirubin content compared with the control (P < 0.05. Pre-treatment with the flower extract of M. hortensis significantly enhanced the levels of endogenous antioxidants and reduced the levels of hepatic marker enzymes in relation to the CCl 4 treated group (P < 0.05. Balloning degeneration and fatty changes in hepatocytes was prevented by pre-treatment with the flower extract. Conclusion: The antioxidant nature of the flower extract of M. hortensis could be responsible for averting damage to the liver.

  16. Protective Effect of Berberis integerrima Fruit Extract on Carbon-Tetrachloride Induced Hepatotoxicity in Rats

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    fereshteh rafiee

    2013-09-01

    Full Text Available Background & Objective: Hepatoprotective effect of antioxidants such as flavnoids has been demonstrated. The aim of the present study was to assess the hepatoprotective effect of the methanolic extract of Berberis integerrima fruit (MEBIF on carbon-tetrachloride (CCL4 induced hepatotoxicity in rats. Materials & Methods: Forty male rats were divided into 5 groups as follows: 1 normal, 2 toxicant control (CCL4 was injected intraperitoneally (1 mg/kg bw, 3&4 toxicant rats treated with MEBIF at dose 250 and 500 mg/kg bw, and 5 toxicant rats treated with silymarin. At the end of the study, all the rats were sacrificed and some biochemical parameters of serum such as Alanine Aminotransferase (ALT, aspartate aminotransferase (AST and Alk‌aline Phosphatase (ALP, total proptein, total bilirubin and albumin, and concentrations of malondialdehyde (MDA, superoxide dismutase (SOD, Catalase (CAT and FRAP (Ferric Reducing/Antioxidant Power in liver tissue hemogenate were estimated. The Data was analyzed by one way variance analysis and Tukey’s test using SPSS 21. Results: injection of CCl4 significantly (P≤001/0 increased levels of ALT, AST, ALP, total bilirubin and MDA and decreased levels of total protein, albumin CAT, SOD (P≤ (001/0and FRAP in toxicant rats. In groups toxicant + Berberis (250&500 and toxicant + silymarin restored these changes to normal levels. Histopathological findings are cosistent with biochemical findings. Conclusion: MEBIF have a hepatoprotective effect on CCL4- induced hepatic damage in rats and these effects might be contributed to modulation of detoxification enzymes and antioxidant and free radical scavenger effects.

  17. Hepatoprotective activity of Eclipta alba against carbon tetrachloride-induced hepatotoxicity in albino rats

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    Ravindra S. Beedimani

    2015-06-01

    Conclusion: The results of the study confirmed the hepatoprotective activity of aqueous extracts of E. alba at doses of 250 mg/kg and 500 mg/kg against CCl4 induced hepatotoxicity in rats. However, the dose adjustments may be necessary to optimize the similar hepatoprotective efficacy in clinical settings. [Int J Basic Clin Pharmacol 2015; 4(3.000: 404-409

  18. Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity

    Institute of Scientific and Technical Information of China (English)

    Yuichi Yamazaki; Satoru Kakizaki; Norio Horiguchi; Hitoshi Takagi; Masatomo Mori; Masahiko Negishi

    2005-01-01

    AIM: To investigate the precise roles of CAR in CCl4-induced acute hepatotoxicity.METHODS: To prepare an acute liver injury model, CCl4 was intraperitoneally injected in CAR+/+ and CAR-/- mice.RESULTS: Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR-/- mice compared to CAR+/+ mice without PB. Administration of a CAR inducer, PB, revealed that CCl4-induced liver toxicity was partially inhibited in CAR-/- mice compared with CAR+/+ mice. On the other hand,androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR+/+ but not in CAR-/- mice. Thus, CAR activation caused CCl4 hepatotoxicity while CAR inhibition resulted in partial protection against CCl4-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl4, between CAR+/+ and CAR-/- mice. However, the expression of other CCl4-metabolizing enzymes, such as CYP2B10 and 3A11, was induced by PB in CAR+/+ but not in CAR-/- mice. Although the main pathway of CCl4-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3A11 in the presence of activator or inhibitor.CONCLUSION: The nuclear receptor CAR modulates CCl4-induced liver injury via induction of CCl4-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drugdrug interaction even though such drugs themselves are not hepatotoxic.

  19. Hepatoprotective potential of Aloe barbadensis Mill. against carbon tetrachloride induced hepatotoxicity.

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    Chandan, B K; Saxena, A K; Shukla, Sangeeta; Sharma, Neelam; Gupta, D K; Suri, K A; Suri, Jyotsna; Bhadauria, M; Singh, B

    2007-05-22

    Aloe barbadensis Mill. Syn. Aloe vera Tourn. ex Linn.(Liliaceae) has been used in variety of diseases in traditional Indian system of medicine in India and its use for hepatic ailments is also documented. In the present study an attempt has been made to validate its hepatoprotective activity. The shade dried aerial parts of Aloe barbadensis were extracted with petroleum ether (AB-1), chloroform (AB-2) and methanol (AB-3). The plant marc was extracted with distilled water (AB-4). All the extracts were evaluated for hepatoprotective activity on limited test models as hexobarbitone sleep time, zoxazolamine paralysis time and marker biochemical parameters. AB-1 and AB-2 were observed to be devoid of any hepatoprotective activity. Out of two active extracts (AB-3 and AB-4), the most active AB-4 was studied in detail. AB-4 showed significant hepatoprotective activity against CCl4 induced hepatotoxicity as evident by restoration of serum transaminases, alkaline phosphatase, bilirubin and triglycerides. Hepatoprotective potential was confirmed by the restoration of lipid peroxidation, glutathione, glucose-6-phosphatase and microsomal aniline hydroxylase and amidopyrine N-demethylase towards near normal. Histopathology of the liver tissue further supports the biochemical findings confirming the hepatoprotective potential of AB-4. The present study shows that the aqueous extract of Aloe barbadensis is significantly capable of restoring integrity of hepatocytes indicated by improvement in physiological parameters, excretory capacity (BSP retention) of hepatocytes and also by stimulation of bile flow secretion. AB-4 did not show any sign of toxicity up to oral dose of 2 g/kg in mice.

  20. Hepatoprotective activity of Ficus carica Linn leaf extract against carbon tetrachloride-induced hepatotoxicity in rats

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    Mohan G.K.

    2007-06-01

    Full Text Available The methanol extract of the leaves of Ficus carica Linn. (Moraceae was evaluated for hepatoprotective activity in rats with liver damage induced by carbon tetrachloride. The extract at an oral dose of 500 mg/kg exhibited a significant protective effect by lowering the serum levels of aspartate aminotransferase, alanine aminotransferase, total serum bilirubin, and malondialdehyde equivalent, an index of lipid peroxidation of the liver. These biochemical observations were supplemented by histopathological examination of liver sections. The activity of extract was also comparable to that of silymarin, a known hepatoprotective. 

  1. Protective effects of sodium molybdate on carbon tetrachloride-induced hepatotoxicity in rats.

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    Eidi, Akram; Eidi, Maryam; Al-Ebrahim, Mahsa; Rohani, Ali Haeri; Mortazavi, Pejman

    2011-01-01

    Molybdenum is an essential trace micronutrient element that plays an important role in animal and plant physiology. Molybdenum is a constituent of at least three mammalian metalloflavoproteins: xanthine oxidase, aldehyde oxidase and sulphite oxidase. In the present study, the hepatoprotective potential of sodium molybdate was investigated against carbon tetrachloride (CCl(4))-induced liver damage in rats. Administration of CCl(4) increased the serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in rats and reduced levels of the antioxidant enzymes superoxide dismutase and catalase in the liver. Treatment with sodium molybdate significantly attenuated these changes to nearly undetectable levels. The histopathological changes induced by CCl(4) were also significantly attenuated by sodium molybdate treatment. Therefore, the results of this study suggest that sodium molybdate can protect the liver against CCl(4)-induced oxidative damage in rats, and this hepatoprotective effect might be attributable to its modulation of detoxification enzymes and/or its antioxidant and free radical scavenger effects.

  2. Carbon tetrachloride-induced hepatotoxicity: Protective effect of 'Rocket' Eruca sativa L. in rats.

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    Alqasoumi, Saleh

    2010-01-01

    The hepatoprotective and antioxidant effect of an ethanolic extract of 'Rocket' Eruca sativa L. (EER), on liver injury induced by carbon tetrachloride (CCl(4)) was investigated. Wistar albino rats were administered 250 and 500 mg/kg body weight extract orally for 10 consecutive days. Marker enzymes GOT, GPT, ALP, GGT and bilirubin were estimated in serum. Whereas, non-protein sulfhydryl (NP-SH), total protein (TP) and malondialdehyde (MDA) were estimated in liver tissue as markers for oxidative stress. Histopathological assessment was also done on liver tissue. CCl(4) induced liver poisoning in all treated animals was evident by elevated serum GOT, GPT, ALP, GGT and bilirubin levels. Induction of oxidative stress in the liver tissue by CCl(4) was evidenced by a fall in the levels of NP-SH and TP; and an increased level of MDA concentration. EER administration for 10 days prevented the CCl(4) induced hepatic injury and oxidative stress. Furthermore, the extract also reduced the pentobarbital-induced prolongation of sleeping time in mice. The ability of rocket extract to protect the liver toxicity in rats was further confirmed by histological findings in the liver tissue. In conclusion, it was observed that Eruca sativa L. extract protects the liver against CCl(4) induced hepatic injury through its potent antioxidant activity in rats.

  3. Antihepatotoxic effect of marrubium vulgare and withania somnifera extracts on carbon tetrachloride-induced hepatotoxicity in rats.

    Science.gov (United States)

    Elberry, Ahmed A; Harraz, Fathalla M; Ghareib, Salah A; Nagy, Ayman A; Gabr, Salah A; Suliaman, Mansour I; Abdel-Sattar, Essam

    2010-09-01

    Marrubium vulgare and Withania somnifera are used in folk medicine of several countries. Many researches showed that they are used for the treatment of variety of diseases due to their antioxidant effects. The present aim of this study was to evaluate the antihepatotoxic and antioxidant activities of the both extracts against carbon tetrachloride (CCl4)-induced hepatic damage in rats. Both extracts were given orally in a dose of 500 mg/kg/day for 4 weeks along with CCl4 started at the 7th week of induction of hepatotoxicity. The antihepatotoxic activity was assessed by measuring aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), reduced glutathione (GSH), tissue content and malondialdehyde (MDA) as well as histopathological examination. Both extracts showed a significant antihepatotoxic effect by reducing significantly the levels of AST, ALT and LDH. However, ALP levels were decreased non-significantly. Regarding the antioxidant activity, they exhibited significant effects by increasing the GPx, GR and GST activities with increased GSH tissue contents and decreased production of MDA level. Furthermore, both extracts alleviated histopathological changes in rats' liver treated with CCl4. M. vulgare and W. somnifera protect the rats' liver against CCl4-induced hepatotoxicity. This effect may be attributed, at least in part, to the antioxidant activities of these extracts.

  4. Hepatoprotective effects of sesamol loaded solid lipid nanoparticles in carbon tetrachloride induced sub-chronic hepatotoxicity in rats.

    Science.gov (United States)

    Singh, Neha; Khullar, Neeraj; Kakkar, Vandita; Kaur, Indu Pal

    2016-05-01

    Sesamol is a phenolic component of sesame seed oil, which has been established as an antioxidant and also possesses potential for hepatoprotection. However, its protective role in carbon tetrachloride (CCl4 ) induced sub-chronic hepatotoxicity has not been studied. Limited oral bioavailability (BA) and rapid elimination (as conjugates) in rats is reported for sesamol. Considering its significant antioxidant potential and compromised BA, we packaged sesamol into solid lipid nanoparticles (S-SLNs) to enhance its hepatoprotective bioactivity. S-SLNs prepared by microemulsification method were nearly spherical in shape with an average particle size of 120.30 nm and their oral administration at 8 mg/kg body weight (BW) showed significantly (p induced sub-chronic liver injury in rats. Evaluations were done in terms of histological changes in the liver tissue, liver injury markers (serum alanine aminotransferase, serum aspartate aminotransferase, and serum lactate dehydrogenase); oxidative stress markers (lipid peroxidation, superoxide dismutase, and reduced glutathione) and proinflammatory response marker (tumor necrosis factor-alpha).

  5. Protective effects of melatonin against carbon tetrachloride-induced hepatotoxicity in rats: a light microscopic and biochemical study.

    Science.gov (United States)

    Kus, Ilter; Ogeturk, Murat; Oner, Hakan; Sahin, Semsettin; Yekeler, Hayrettin; Sarsilmaz, Mustafa

    2005-01-01

    The aim of this study was to examine the protective effects of melatonin against CCl4-induced hepatotoxicity in the rat. Twenty-four male Wistar rats were divided into three groups. Group I was used as a control. Rats in group II were injected every other day with CCl4 for 1 month, whereas rats in group III were injected every other day with CCl4 and melatonin for 1 month. At the end of the experiment, all animals were killed by decapitation and blood samples were obtained. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total and conjugated bilirubin levels were determined. For histopathological evaluation, livers of all rats were removed and processed for light microscopy. All serum biochemical parameters were significantly higher in animals treated with CCl4 than in the controls. When rats injected with CCl4 were treated with melatonin, significantly reduced elevations in serum biochemical parameters were found. In liver sections of the CCl4-injected group, necrosis, fibrosis, mononuclear cell infiltration, haemorrhage, fatty degeneration and formation of regenerative nodules were observed. Additionally, apoptotic figures, microvesicular steatosis and hydropic degeneration in hepatocytes were seen in this group. In contrast, the histopathological changes observed after administration of CCl4 were lost from rats treated with CCl4 and melatonin. Except for mild hydropic degeneration of the hepatocytes, a normal lobular appearance was seen in the livers of this group. The results of our study indicate that melatonin treatment prevents CCl4-induced liver damage in rats.

  6. Umbelliferone and daphnetin ameliorate carbon tetrachloride-induced hepatotoxicity in rats via nuclear factor erythroid 2-related factor 2-mediated heme oxygenase-1 expression.

    Science.gov (United States)

    Mohamed, Mohamed R; Emam, Manal A; Hassan, Nahla S; Mogadem, Abeer I

    2014-09-01

    Among various phytochemicals, coumarins comprise a very large class of plant phenolic compounds that have good nutritive value, in addition to their antioxidant effects. The purpose of the present study was to investigate the protective effects of two coumarin derivatives, umbelliferone and daphnetin, against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats and elucidate the underlying mechanism. Treatment of rats with either umbelliferone or daphnetin significantly improved the CCl4-induced biochemical alterations. In addition, both compounds alleviated the induced-lipid peroxidation and boosted the antioxidant defense system. Moreover, the investigated compounds attenuated CCl4-induced histopathological alterations of the liver. Finally, umbelliferone and daphnetin induced the nuclear translocation of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), thereby inducing the expression and activity of the cytoprotective heme oxygenase-1 (HO-1). These results suggest that umbelliferone and daphnetin ameliorate oxidative stress-related hepatotoxicity via their ability to augment cellular antioxidant defenses by activating Nrf2-mediated HO-1 expression.

  7. Effects of Peppermint (Mentha piperita L. Alcoholic Extract on Carbon Tetrachloride-induced Hepatotoxicity in Broiler Chickens Under Heat Stress Condition

    Directory of Open Access Journals (Sweden)

    Khodadust MR

    2015-06-01

    Full Text Available In order to investigate the effects of peppermint (Mentha piperita L. alcoholic extract on liver injury caused by the oxidant carbon tetrachloride (CCl4, an experiment was performed as a completely randomized design in a factorial arrangement (2 × 2 with 4 replications of 10 broilers each. Factors included two levels of peppermint leaf alcoholic extract (0 and 2 mL/Kg body weight and CCl4 (0 and 1 mL/Kg body weight. Results showed significant (P interactions for body weight gain (BWG, feed intake (FI and feed conversion ratio (FCR on d 42 of the experiment. The alcoholic extract of peppermint leaf did not improve growth performance, whereas CCl4 worsened BWG and FCR (P. The interaction between peppermint extract and CCl4 indicated an ameliorative effect of peppermint extract on BWG and FCR (P. The interaction effects between peppermint extract and CCl4 significantly differed for blood serum concentrations of total protein, albumin, albumin:globulin ratio, glucose, triglyceride, total cholesterol, HDLC, LDLC, LDLC:HDLC ratio, and VLDLC as well as the amount of blood liver enzymes (P. Peppermint extract significantly increased blood serum concentrations of total protein, albumin, triglyceride and HDLC, whilst CCl4 decreased those concentrations (P. Blood serum concentrations of total cholesterol, LDLC, LDLC:HDLC ratio, VLDLC and glucose were decreased by peppermint extract, whereas those concentrations were increased by CCl4 (P. A significantly higher level of liver enzymes was found in blood serum of birds treated by CCl4 than those by peppermint extract (P. A moderate effect on blood serum liver enzymes was observed by the interaction between 2 mL of peppermint extract and 1 mL of CCl4 (P. Generally, this study indicated that in vivo administration of peppermint alcoholic extract ameliorated the adverse effects of CCl4 on growth performance and liver function, therefore it might be useful for the prevention of oxidative stress

  8. Urinary metabonomics study of the hepatoprotective effects of total alkaloids from Corydalis saxicola Bunting on carbon tetrachloride-induced chronic hepatotoxicity in rats using (1)H NMR analysis.

    Science.gov (United States)

    Wu, Fang; Zheng, Hua; Yang, Zheng-Teng; Cheng, Bang; Wu, Jin-Xia; Liu, Xu-Wen; Tang, Chao-Ling; Lu, Shi-Yin; Chen, Zhao-Ni; Song, Fang-Ming; Ruan, Jun-Xiang; Zhang, Hong-Ye; Liang, Yong-Hong; Song, Hui; Su, Zhi-Heng

    2017-03-19

    Chronic liver injury has been shown to cause liver fibrosis due to the sustained pathophysiological wound healing response of the liver, and eventually progresses to cirrhosis. The total alkaloids of Corydalis saxicola Bunting (TACS), a collection of important bioactive ingredients derived from the traditional Chinese folk medicine Corydalis saxicola Bunting (CS), have been reported to have protective effects on the liver. However, the underlying molecular mechanisms need further elucidation. In this study, the urinary metabonomics and the biochemical changes in rats with carbon tetrachloride (CCl4)-induced chronic liver injury due to treatment TACS or administration of the positive control drug-bifendate were studied via proton nuclear magnetic resonance ((1)H NMR) analysis. Partial least squares-discriminate analysis (PLS-DA) suggested that metabolic perturbation caused by CCl4 damage was recovered with TACS and bifendate treatment. A total of seven metabolites including 2-oxoglutarate, citrate, dimethylamine, taurine, phenylacetylglycine, creatinine and hippurate were considered as potential biomarkers involved in the development of CCl4-induced chronic liver injury. According to pathway analysis using identified metabolites and correlation network construction, the tricarboxylic acid (TCA) cycle, gut microbiota metabolism and taurine and hypotaurine metabolism were recognized as the most affected metabolic pathways associated with CCl4 chronic hepatotoxicity. Notably, the changes in 2-oxoglutarate, citrate, taurine and hippurate during the process of CCl4-induced chronic liver injury were significantly restored by TACS treatment, which suggested that TACS synergistically mediated the regulation of multiple metabolic pathways including the TCA cycle, gut microbiota metabolism and taurine and hypotaurine metabolism. This study could bring valuable insight to evaluating the efficacy of TACS intervention therapy, help deepen the understanding of the

  9. Protective effects of the apigenin-O/C-diglucoside saponarin from Gypsophila trichotoma on carbone tetrachloride-induced hepatotoxicity in vitro/in vivo in rats.

    Science.gov (United States)

    Simeonova, Rumyana; Kondeva-Burdina, Magdalena; Vitcheva, Vessela; Krasteva, Ilina; Manov, Vassil; Mitcheva, Mitka

    2014-01-15

    This study investigated the hepatoprotective activity of saponarin, isolated from Gypsophila trichotoma Wend., using in vitro/in vivo hepatotoxicity model based on carbone tetrachloride (CCl₄)-induced liver damage in male Wistar rats. The effect of saponarin was compared with those of silymarin. In vitro experiments were carried out in primary isolated rat hepatocytes. Cell incubation with CCl₄ (86 μmol l⁻¹) led to a significant decrease in cell viability, increased LDH leakage, decreased levels of cellular GSH and elevation in MDA quantity. Cell pre-incubation with saponarin (60-0.006 μg/ml) significantly ameliorated CCl₄-induced hepatic damage in a concentration-dependent manner. These results were supported by the following in vivo study. Along with decreased MDA quantity and increased level of cell protector GSH, seven day pre-treatment of rats with saponarin (80 mg/kg bw; p.o.) also prevented CCl₄ (10%, p.o.)-caused oxidative damage by increasing antioxidant enzyme activities (CAT, SOD, GST, GPx, GR). Biotransformation phase I enzymes were also assessed. Administered alone, saponarin decreased EMND and AH activities but not at the same extent as CCl₄ did. However, pre-treatment with saponarin significantly increased enzyme activities in comparison to CCl₄ only group. The observed biochemical changes were consistent with histopathological observations where the hepatoprotective effect of saponarin was comparative to the effects of the known hepatoprotecor silymarin. Our results suggest that saponarin, isolated from Gypsophila trichotoma Wend., showed in vitro and in vivo hepatoprotective and antioxidant activity against CCl₄-induced liver damage.

  10. Hepatoprotective effect of Centella asiatica (L in carbon tetrachloride-induced liver injury in rats

    Directory of Open Access Journals (Sweden)

    Antony B

    2006-01-01

    Full Text Available The present study was conducted to evaluate the hepatoprotective effects of the Centella asiatica extract in carbon tetrachloride-induced liver injury in rats. Sprague Dawley rats were treated with alcohol extract of Centella asiatica orally in two doses (20 and 40 mg/kg/day for 3 mo along with intraperitoneal injection of carbon tetrachloride (1 ml/kg. Biochemical parameters such as serum total protein, albumin and marker enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase were estimated both before and after the experiment. Histopathological studies of liver were also carried out to confirm the biochemical changes. Carbon tetrachloride-induced hepatotoxic effects were evident by a significant (p < 0.05 increase in the serum marker enzymes and a decrease in the total serum protein and albumin. Administration of extract of Centella asiatica effectively inhibited these changes in a dose-dependent manner; maximum effect was with 40 mg/kg. Histopathological examination of liver tissue corroborated well with the biochemical changes. Hepatic steatosis, hydropic degeneration and necrosis were observed in carbon tetrachloride-treated group, while these were completely absent in the treatment group. Centella asiatica extract exhibited hepatoprotective action against carbon tetrachloride-induced liver injury. This effect is attributed to the presence of asiaticoside (14.5% in the extract.

  11. Tratamento homeopático da hepatotoxicose aguda induzida por tetracloreto de carbono em coelhos Homeopatic treatment of acute carbon tetrachloride induced hepatotoxicity in rabbits

    Directory of Open Access Journals (Sweden)

    Maria Cecília Ribeiro Moncorvo

    1998-09-01

    Full Text Available Quinze (15 coelhos (Oryctolagus cuniculus foram submetidos à intoxicação pelo tetracloreto de carbono na dosagem de 0,5 ml/kg de peso corporal, dose única, administrado por sonda gástrica. Foram realizadas as dosagens de alanina amino transferase (ALT, aspartato amino transferase (AST, fosfatase alcalina (FA e gama glutamil transferase (GGT antes e durante o experimento. Vinte e quatro (24 horas após a intoxicação, os coelhos foram divididos aleatoriamente em três grupos de 5 animais. Cada grupo recebeu um tratamento diferente durante 13 dias. O grupo I foi tratado com tetracloreto de carbono diluído na 30ª centesimal hahnemanniana (30 CH, uma vez ao dia. O grupo II recebeu Phosphorus 30 CH, também uma vez ao dia. O grupo III desempenhou o papel de controle, recebendo diariamente uma dose de placebo, pelo mesmo período de tempo que os grupos anteriores. Os resultados das concentrações séricas de ALT, AST, GGT e FA foram submetidos à análise estatística. A variação da concentração de todas as enzimas foi significativa entre os dias, mas nem todas variaram significativamente entre os grupos considerados. O tetracloreto de carbono 30 CH foi capaz de acelerar a recuperação do quadro de hepatite tóxica aguda determinada pela redução dos níveis de ALT. O tratamento com Phosphorus 30 CH mostrou-se incapaz seja de reverter o quadro de hepatite tóxica, seja de acelerar a regeneração hepática.Fithteen (15 New Zeland and Californian rabbits (Oryctolagus cuniculus were submitted to intoxication with carbon tethracloride in a dose 0/0.5 ml/kg, once a day, administred by orogastric sonde. Enzimatic parameters: alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase and gamma-glutamyltransferase of those rabbits were tested before and during the experiment. After the intoxication, the rabbits were divided in three groups of five animals. Each group received differents treatments during 13 days. The

  12. The Protective Properties of the Strawberry (Fragaria ananassa) against Carbon Tetrachloride-Induced Hepatotoxicity in Rats Mediated by Anti-Apoptotic and Upregulation of Antioxidant Genes Expression Effects.

    Science.gov (United States)

    Hamed, Sherifa S; Al-Yhya, Nouf A; El-Khadragy, Manal F; Al-Olayan, Ebtesam M; Alajmi, Reem A; Hassan, Zeinab K; Hassan, Salwa B; Abdel Moneim, Ahmed E

    2016-01-01

    The strawberry (Fragaria ananassa) has been extensively used to treat a wide range of ailments in many cultures. The present study was aimed at evaluating the hepatoprotective effect of strawberry juice on experimentally induced liver injury in rats. To this end, rats were introperitoneally injected with carbon tetrachloride (CCl4) with or without strawberry juice supplementation for 12 weeks and the hepatoprotective effect of strawberry was assessed by measuring serum liver enzyme markers, hepatic tissue redox status and apoptotic markers with various techniques including biochemistry, ELISA, quantitative PCR assays and histochemistry. The hepatoprotective effect of the strawberry was evident by preventing CCl4-induced increase in liver enzymes levels. Determination of oxidative balance showed that strawberry treatment significantly blunted CCl4-induced increase in oxidative stress markers and decrease in enzymatic and non-enzymatic molecules in hepatic tissue. Furthermore, strawberry supplementation enhanced the anti-apoptotic protein, Bcl-2, and restrained the pro-apoptotic proteins Bax and caspase-3 with a marked reduction in collagen areas in hepatic tissue. These findings demonstrated that strawberry (F. ananassa) juice possessed antioxidant, anti-apoptotic and anti-fibrotic properties, probably mediated by the presence of polyphenols and flavonoids compounds.

  13. Development of quercetin-phospholipid complex to improve the bioavailability and protection effects against carbon tetrachloride-induced hepatotoxicity in SD rats.

    Science.gov (United States)

    Zhang, Kexia; Zhang, Meiyu; Liu, Ziying; Zhang, Yuanyuan; Gu, Liqiang; Hu, Gaosheng; Chen, Xiaohui; Jia, Jingming

    2016-09-01

    Quercetin (QT) is a natural flavonoid with various biological activities and pharmacological actions. However, the bioavailability of QT is relatively low due to its low solubility which severely limits its use. In this study, we intended to improve the bioavailability of QT by preparing quercetin-phospholipid complex (QT-PC) and investigate the protective effect of QT-PC against carbon tetrachloride (CCl4) induced acute liver damage in Sprague-Dawley (SD) rats. The physicochemical properties of QT-PC were characterized in terms of infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD) and water/n-octanol solubility. FTIR, DSC and XRPD data confirmed the formation of QT-PC. The water solubility of QT was improved significantly in the prepared complex, indicating its increased hydrophilicity. Oral bioavailability of QT and QT-PC was evaluated in SD rats, and the plasma QT was estimated by HPLC-MS. QT-PC exhibited higher Cmax (1.58±0.11 vs. 0.67±0.08μg/mL), increased AUC0-∞ (8.60±1.25 vs. 2.41±0.51mg/Lh) and t1/2z (7.76±1.09 vs. 4.81±0.87h) when compared to free QT. The greater absorption of QT-PC group suggested the improved bioavailability. Moreover, biochemical changes and histopathological observations revealed that QT-PC provided better protection to rat liver than free QT at the same dose. Thus, phospholipid complexation might be one of the suitable approaches to improve the oral bioavailability of QT and obtain better protective effects against CCl4 induced acute liver damage in SD rats than free QT at the same dose level.

  14. Bioavailability of andrographolide and protection against carbon tetrachloride-induced oxidative damage in rats

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Haw-Wen [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Huang, Chin-Shiu [Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan (China); Li, Chien-Chun [School of Nutrition, Chung Shan Medical University, Taichung, Taiwan (China); Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan (China); Lin, Ai-Hsuan; Huang, Yu-Ju [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Wang, Tsu-Shing [Department of Biomedical Science, Chung Shan Medical University, Taichung, Taiwan (China); Yao, Hsien-Tsung, E-mail: htyao@mail.cmu.edu.tw [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Lii, Chong-Kuei, E-mail: cklii@mail.cmu.edu.tw [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan (China)

    2014-10-01

    in various tissues. • Andrographolide ameliorates carbon tetrachloride-induced hepatotoxicity in rats.

  15. The potential protective effect of Physalis peruviana L. against carbon tetrachloride-induced hepatotoxicity in rats is mediated by suppression of oxidative stress and downregulation of MMP-9 expression.

    Science.gov (United States)

    Al-Olayan, Ebtisam M; El-Khadragy, Manal F; Aref, Ahmed M; Othman, Mohamed S; Kassab, Rami B; Abdel Moneim, Ahmed E

    2014-01-01

    The active constituent profile in Cape gooseberry (Physalis peruviana L.) juice was determined by GC-MS. Quercetin and kaempferol were active components in the juice. In this study we have evaluated its potential protective effect on hepatic injury and fibrosis induced by carbon tetrachloride (CCl4). Twenty-eight rats divided into 4 groups: Group I served as control group, and Group II received weekly i.p. injection of 2 mL CCl4/kg bwt for 12 weeks. Group III were supplemented with Physalis juice via the drinking water. The animals of Group IV received Physalis juice as Group III and also were intraperitoneally injected weekly with 2 mL CCl4/kg bwt for 12 weeks. Hepatoprotective effect was evaluated by improvement in liver enzymes serum levels, reduction in collagen areas, downregulation in expression of the fibrotic marker MMP-9, reduction in the peroxidative marker malonaldehyde and the inflammatory marker nitric oxide, and restoration of the activity of antioxidant enzymatic and nonenzymatic systems, namely, glutathione content, superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase, and glutathione reductase activities. The results show that the potential hepatoprotective effects of Physalis peruviana may be due to physalis acts by promotion of processes that restore hepatolobular architecture and through the inhibition of oxidative stress pathway.

  16. Effect of Apitherapy Formulations against Carbon Tetrachloride-Induced Toxicity in Wistar Rats after Three Weeks of Treatment

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    Calin Vasile Andritoiu

    2014-08-01

    Full Text Available The human body is exposed nowadays to increasing attacks by toxic compounds in polluted air, industrially processed foods, alcohol and drug consumption that increase liver toxicity, leading to more and more severe cases of hepatic disorders. The present paper aims to evaluate the influence of the apitherapy diet in Wistar rats with carbon tetrachloride-induced hepatotoxicity, by analyzing the biochemical determinations (enzymatic, lipid and protein profiles, coagulation parameters, minerals, blood count parameters, bilirubin levels and histopathological changes at the level of liver, spleen and pancreas. The experiment was carried out on six groups of male Wistar rats. Hepatic lesions were induced by intraperitoneal injection of carbon tetrachloride (dissolved in paraffin oil, 10% solution. Two mL per 100 g were administered, every 2 days, for 2 weeks. Hepatoprotection was achieved with two apitherapy diet formulations containing honey, pollen, propolis, Apilarnil, with/without royal jelly. Biochemical results reveal that the two apitherapy diet formulations have a positive effect on improving the enzymatic, lipid, and protein profiles, coagulation, mineral and blood count parameters and bilirubin levels. The histopathological results demonstrate the benefits of the two apitherapy diet formulations on reducing toxicity at the level of liver, spleen and pancreas in laboratory animals.

  17. Transcriptome Analysis of the Effects of Gomisin A on the Recovery of Carbon Tetrachloride-Induced Damage in Rat Liver

    OpenAIRE

    Choi, Young Mi; Choi, In Soo; Lee, Sang Mong; Hwang, Dae Youn; Choi, Young Whan; Park, Young Hoon

    2011-01-01

    Gomisin A possesses a hepatic function-facilitating property in liver-injured rats. Its preventive action on carbon tetrachloride-induced cholestasis is due to maintenance of the function of the bile acids-independent fraction. To investigate alterations in gene expression after gomisin A treatment on injured rat liver, DNA microarray analyses were performed on a Rat 44K 4-Plex Gene Expression platform with duplicated reactions after gomisin A treatment. We identified 255 up-regulated and 230...

  18. Hepatocurative potential of sesquiterpene lactones of Taraxacum officinale on carbon tetrachloride induced liver toxicity in mice.

    Science.gov (United States)

    Mahesh, A; Jeyachandran, R; Cindrella, L; Thangadurai, D; Veerapur, V P; Muralidhara Rao, D

    2010-06-01

    The hepatocurative potential of ethanolic extract (ETO) and sesquiterpene lactones enriched fraction (SL) of Taraxacum officinale roots was evaluated against carbon tetrachloride (CCl 4 ) induced hepatotoxicity in mice. The diagnostic markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin contents were significantly elevated, whereas significant reduction in the level of reduced glutathione (GSH) and enhanced hepatic lipid peroxidation, liver weight and liver protein were observed in CCl 4 induced hepatotoxicity in mice. Post-treatment with ETO and SL significantly protected the hepatotoxicity as evident from the lower levels of hepatic enzyme markers, such as serum transaminase (ALT, AST), ALP and total bilirubin. Further, significant reduction in the liver weight and liver protein in drug-treated hepatotoxic mice and also reduced oxidative stress by increasing reduced glutathione content and decreasing lipid peroxidation level has been noticed. The histopathological evaluation of the liver also revealed that ETO and SL reduced the incidence of liver lesions induced by CCl 4 . The results indicate that sesquiterpene lactones have a protective effect against acute hepatotoxicity induced by the administration of CCl 4 in mice. Furthermore, observed activity of SL may be due to the synergistic action of two sesquiterpene lactones identified from enriched ethyl acetate fraction by HPLC method.

  19. In vitro and in vivo protective effects of proteoglycan isolated from mycelia of Ganoderma lucidum on carbon tetrachloride-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Xiao-Jun Yang; Jing Liu; Lin-Bai Ye; Fan Yang; Li Ye; Jin-Rong Gao; Zheng-Hui Wu

    2006-01-01

    AIM: To investigate the possible mechanism of the protective effects of a bioactive fraction, Ganoderma lucidum proteoglycan (GLPG) isolated from Ganoderma lucidum mycelia, against carbon tetrachloride-induced liver injury.METHODS: A liver injury model was induced by carbon tetrachloride. Cytotoxicity was measured by MTT assay.The activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined with an automatic multifunction-biochemical analyzer and the levels of superoxide dismutase (SOD) and TNF-α were determined following the instructions of SOD kit and TNF radioimmunoassay kit. Liver sections were stained with hematoxylin and eosin (H&E) for histological evaluation and examined under light microscope.RESULTS: We found that GLPG can alleviate the L-02liver cells injury induced by carbon tetrachloride (CCl4)through the measurements of ALT and AST activities and the administration of GLPG to L-02 cells did not display any toxicity. Furthermore, histological analysis of mice liver injury induced by CCl4 with or without GLPG pretreatment indicated that GLPG can significantly suppress the toxicity induced by CCl4 in mice liver. We also found that GLPG reduced TNF-α level induced by CCl4 in the plasma of mice, whereas increased SOD activity in the rat serum.CONCLUSION: GLPG has hepatic protective activity against CCl4-induced injury both in vitro and in vivo. The possible anti-hepatotoxic mechanisms may be related to the suppression of TNF-α level and the free radical scavenging activity.

  20. Transcriptome analysis of the effects of gomisin a on the recovery of carbon tetrachloride-induced damage in rat liver.

    Science.gov (United States)

    Choi, Young Mi; Choi, In Soo; Lee, Sang Mong; Hwang, Dae Youn; Choi, Young Whan; Park, Young Hoon

    2011-06-01

    Gomisin A possesses a hepatic function-facilitating property in liver-injured rats. Its preventive action on carbon tetrachloride-induced cholestasis is due to maintenance of the function of the bile acids-independent fraction. To investigate alterations in gene expression after gomisin A treatment on injured rat liver, DNA microarray analyses were performed on a Rat 44K 4-Plex Gene Expression platform with duplicated reactions after gomisin A treatment. We identified 255 up-regulated and 230 down-regulated genes due to the effects of gomisin A on recovery of carbon tetrachloride-induced rat liver damage. For functional characterization of these genes, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes biochemical pathways analyses were performed. Many up-regulated or down-regulated genes were related to cell cycle or focal adhesion and cell death genes, respectively. Our microarray experiment indicated that the liver repair mechanism induced by gomisin A was strongly associated with increased gene expressions related to cell cycle and suppression of the gene expression related in cell death.

  1. Hepatoprotective and antioxidant activity of pentagamavunon-0 against carbon tetrachloride-induced hepatic injury in rats

    Institute of Scientific and Technical Information of China (English)

    Arief Nurrochmad; Supardjan Amir Margono; Sardjiman; Arief Rahman Hakim; Ernawati; Erna Kurniawati; Erva Fatmawati

    2013-01-01

    Objective: To investigate the hepatoprotective and antioxidant activity of pentagamavunon-0(PGV-0) against CCl4-induced hepatic injury in rats. Methods: The groups of animals were administered with PGV-0 at the doses 2.5, 5, 10, and 20 mg/kg b.w., p.o. once in a day for 6 days and at day 7 the animals were administrated with carbon tetrachloride (CCl4) (20%, 2 mL/kg b.w. in liquid paraffin (i.p.). The effect of PGV-0 on serum transaminase (SGPT), alkaline phosphates (ALP) and total bilirubin were determined in CCl4-induced hepatotoxicity in rats. Further, the effects of PGV-0 on glutathione (GSH) content, catalase (CAT) and NO free radical scavenging activity also were investigated. Results: The results demonstrated that PGV-0 significantly reduced the activity of SGPT, serum ALP and total bilirubin in CCl4 induced rat hepatotoxicity. PGV-0 has effect on the antioxidant and free radical defense system. It prevented the depletion level of GSH and decrease activity of CAT in CCl4-induced liver injury in rats. PGV-0 also demonstrated the free radical scavenger effects on NO free radical scavenging activity with ES value of 32.32 μM. Conculsion: All of our findings suggests that PGV-0 could protect the liver cells from CCl4-induced liver damages and the mechanism may through the antioxidative effect of PGV-0 to prevent the accumulation of free radicals and protect the liver damage.

  2. Hepatoprotective effect of commercial herbal extracts on carbon tetrachloride-induced liver damage in Wistar rats

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    Paula Cordero-Pérez

    2013-01-01

    Full Text Available Background : Various hepatoprotective herbal products from plants are available in Mexico, where up to 85% of patients with liver disease use some form of complementary and alternative medicine. However, only few studies have reported on the biological evaluation of these products. Objective : Using a model of carbon tetrachloride (CCl4 -induced hepatotoxicity in rats, we evaluated the effects of commercial herbal extracts used most commonly in the metropolitan area of Monterrey, Mexico. Materials and Methods : The commercial products were identified through surveys in public areas. The effect of these products given with or without CCl4 in rats was evaluated by measuring the serum concentrations of aspartate amino transferase (AST and alanine amino transferase (ALT, and histopathological analysis. Legalon® was used as the standard drug. Results : The most commonly used herbal products were Hepatisan® capsules, Boldo capsules, Hepavida® capsules, Boldo infusion, and milk thistle herbal supplement (80% silymarin. None of the products tested was hepatotoxic according to transaminase and histological analyses. AST and ALT activities were significantly lower in the Hepavida+CCl4 -treated group as compared with the CCl4 -only group. AST and ALT activities in the silymarin, Hepatisan, and Boldo tea groups were similar to those in the CCl4 group. The CCl4 group displayed submassive confluent necrosis and mixed inflammatory infiltration. Both the Hepatisan+CCl4 and Boldo tea+CCl4 groups exhibited ballooning degeneration, inflammatory infiltration, and lytic necrosis. The silymarin+CCl4 group exhibited microvesicular steatosis. The Hepavida+CCl4 - and Legalon+CCL4 -treated groups had lower percentages of necrotic cells as compared with the CCl4 -treated group; this treatment was hepatoprotective against necrosis. Conclusion : Only Hepavida had a hepatoprotective effect.

  3. The protective role of pomegranate juice against carbon tetrachloride-induced oxidative stress in rats.

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    Pirinççioğlu, Mihdiye; Kızıl, Göksel; Kızıl, Murat; Kanay, Zeki; Ketani, Aydın

    2014-11-01

    Most pomegranate (Punica granatum Linn., Punicaceae) fruit parts are known to possess enormous antioxidant activity. The present study was carried out to determine the phenolic and flavonoid contents of Derik pomegranate juice and determine its effect against carbon tetrachloride (CCl4)-induced toxicity in rats. Animals were divided into four groups (n = 6): group I: control, group II: CCl4 (1 ml/kg), group III: CCl4 + pomegranate juice and group IV: CCl4 + ursodeoxycholic acid (UDCA). Treatment duration was 4 weeks, and the dose of CCl4 was administered once a week to groups II, III and IV during the experimental period. CCl4-treated rats caused a significant increase in serum enzyme levels, such as aspartate aminotransferase, alanine aminotransferase and total bilirubin, and decrease in albumin, when compared with control. Administration of CCl4 along with pomegranate juice or UDCA significantly reduces these changes. Analysis of lipid peroxide (LPO) levels by thiobarbutiric acid reaction showed a significant increase in liver, kidney and brain tissues of CCl4-treated rats. However, both pomegranate juice and UDCA prevented the increase in LPO level. Histopathological reports also revealed that there is a regenerative activity in the liver and kidney cells. Derik pomegranate juice showed to be hepatoprotective against CCl4-induced hepatic injury. In conclusion, present study reveals a biological evidence that supports the use of pomegranate juice in the treatment of chemical-induced hepatotoxicity.

  4. Hepatoprotective effects of fermented Curcuma longa L. on carbon tetrachloride-induced oxidative stress in rats.

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    Kim, Yongjae; You, Yanghee; Yoon, Ho-Geun; Lee, Yoo-Hyun; Kim, Kyungmi; Lee, Jeongmin; Kim, Min Soo; Kim, Jong-Choon; Jun, Woojin

    2014-05-15

    The hepatoprotective effect of fermented Curcuma longa L. (FC) was investigated in rats under CCl4-induced oxidative stress. FC at a dose of 30 or 300 mg/kg body weight (b.w.) was orally administered for 14 days followed by a single dose of CCl4 (1.25 mL/kg b.w. in 20% corn oil) on day 14. Pretreatment with FC drastically prevented the elevated activities of serum AST, ALT, LDH, and ALP caused by CCl4-induced hepatotoxicity. Histopathologically evident hepatic necrosis was significantly ameliorated by FC pretreatment. When compared to the CCl4-alone treated group, rats pretreated with FC displayed the reduced level of malondialdehyde. Furthermore, FC enhanced antioxidant capacities with higher activities of catalase, glutathione-S-transferase, glutathione reductase, and glutathione peroxidase, and level of reduced glutathione. These results suggest that FC could be a candidate used for the prevention against various liver diseases induced by oxidative stress via elevating antioxidative potentials and decreasing lipid peroxidation.

  5. Hepatoprotective Activity of Cassia fistula root against Carbon tetrachloride-Induced Hepatic Injury in rats (Wistar

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    SAGAR DAWADA

    2012-04-01

    Full Text Available The protective effects of the alcoholic extract of Cassia fistula root; against CCl4 induced hepatic failure in male albino rats (wistar strain was investigated. For acute and massive invasion of hepatopathy, CCl4 (s.c injection of CCl4+Olive Oil in 1:1 ratio; 2ml/kg was used and the insidious intoxication was evidenced bysignificant turmoil of various biochemical parameters followed by significant (p<0.001 weight loss in toxic control group. The administration of alcoholic root extract (200mg/kg and 100mg/kg of body weight for 7 days, elicited protective action since the elevated levels of marker enzymes (SGOT, SGPT, ALP of liver functionswere found to be decreasing progressively in a dose dependent manner. The final body weight was also significantly (p<0.001 increased when compared with the toxic control group. The serum total protein and theserum albumin were also approaching normal values. The results found in alcoholic extract 200mg/kg treated rat were quite promising and were comparable with a standard drug Silymarin. In the alcoholic extract 200mg/kg treated rat group all the marker enzymes were analyzed to be decreasing significantly. The statistically processed results support the conclusion, that the alcoholic root extract of Cassia fistula root (200mg/kg and 100mg/kg possesses dose dependent, significant protective activity against CCl4 induced hepatotoxicity.

  6. Synthesis of platelet-activating factor and its receptor expression in Kupffer cells in rat carbon tetrachloride-induced cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Yin-Ying Lu; Chun-Ping Wang; Lin Zhou; Yan Chen; Shu-Hui Su; Yong-Yi Feng; Yong-Ping Yang

    2008-01-01

    AIM:To determine the platelet-activating factor (PAF)synthesis and its receptor expression in Kupffer cells in rat carbon tetrachloride-induce dcirrhosis.METHODS:Kupffer cells,isolated from the livers of control and CCl4-induced cirrhotic rats,were placed in serum-free medium overnight.PAF saturation binding,ET-1 saturation and competition binding were assayed.ET-1 induced PAF synthesis,mRNA expression of PAF,preproendothelin-1,endothelin A (ETA) and endothelin B (ETB) receptors were also determined.RESULTS:A two-fold increase of PAF synthesis (1.42±0.14 vs 0.66±0.04 pg/μg DNA) and a 1.48-fold increase of membrane-bound PAF (1.02±0.06 vs 0.69±0.07 Pg/μg DNA) were observed in activated Kupffer cells of cirrhotic rats.The application of ET-1 to Kupffer cells induced PAF synthesis in a concentration-dependent manner in both cirrhotic and normal rats via ETB receptor,but PAF synthesis in the activated Kupffer cells was more effective than that in the normal Kupffer cells.In activated Kupffer cells,PAF receptor expression and PAF binding capacity were markedly enhanced.Activated Kupffer cells raised the [125I]-ET-1 binding capacity,but changed neither the affinity of the receptors,nor the expression of ETA receptor.CONCLUSION:Kupffer cells in the course of CCl4-induced cirrhosis are the main source of increased PAF.ET-1 is involved endogenously in stimulating the PAF synthesis in activated Kupffer cells via ETB receptor by paracrine.ETA receptor did not appear in activated Kupffer cells,which may exacerbate the hepatic and extrahepatic complications of cirrhosis.

  7. Buckwheat Honey Attenuates Carbon Tetrachloride-Induced Liver and DNA Damage in Mice

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    Cheng, Ni; Wu, Liming; Zheng, Jianbin; Cao, Wei

    2015-01-01

    Buckwheat honey, which is widely consumed in China, has a characteristic dark color. The objective of this study was to investigate the protective effects of buckwheat honey on liver and DNA damage induced by carbon tetrachloride in mice. The results revealed that buckwheat honey had high total phenolic content, and rutin, hesperetin, and p-coumaric acid were the main phenolic compounds present. Buckwheat honey possesses super DPPH radical scavenging activity and strong ferric reducing antioxidant power. Administration of buckwheat honey for 10 weeks significantly inhibited serum lipoprotein oxidation and increased serum oxygen radical absorbance capacity. Moreover, buckwheat honey significantly inhibited aspartate aminotransferase and alanine aminotransferase activities, which are enhanced by carbon tetrachloride. Hepatic malondialdehyde decreased and hepatic antioxidant enzymes (superoxide dismutase and glutathione peroxidase) increased in the presence of buckwheat honey. In a comet assay, lymphocyte DNA damage induced by carbon tetrachloride was significantly inhibited by buckwheat honey. Therefore, buckwheat honey has a hepatoprotective effect and inhibits DNA damage, activities that are primarily attributable to its high antioxidant capacity. PMID:26508989

  8. Buckwheat Honey Attenuates Carbon Tetrachloride-Induced Liver and DNA Damage in Mice

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    Ni Cheng

    2015-01-01

    Full Text Available Buckwheat honey, which is widely consumed in China, has a characteristic dark color. The objective of this study was to investigate the protective effects of buckwheat honey on liver and DNA damage induced by carbon tetrachloride in mice. The results revealed that buckwheat honey had high total phenolic content, and rutin, hesperetin, and p-coumaric acid were the main phenolic compounds present. Buckwheat honey possesses super DPPH radical scavenging activity and strong ferric reducing antioxidant power. Administration of buckwheat honey for 10 weeks significantly inhibited serum lipoprotein oxidation and increased serum oxygen radical absorbance capacity. Moreover, buckwheat honey significantly inhibited aspartate aminotransferase and alanine aminotransferase activities, which are enhanced by carbon tetrachloride. Hepatic malondialdehyde decreased and hepatic antioxidant enzymes (superoxide dismutase and glutathione peroxidase increased in the presence of buckwheat honey. In a comet assay, lymphocyte DNA damage induced by carbon tetrachloride was significantly inhibited by buckwheat honey. Therefore, buckwheat honey has a hepatoprotective effect and inhibits DNA damage, activities that are primarily attributable to its high antioxidant capacity.

  9. Carbon tetrachloride-induced hepatic and renal damages in rat: inhibitory effects of cacao polyphenol.

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    Suzuki, Koichiro; Nakagawa, Kiyotaka; Yamamoto, Takayuki; Miyazawa, Taiki; Kimura, Fumiko; Kamei, Masanori; Miyazawa, Teruo

    2015-01-01

    Here, we investigated the protective effect of cacao polyphenol extract (CPE) on carbon tetrachloride (CCl4)-induced hepato-renal oxidative stress in rats. Rats were administered CPE for 7 days and then received intraperitoneal injection of CCl4. Two hours after injection, we found that CCl4 treatment significantly increased biochemical injury markers, lipid peroxides (phosphatidylcholine hydroperoxide (PCOOH) and malondialdehyde (MDA)) and decreased glutathione peroxidase activity in kidney rather than liver, suggesting that kidney is more vulnerable to oxidative stress under the present experimental conditions. CPE supplementation significantly reduced these changes, indicating that this compound has antioxidant properties against CCl4-induced oxidative stress. An inhibitory effect of CPE on CCl4-induced CYP2E1 mRNA degradation may provide an explanation for CPE antioxidant property. Together, these results provide quantitative evidence of the in vivo antioxidant properties of CPE, especially in terms of PCOOH and MDA levels in the kidneys of CCl4-treated rats.

  10. Curcuma longa attenuates carbon tetrachloride-induced oxidative stress in T-lymphocyte subpopulations.

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    Abu-Rizq, H A; Mansour, Mohamed H; Afzal, Mohammad

    2015-01-01

    A comparison of crude curcuminoid extract and purified curcumin was made to evaluate the immunoprotective effect of Curcuma longa (turmeric) Zingiberaceae. Carbon tetrachloride (CCl4) induced selective cytolytic effects among immature (PNA(+)) thymocytes and peripheral helper (CD4(+)) T lymphocytes in the spleen were paralleled by a significant reduction in CD25, CD71, and Con A receptor expression. Treatment with curcumanoid crude extract, at two different doses, showed a significant restoration of lymphocyte viability and CD25, CD71, and Con A receptor expression in both immature (PNA+) thymocytes and splenic helper (CD4(+)) T lymphocytes. Turmeric crude extract, at both low and high dose, was found to be more efficient as compared to purified curcumin, suggesting synergistic effect of curcumin with other components of the crude extract.

  11. Hepatoprotective mechanism of lycorine against carbon tetrachloride induced toxicity in swiss albino mice - A proteomic approach

    Institute of Scientific and Technical Information of China (English)

    Soundarrajan Ilavenil; Dhanaraj Karthik; Mariadhas Valan Arasu; Mayakrishnan Vijayakumar; Srisesharam Srigopalram; Selvaraj Arokiyaraj; Sivanesan Ravikumar; Ki Choon Choi

    2015-01-01

    Objective: To investigate the differential of protein expression in CCl4 induced mice treated with lycorine. Methods: The present study was carried out to identify the differentially expressed protein in carbon tetrachloride (CCl4) induced oxidative stress mice treated with lycorine (5 mg/kg. bw) using 2D gel and MALDI-TOF. Results: We observed many kinds of differentially expressed protein in experimental liver. Among these, three are much differently expressed protein which is identified as ATP synthase, regucalcin and HSP60; these proteins are involved in the ATP synthesis, calcium regulation and rescue the integrity cellular proteins respectively. Conclusion: This investigation provided a molecular mechanism of the lycorine during CCl4 induced oxidative stress in mice liver.

  12. HEPATOPROTECTIVE ACTIVITY OF METHANOLIC EXTRACT OF ECBOLIUM VIRIDE (FORSSK. ALSTON ROOTS AGAINST CARBON TETRACHLORIDE INDUCED HEPATOTOXICITY

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    Ashoka Babu V.L

    2012-08-01

    Full Text Available In the present study, the methanolic extract of Ecbolium viride root was evaluated for its hepatoprotective effect against CCl4 induced hepatic injury in rats. Alteration in the levels of biochemical markers of hepatic damage like SGOT, SGPT, ALP, triglycerides, bilirubin, total proteins and liver weight were tested in both treated and untreated groups. CCl4 (1ml/kg enhanced the SGPT, SGOT, ALP, triglycerides, liver weight and reduced total proteins significantly. Treatment with methanolic extract of Ecbolium viride roots (200mg/kg and 400mg/kg has brought back the altered levels of altered levels of biochemical markers significantly to the near normal levels in the dose dependant manner.

  13. Hepatoprotective activity of Leptadenia reticulata stems against carbon tetrachloride-induced hepatotoxicity in rats

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    Amit Kumar Nema

    2011-01-01

    Conclusion: The ethanolic and aqueous extracts of stems of L. reticulata showed significant hepatoprotective activity. The ethanolic extract is more potent in hepatoprotection in CCl 4 -indiced liver injury model as compared with aqueous extract.

  14. Protective effects of Coriandrum sativum extracts on carbon tetrachloride-induced hepatotoxicity in rats.

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    Sreelatha, S; Padma, P R; Umadevi, M

    2009-04-01

    Oxidative damage is implicated in the pathogenesis of various liver injuries. The study was aimed to investigate the antioxidant activity of Coriandrum sativum on CCl(4) treated oxidative stress in Wistar albino rats. CCl(4) injection induced oxidative stress by a significant rise in serum marker enzymes and thiobarbituric acid reactive substances (TBARS) along with the reduction of antioxidant enzymes. In serum, the activities of enzymes like ALP, ACP and protein and bilirubin were evaluated. Pretreatment of rats with different doses of plant extract (100 and 200mg/kg) significantly lowered SGOT, SGPT and TBARS levels against CCl(4) treated rats. Hepatic enzymes like SOD, CAT, GPx were significantly increased by treatment with plant extract, against CCl(4) treated rats. Histopathological examinations showed extensive liver injuries, characterized by extensive hepatocellular degeneration/necrosis, inflammatory cell infiltration, congestion, and sinusoidal dilatation. Oral administration of the leaf extract at a dose of 200mg/kg body weight significantly reduced the toxic effects of CCl(4). The activity of leaf extract at the dose of 200mg/kg was comparable to the standard drug, silymarin. Based on these results, it was observed that C. sativum extract protects liver from oxidative stress induced by CCl(4) and thus helps in evaluation of traditional claim on this plant.

  15. Protective effects of Cornus mas fruit extract on carbon tetrachloride induced nephrotoxicity in rats.

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    Es Haghi, M; Dehghan, G; Banihabib, N; Zare, S; Mikaili, P; Panahi, F

    2014-09-01

    Oxidative damage is implicated in the pathogenesis of kidney injury. Cornus mas is used for in renal aliments traditionally in Iran. The present study was aimed to investigate the antioxidant activity of C. mas fruit extract (CMFE) on carbon tetrachloride (CCl4) treated oxidative stress in Wistar albino rats. Forty two male albino rats were divided into seven groups. Group I served as a sham; Group II served as a normal control; Group III served as a toxic control, with CCl4 (1 ml/kg body weight; 80% in olive oil); Groups IV and V received CMFE at doses of 300 and 700 mg/kg before CCl4 injection; Groups VI and VII received extract at same doses orally at 2, 6, 12, 24 and 48 h after CCl4 intoxication. CCl4 injection produced a significant rise in serum markers of oxidative stress and lipid peroxidation product malondialdehyde along with the reduction of antioxidant enzymes such as superoxide dismuta, catalase and glutathion peroxidase. Serum creatinine, urea and uric acid concentrations were increased whereas level of protein and albumin were reduced. Treatment of rats with different doses of fruit extract (300 and 700 mg/kg) significantly (P induced with CCl4 in lipid peroxidation, antioxidant defenses, biochemical and renal lesions. Based on these results, we conclude that CMFE protects kidney from oxidative stress induced by CCl4.

  16. Evaluation of hepatoprotective effect of Amalkadi Ghrita against carbon tetrachloride-induced hepatic damage in rats.

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    Achliya, Girish S; Wadodkar, Sudhir G; Dorle, Avinash K

    2004-02-01

    Amalkadi Ghrita (AG), a polyherbal formulation, was evaluated for its hepatoprotective activity against carbon tetrachloride (CCl4)-induced hepatic damage in rats. The hepatoprotective activity of AG was evaluated by measuring levels of serum marker enzymes like serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), and acid phosphatase (ACP). The serum levels of total proteins and bilirubin were also estimated. The histological studies were also carried out to support the above parameters. Silymarin was used as standard drug. Administration of AG (100 and 300 mg/kg, p.o.) markedly prevented CCl4-induced elevation of levels of serum GPT, GOT, ACP, ALP, and bilirubin. The decreased level of total proteins due to hepatic damage induced by CCl4 was found to be increased in AG-treated group. The results are comparable to that of silymarin. A comparative histopathological study of liver exhibited almost normal architecture, as compared to CCl4-treated group. Hepatoprotective effect of AG is probably due to combined action of all ingredients.

  17. Hepatoprotective effect of pinoresinol on carbon tetrachloride-induced hepatic damage in mice.

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    Kim, Hyo-Yeon; Kim, Joon-Ki; Choi, Jun-Ho; Jung, Joo-Yeon; Oh, Woo-Yong; Kim, Dong Chun; Lee, Hee Sang; Kim, Yeong Shik; Kang, Sam Sik; Lee, Seung-Ho; Lee, Sun-Mee

    2010-01-01

    Forsythiae Fructus is known to have diuretic, anti-bacterial, and anti-inflammatory activities. This study examined the hepatoprotective effects of pinoresinol, a lignan isolated from Forsythiae Fructus, against carbon tetrachloride (CCl(4))-induced liver injury. Mice were treated intraperitoneally with vehicle or pinoresinol (25, 50, 100, and 200 mg/kg) 30 min before and 2 h after CCl4 (20 microl/kg) injection. In the vehicle-treated CCl(4 )group, serum aminotransferase activities were significantly increased 24 h after CCl4 injection, and these increases were attenuated by pinoresinol at all doses. Hepatic glutathione contents were significantly decreased and lipid peroxidation was increased after CCl4 treatment. These changes were attenuated by 50 and 100 mg/kg of pinoresinol. The levels of protein and mRNA expression of inflammatory mediators, including tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2, were significantly increased after CCl4 injection; and these increases were attenuated by pinoresinol. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of c-Jun, one of the components of activating protein 1 (AP-1), were inhibited by pinoresinol. Our results suggest that pinoresinol ameliorates CCl4)-induced acute liver injury, and this protection is likely due to anti-oxidative activity and down-regulation of inflammatory mediators through inhibition of NF-kappaB and AP-1.

  18. Xanthohumol prevents carbon tetrachloride-induced acute liver injury in rats.

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    Pinto, Carmen; Duque, Antonio L; Rodríguez-Galdón, Beatriz; Cestero, Juan J; Macías, Pedro

    2012-10-01

    Xanthohumol (XN), a prenyl flavonoid present in beer, prevents the acute hepatic injury induced by carbon tetrachloride (CCl4) in rats. Pre-treatment of rats with XN significantly reduced the increased liver weight observed in CCl4-intoxicated rats, normalised the increased values of plasma lactate dehydrogenase, glutamate oxaloacetate transaminase and glutamate pyruvate transaminase activities and reduced the incidence of histopathological alterations produced by CCl4. The oxidative stress induced by CCl4 administration elicited a significant decrease in the levels of reduced glutathione as well as an increase in thiobarbituric acid reactive substances (TBARS) and H2O2 concentrations. Pre-treatment of rats with XN resulted in a significant (p<0.05) increase in reduced glutathione (GSH) content and a reduction in TBARS and H2O2 concentrations to their normal values. XN pre-treatment also prevented the significant reductions of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase activities observed in CCl4-treated rats compared to control animals. Our results suggest that the hepatoprotective effect of XN is based on its antioxidant properties as well as it being an efficient inhibitor of lipid peroxidation and a protector against the degradation of antioxidant enzymes induced by CCl4 intoxication.

  19. Protective effects of polydatin from Polygonum cuspidatum against carbon tetrachloride-induced liver injury in mice.

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    Hong Zhang

    Full Text Available Polydatin is one of main compounds in Polygonum cuspidatum, a plant with both medicinal and nutritional value. The possible hepatoprotective effects of polydatin on acute liver injury mice induced by carbon tetrachloride (CCl(4 and the mechanisms involved were investigated. Intraperitoneal injection of CCl(4 (50 µl/kg resulted in a significant increase in the levels of serum aspartate aminotransferase (AST, alanine aminotransferase (ALT and hepatic malondialdehyde (MDA, also a marked enhancement in the expression of hepatic tumor necrosis factor-alpha (TNF-α, interleukin-1 beta (IL-1β, cyclooxygenase-2 (COX-2, inducible nitric oxide synthase (iNOS and nuclearfactor-kappa B (NF-κB. On the other hand, decreased glutathione (GSH content and activities of glutathione transferase (GST, superoxide dismutase (SOD, catalase (CAT and glutathione peroxidase (GPx were observed following CCl(4 exposure. Nevertheless, all of these phenotypes were evidently reversed by preadministration of polydatin for 5 continuous days. The mRNA and protein expression levels of hepatic growth factor-beta1 (TGF-β(1 were enhanced further by polydatin. These results suggest that polydatin protects mice against CCl(4-induced liver injury through antioxidant stress and antiinflammatory effects. Polydatin may be an effective hepatoprotective agent and a promising candidate for the treatment of oxidative stress- and inflammation-related diseases.

  20. Radon inhalation protects mice from carbon-tetrachloride-induced hepatic and renal damage.

    Science.gov (United States)

    Kataoka, Takahiro; Nishiyama, Yuichi; Toyota, Teruaki; Yoshimoto, Masaaki; Sakoda, Akihiro; Ishimori, Yuu; Aoyama, Yutaka; Taguchi, Takehito; Yamaoka, Kiyonori

    2011-12-01

    We assessed whether radon inhalation provided protection from carbon tetrachloride (CCl4)-induced hepatic and renal damage in mice. Mice were subjected to intraperitoneal injection of CCl4 after inhaling approximately 18 kBq/m3 radon for 6 h. Radon inhalation significantly increased total glutathione (t-GSH) content and glutathione peroxidase (GPx) activity in the liver and kidney. Injection of CCl4 was associated with significantly higher levels of glutamic oxaloacetic transaminase (GOT) and alkaline phosphatase (ALP) activity and creatinine level in serum, and pretreatment with radon significantly decreased the GOT and ALP activity and creatinine level associated with CCl4 injection, suggesting that radon inhalation alleviates CCl4-induced hepatic and renal damage. The t-GSH contents and GPx activity in the liver and kidney of animals pretreated with radon were significantly higher than those of the CCl(4)-only group. These findings suggested that radon inhalation activated antioxidative functions and inhibited CCl4-induced hepatic and renal damage in mice.

  1. Total Flavonoids from Mimosa Pudica Protects Carbon Tetrachloride-Induced Acute Liver Injur y in Mice

    Institute of Scientific and Technical Information of China (English)

    QIU Zhen-qin; CAI Lei; CHEN Da-shuai

    2015-01-01

    Objective:To observe the protective effect of total lfavonoids from Mimosa pudica on carbon tetrachloride (CCl4)-induced acute liver injury in mice. Methods:CCl4-induced acute liver injury model in mice was established. The activity of ALT and AST, the content of serum albumin (Alb) and total antioxidant capacity (T-AOC) were determined. The content of malondiadehyde (MDA) was measured and the activity of superoxide dismutase (SOD) was determined. The histopathological changes of liver were observed. Results:Compared with CCl4 model group, each dose group of total lfavonouida from Mimosa pudica could reduced the activity of ALT and AST in mice obviously (P<0.01), indicating they had remarkably protective effect on CCl4-induced acute liver injury in mice. High and middle dose groups of total lfavonouida from Mimosa pudica could increase the content of Alb in mice (P<0.01). Each dose group of total lfavonouida from Mimosa pudica could enhance the level of T-AOC (P<0.01), and lower the content of liver homogenate MDA, but enhance the activity of SOD in a dose-depended manner (P<0.01).

  2. Protection effect of kallistatin on carbon tetrachloride-induced liver fibrosis in rats via antioxidative stress.

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    Xiaoping Huang

    Full Text Available Prolonged inflammation and oxidative stress are emerging as key causes of pathological wound healing and the development of liver fibrosis. We have investigated the effects of recombinant human kallistatin, produced in Pichia. pastoris, on preventing carbon tetrachloride (CCl4-induced liver fibrosis in rats. Daily administration of kallistatin prevented development of CCl4-induced liver fibrosis, which was evidenced by histological study. In all kallistatin treated rats, activation of hepatic stellate cells (HSC as assessed by s-smooth muscle actin staining was attenuated, TGF- β1 expression was inhibited, class I serum biomarkers associated with the process of fibrogenesis, such as hyaluronic acid, laminin, and procollagen III, were lowered, compared with that in the model control group. Furthermore, residual hepatic functional reserve was improved by kallistatin treatment. CCl4 induced elevation of malondialdehyde level and reduced superoxide dismutase activity in the liver, while kallistatin reduced these oxidative parameters. We also investigated the effects of kallistatin on rat primary HSC and LX-2, the human HSC cell line. Kallistatin scavenged H2O2-induced ROS in the LX-2 cells, and suppressed the activation of primary HSC. These results suggest recombinant human kallistatin might be a promising drug candidate for therapeutic intervention of liver fibrosis.

  3. Erythropoietin decreases carbon tetrachloride-induced hepatic fibrosis by inhibiting transforming growth factor-beta

    Institute of Scientific and Technical Information of China (English)

    Soo Young Park; Joo Young Lee; Won Young Tak; Young Oh Kweon; Mi Suk Lee

    2012-01-01

    Background In addition to hematopoietic effect,the erythropoietin is known as a multifunctional cytokine with anti-fibrosis and organ-protective activities.The purpose of this study was to evaluate the effect of recombinant human erythropoietin (rhEPO) on hepatic fibrosis and hepatic stellate cells (HSCs).Methods Carbon tetrachloride (CCl4) induced hepatic fibrosis mice models were used for in vivo study and HSCs line for in vitro study.CCl4 and rhEPO (0,200 or 1000 U/kg) was injected intraperitoneally in BALB/c mice three times a week for 4 weeks.Immunohistochemistry and immunoblotting were performed to evaluate expressions of transforming growth factor-β31 (TGF-β1),α-smooth muscle actin (α-SMA),and fibronectin in explanted liver.Immunoblotting of α-SMA,phophorylated Smad-2 and Smad-2/3 was performed in HSCs treated with TGF-β1 and/or rhEPO.Results Expressions of TGF-β1,α-SMA,and fibronectin were increased in CCl4 injected mice livers,but significantly attenuated by co-treatment with CCl4 and rhEPO.Co-treatment of rhEPO markedly suppressed fibrosis in Masson's trichrome compared with treatment of only CCl4.TGF-β1 increased phosphorylated α-SMA,Smad-2 expressions in HSCs,which were decreased by rhEPO co-treatment.Conclusions Treatment of rhEPO effectively suppressed fibrosis in CCl4-induced liver fibrosis mice models.Anti-fibrosis effect of rhEPO could be related to inhibition of TGF-β1 induced activation of HSCs.

  4. Contribution of mononuclear bone marrow cells to carbon tetrachloride-induced liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Bao-Qiang Cao; Ji-Zong Lin; Yue-Si Zhong; Shao-Bin Huang; Nan Lin; Zhao-Feng Tang; Rui Chen; Peng Xiang; Rui-Yun Xu

    2007-01-01

    AIM:To study the inhibitory effect of mononuclear bone marrow cell (BMC) transplantation on carbon tetrachloride (CCIt) -induced liver fibrosis in rats.METHODS:Rat liver fibrosis models were induced by CCN and alcohol administration. After 8 wk,twenty rats were randomly allocated into treatment group (n = 10) and control group (n = 10). BMC were infused into the rats in treatment group via the portal vein,while heparinized saline was infused in control group. CCU was hypodermically injected into the rats twice a week for 4 wk. At the end of wk 12,all rats were humanely sacrificed. Liver samples were taken and stained with HE or Masson trichrome. The general conditions,liver fibrSsis (hydroxyproline and collagen fibre) and liver pathological grades in rats were evaluated.± 128.8μg/g in treatment group,and 596.0 ± 341. 8μg/g in control group.The percentage of collagen fibre was 3.75% ± 0.98% in treatment group and 5.02% ± 0.44% in control group.There was a significant difference berween the two groups (P<0.05).Liver pathological grade decreased from grade Ⅳ to grade Ⅲ partially in treatment group (P<0.05) with no obvious improvement in control group (P<0.05).There was a significant difference between treatment group and control group(P<0.05).CONCLUSION: Transplantation of BMC can improve liver fibrosis due to chronic liver injury in rats.

  5. Effect of Ribavirin Alone or Combined with Silymarin on Carbon Tetrachloride Induced Hepatic Damage in Rats

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    Omar M.E. Abdel Salam

    2007-01-01

    Full Text Available The effect of the antiviral agent ribavirin given alone or in combination with silymarin on the development of liver injury induced in rats with carbon tetrachloride (CCl4; 2.8 ml/kg followed by 1.4 ml/kg after one week was studied. Ribavirin at three dose levels (30, 60 or 90 mg/kg, silymarin (25 mg/kg or combination of ribavirin (60 mg/kg and silymarin (25 mg/kg was administered once daily orally for 14 days, starting at time of administration of CCl4. The administration of ribavirin decreased the elevations in serum alanine aminotransferase (ALT by 78.5, 82.1, 75.1%, aspartate aminotransferase (AST 47.5, 37.4, 38.8%, and alkaline phosphatase (ALP by 23.4, 16, 21.6%, respectively and also prevented the development of hepatic necrosis caused by CCl4. In comparison, the elevated serum ALT, AST and ALP levels decreased to 43.3%, 46%, and 37.5% of controls, respectively by silymarin. When silymarin was combined with ribavirin, the serum activities of AST and ALP were further decreased, indicating a benefi cial additive effect. Morphometric analysis indicated signifi cant reduction in the area of necrosis and fi brosis on ribavirin treatment and this was further reduced after the addition of silymarin. Metabolic pertuberations caused by CCl4 as refl ected in a decrease in intracellular protein content in hepatocytes were improved by ribavirin monotherapy and to higher extent by combined silymarin and ribavirin therapy. Proliferating cell nuclear antigen was reduced in nuclei of hepatocytes by ribavirin montherapy or the combination of ribavirin and silymarin compared with CCl4-control group. The study demonstrates that ribavirin treatment in the model of CCl4- induced liver injury results in less liver damage. Results also indicate that the combined application of ribavirin and silymarin is likely to be a useful additive in reducing liver injury.

  6. The effects of grape seed and colchicine on carbon tetrachloride induced hepatic damage in rats.

    Science.gov (United States)

    Atasever, Ayhan; Yaman, Duygu

    2014-10-01

    This study aims to determine the effects of grape seed and colchicine on carbon tetrachloride (CCl4) induced hepatic damage and on some serum biochemical parameters. Sixty male Wistar albino rats (200-250 g) were randomly divided into six groups (ten rats/group) and included the control group the group were given isotonic sodium chloride (1 mL/kg b.w) intraperitonealy (i.p.), group 2 the group treated i.p. injection of CCl4 (1.0 mL/kg b.w) in corn oil twice in the first week, Groups 3 and 4 injected with CCl4 as described for group 2 and the rats were orally given (100 mg/kg b.w) GSE and i.p. injected (10 μg/rat) with colchicine for four weeks, respectively and groups 5 and 6 were the grape seed and colchicine control groups in which rats were orally given grape seed (100 mg/kg b.w) and i.p. injected with colchicine (10 μg/rat), respectively. Anorexia, weight loss, motionlessness and hepatic colour variation at necropsy were observed in groups 2, 3, and 4. Hyperemia, focal bleeding, fat degeneration, changes ranging from degenerative to necrotic, increase in connective tissue elements, pronounced in portal sites in particular, and infiltration of lymphoid series cell observed in the livers of the rats in group 2, treated with CCl4. Histological hepatic changes in the rats in group 3 and 4 were similar to those in group 2. The levels of serum total protein, albumin and globulin decreased in groups 2, 3, and 4, compared with groups 1, 5 and 6; aspartate transaminase (ALT) activities increased. The lowest alkaline phosphatase (ALP) activities were in groups 4 and 5. We concluded that GSE and colchicine have not sufficient ameliorative effects to CCl4 induced acute hepatic damage.

  7. Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis.

    Science.gov (United States)

    Kang, Jung-Woo; Hong, Jeong-Min; Lee, Sun-Mee

    2016-05-01

    Liver fibrosis leads to liver cirrhosis and failure, and no effective treatment is currently available. Growing evidence supports a link between mitochondrial dysfunction and liver fibrogenesis and mitochondrial quality control-based therapy has emerged as a new therapeutic target. We investigated the protective mechanisms of melatonin against mitochondrial dysfunction-involved liver fibrosis, focusing on mitophagy and mitochondrial biogenesis. Rats were treated with carbon tetrachloride (CCl4) dissolved in olive oil (0.5 mL/kg, twice a week, i.p.) for 8 wk. Melatonin was administered orally at 2.5, 5, and 10 mg/kg once a day. Chronic CCl4 exposure induced collagen deposition, hepatocellular damage, and oxidative stress, and melatonin attenuated these increases. Increases in mRNA and protein expression levels of transforming growth factor β1 and α-smooth muscle actin in response to CCl4 were attenuated by melatonin. Melatonin attenuated hallmarks of mitochondrial dysfunction, such as mitochondrial swelling and glutamate dehydrogenase release. Chronic CCl4 exposure impaired mitophagy and mitochondrial biogenesis, and melatonin attenuated this impairment, as indicated by increases in mitochondrial DNA and in protein levels of PTEN-induced putative kinase 1 (PINK1); Parkin; peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α); nuclear respiratory factor 1 (NRF1); and transcription factor A, mitochondrial (TFAM). CCl4-mediated decreases in mitochondrial fission- and fusion-related proteins, such as dynamin-related protein 1 (DRP1) and mitofusin 2, were also attenuated by melatonin. Moreover, melatonin induced AMP-activated protein kinase (AMPK) phosphorylation. These results suggest that melatonin protects against liver fibrosis via upregulation of mitophagy and mitochondrial biogenesis, and may be useful as an anti-fibrotic treatment.

  8. Hepatoprotective effects of Bupleurum exalatum extracts against carbon tetrachloride induced liver injury in rats

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    s Roozbehi

    2015-03-01

    Full Text Available Background & aim: Some of natural and synthetic products have antioxidant properties which protect the liver against the destructive factors. This study aimed to investigate the effect of Bupleurum exelatum (B. exalatum extracts on rat liver. Material and method: This experimental study was conducted at Yasouj University of Medical Sciences in 2013 on 50 healthy adult male Wistar rats. Animals were randomly divided into five equal groups: the normal group (receiving, olive oil, control and experiment groups receiving different dose of carbon tetrachloride and olive oil. The experiment group was given daily doses of 75, 150 and 300 mg per Kg of B. exalatum extract by gavage respectively. After two months, the liver enzymes, total protein, albumin and bilirubin in animal’s sera were measured. Data were analyzed by the SPSS software, using ANOVA and tuky-test. Result: The toxicant significantly (P < 0.05 increased the levels of ALT, AST, ALP, TB, DB, and decrease the level of TP and ALB. Oral administration of B. exalatum extracts showed a significant (P < 0.05 decrease in all the elevated serum and significant increase (P < 0.05 in TP and ALB levels at all usage doses. These results indicate the maximum recovery was observed in 300 mg/kg/day. The histopathological changes i.e. fatty changes, necrosis etc were partly or fully prevented in animals treated with the extracts. Conclusion: These findings suggest that the extract of B. exalatum possessed hepatoprotective activity, which could be linked to their phytochemical constituents and antioxidant activity this therefore requires further in-depth studies.

  9. Hepatoprotective effect of Matrine salvianolic acid B salt on Carbon Tetrachloride-Induced Hepatic Fibrosis

    Science.gov (United States)

    2012-01-01

    The aim of this study was to investigate the hepatoprotective effect of Matrine salvianolic acid B salt on carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats. Salvianolic acid B and Matrine has long been used to treat liver fibrosis. Matrine salvianolic acid B salt is a new compound containing Salvianolic acid B and Matrine. Hepatic fibrosis induced by CCl4 was studied in animal models using Wistar rats. Organ coefficient, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), hydroxyproline (Hyp), and glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) in liver tissues were measured, respectively. Histopathological changes in the livers were studied by hematoxylin-eosin (H&E) staining and Masson Trichrome (MT) examination. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) was observed by immunohistochemical analysis. A significant reduction in serum levels of AST, ALT, HA, LN and Hyp was observed in the Matrine salvianolic acid B salt treated groups, suggesting that the salt had hepatoprotective effects. The depletion of GSH and SOD, as well as MDA accumulation in liver tissues was suppressed by Matrine salvianolic acid B salt too. The expression of TGF-β1 and α-SMA measured by immunohistology was significantly reduced by Matrine salvianolic acid B salt in a dose-dependent manner. Matrine salvianolic acid B salt treatment attenuated the necro-inflammation and fibrogenesis induced by CCl4 injection, and thus it is promising as a therapeutic anti-fibrotic agent against hepatic fibrosis. PMID:22559721

  10. Hepatoprotective effect of Matrine salvianolic acid B salt on Carbon Tetrachloride-Induced Hepatic Fibrosis

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    Gao Hong-Ying

    2012-05-01

    Full Text Available Abstract The aim of this study was to investigate the hepatoprotective effect of Matrine salvianolic acid B salt on carbon tetrachloride (CCl4-induced hepatic fibrosis in rats. Salvianolic acid B and Matrine has long been used to treat liver fibrosis. Matrine salvianolic acid B salt is a new compound containing Salvianolic acid B and Matrine. Hepatic fibrosis induced by CCl4 was studied in animal models using Wistar rats. Organ coefficient, serum aspartate aminotransferase (AST, alanine aminotransferase (ALT, hexadecenoic acid (HA, laminin (LN, hydroxyproline (Hyp, and glutathione (GSH, malondialdehyde (MDA, superoxide dismutase (SOD in liver tissues were measured, respectively. Histopathological changes in the livers were studied by hematoxylin-eosin (H&E staining and Masson Trichrome (MT examination. The expression of transforming growth factor-β1 (TGF-β1 and α-smooth muscle actin (α-SMA was observed by immunohistochemical analysis. A significant reduction in serum levels of AST, ALT, HA, LN and Hyp was observed in the Matrine salvianolic acid B salt treated groups, suggesting that the salt had hepatoprotective effects. The depletion of GSH and SOD, as well as MDA accumulation in liver tissues was suppressed by Matrine salvianolic acid B salt too. The expression of TGF-β1 and α-SMA measured by immunohistology was significantly reduced by Matrine salvianolic acid B salt in a dose-dependent manner. Matrine salvianolic acid B salt treatment attenuated the necro-inflammation and fibrogenesis induced by CCl4 injection, and thus it is promising as a therapeutic anti-fibrotic agent against hepatic fibrosis.

  11. Restrictive model of compensated carbon tetrachloride-induced cirrhosis in rats

    Institute of Scientific and Technical Information of China (English)

    Jean-Marc Regimbeau; David Fuks; Niaz Kohneh-Shahri; Benoit Terris; Olivier Soubrane

    2008-01-01

    AIM: To develop a simplified and quick protocol to induce cirrhosis and standardize models of partial liver resection in rats.METHODS: In Fischer F344 rats two modified protocols of phenobarbital-carbon tetrachloride (CCI4) (dilution 50%) gavage to induce cirrhosis (frequency adjusted according to weight, but each subsequent dose was systematically administered) were tested, i.e. the rapid and slow protocols. Prothrombin time (PT) and total bilirubin (TB) were also evaluated. Animals from the rapid group underwent 15% hepatectomy and animals from the slow group underwent 70% hepatectomy.RESULTS: Rapid protocol: This corresponded to 1 garage/4 d over 6 wk (mortality 30%). Mean PT was 35.2±2.8 s (normal: 14.5 s), and mean TB was 1.8±0.2mg/clL (normal: 0.1 mg/dL). Slow protocol: This corresponded to 1 gavage/6 d over 9 wk (mortality 10%).Mean PT was 11.8±0.2 s (normal: 14.5 s), and mean TB was 0.4 ± 0.04 mg/dL (normal: 0.1 mg/dL). Pathological analyses were performed in both protocols which showed persistent cirrhosis at 3 mo. Rat mortality in the rapid garage group who underwent 15% hepatectomy and in the slow garage group who underwent 70%hepatectomy was 50% and 70%, respectively.CONCLUSION: Our modified model is a simplified method to induce cirrhosis which is rapid (6 to 9 wk),efficient and stable up to 3 mo. Using this method, "Child Pugh A" or "Child Pugh BC" cirrhotic rats were obtained.Our models of cirrhosis and hepatectomy can be used in various situations focusing on postoperative survival.

  12. Ameliorative effect of Ganoderma lucidum on carbon tetrachloride-induced liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Wen-Chuan Lin; Wei-Lii Lin

    2006-01-01

    AIM: To investigate the effects of Reishi mushroom,Ganoderma lucidum extract (GLE), on liver fibrosis induced by carbon tetrachloride (CCl4) in rats.METHODS: Rat hepatic fibrosis was induced by CCl4.Forty Wistar rats were divided randomly into 4 groups:control, CCl4, and two GLE groups. Except for rats in control group, all rats were administered orally with CCl4(20%, 0.2 mL/100 g body weight) twice a week for 8weeks. Rats in GLE groups were treated daily with GLE (1 600 or 600 mg/kg) via gastrogavage throughout the whole experimental period. Liver function parameters,such as ALT, AST, albumin, and albumin/globulin (A/G)ratio, spleen weight and hepatic amounts of protein,malondiladehyde (MDA) and hydroxyproline (HP) were determined. Histochemical staining of Sirius red was performed. Expression of transforming growth factor β1(TGF-β1), methionine adenosyltransferase (MAT1) 1A and MAT2A mRNA were detected by using RT-PCR.RESULTS: CCl4 caused liver fibrosis, featuring increase in plasma transaminases, hepatic MDA and HP contents,and spleen weight; and decrease in plasma albumin,A/G ratio and hepatic protein level. Compared with CCl4group, GLE (600, 1 600 mg/kg) treatment significantly increased plasma albumin level and A/G ratio (P< 0.05)and reduced the hepatic HP content (P<0.01). GLE (1600 mg/kg) treatment markedly decreased the activities of transaminases (P< 0.05), spleen weight (P< 0.05) and hepatic MDA content (P<0.05); but increased hepatic protein level (P<0.05). Liver histology in the GLE (1600 mg/kg)-treated rats was also improved (P<0.01).RT-PCR analysis showed that GLE treatment decreased the expression of TGF-β1 (P< 0.05-0.001) and changed the expression of MAT1A (P<0.05-0.01) and MAT2A (P< 0.05-0.001).CONCLUSION: Oral administration of GLE significantly reduces CCl4-induced hepatic fibrosis in rats, probably by exerting a protective effect against hepatocellular necrosis by its free-radical scavenging ability.

  13. Phenylbutyric acid protects against carbon tetrachloride-induced hepatic fibrogenesis in mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jian-Qing [School of Pharmacy, Anhui Medical University, Hefei, 230032 (China); Second Affiliated Hospital, Anhui Medical University, Hefei 230601 (China); Chen, Xi [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Zhang, Cheng [Department of Toxicology, Anhui Medical University, Hefei, 230032 (China); Tao, Li [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Zhang, Zhi-Hui; Liu, Xiao-Qian [Department of Toxicology, Anhui Medical University, Hefei, 230032 (China); Xu, Yuan-Bao [Department of Toxicology, Anhui Medical University, Hefei, 230032 (China); First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Wang, Hua [Department of Toxicology, Anhui Medical University, Hefei, 230032 (China); Li, Jun, E-mail: lijun@ahmu.edu.cn [School of Pharmacy, Anhui Medical University, Hefei, 230032 (China); Xu, De-Xiang, E-mail: xudex@126.com [Department of Toxicology, Anhui Medical University, Hefei, 230032 (China)

    2013-01-15

    A recent report showed that the unfolded protein response (UPR) signaling was activated in the pathogenesis of carbon tetrachloride (CCl{sub 4})-induced hepatic fibrosis. Phenylbutyric acid (PBA) is a well-known chemical chaperone that inhibits endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling. In the present study, we investigated the effects of PBA on CCl{sub 4}-induced hepatic fibrosis in mice. All mice were intraperitoneally (i.p.) injected with CCl{sub 4} (0.15 ml/kg BW, twice per week) for 8 weeks. In CCl{sub 4} + PBA group, mice were i.p. injected with PBA (150 mg/kg, twice per day) from the beginning of CCl{sub 4} injection to the end. As expected, PBA significantly attenuated CCl{sub 4}-induced hepatic ER stress and UPR activation. Although PBA alleviated, only to a less extent, hepatic necrosis, it obviously inhibited CCl{sub 4}-induced tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β). Moreover, PBA inhibited CCl{sub 4}-induced hepatic nuclear factor kappa B (NF-κB) p65 translocation and extracellular signal-regulated kinase (ERK) and c-Jun N-terminal Kinase (JNK) phosphorylation. Interestingly, CCl{sub 4}-induced α-smooth muscle actin (α-SMA), a marker for the initiation phase of HSC activation, was significantly attenuated in mice pretreated with PBA. Correspondingly, CCl{sub 4}-induced hepatic collagen (Col)1α1 and Col1α2, markers for the perpetuation phase of HSC activation, were inhibited in PBA-treated mice. Importantly, CCl{sub 4}-induced hepatic fibrosis, as determined using Sirius red staining, was obviously attenuated by PBA. In conclusion, PBA prevents CCl{sub 4}-induced hepatic fibrosis through inhibiting hepatic inflammatory response and HSC activation. Highlights: ► CCl{sub 4} induces hepatic ER stress, inflammation, HSC activation and hepatic fibrosis. ► PBA alleviates CCl{sub 4}-induced hepatic ER stress and UPR signaling activation. ► PBA inhibits CCl{sub 4}-induced

  14. Effect of WeiJia on carbon tetrachloride induced chronic liver injury

    Institute of Scientific and Technical Information of China (English)

    Pik-Yuen Cheung; Jay Chun; Hsiang-Fu Kung; Meng-su Yang; Qi Zhang; Ya-Ou Zhang; Gan-Rong Bai; Marie Chia-Mi Lin; Bernard Chan; Chi-Chun Fong; Lin Shi; Yue-Feng Shi

    2006-01-01

    AIM: To study the effect of WeiJia on chronic liver injury using carbon tetrachloride (CCl4) induced liver injury animal model.METHODS: Wistar rats weighing 180-220g were randomly divided into three groups: normal control group (Group A), CCl4 induced liver injury control group (Group B) and CCl4 induction with WeiJia treatment group (Group C). Each group consisted of 14 rats. Liver damage and fibrosis was induced by subcutaneous injection with 40% CCl4 in olive oil at 3 mL/kg body weight twice a week for eight weeks for Groups B and C rats whereas olive oil was used for Group A rats. Starting from the third week,Group C rats also received daily intraperitoneal injection of WeiJia at a dose of 1.25 μg/kg body weight. Animals were sacrificed at the fifth week (4 male, 3 female), and eighth week (4 male, 3 female) respectively. Degree of fibrosis were measured and serological markers for liver fibrosis and function including hyaluronic acid (HA), type Ⅳ collagen (CIV), γ-glutamyl transferase (γ-GT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Alpha smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) immunohistochemistry were also performed.RESULTS: CCl4 induction led to the damage of liver and development of fibrosis in Group B and Group C rats when compared to Group A rats. The treatment of WeiJia in Group C rats could reduce the fibrosis condition significantly compared to Group B rats. The effect could be observed after three weeks of treatment and was more obvious after eight weeks of treatment. Serum HA, CIV,ALT, AST and Y-GT levels after eight weeks of treatment for Group C rats were 58±22 μg/L (P0.05) respectively, similar to normal control group (Group A), but significantly different from CCl4 induced liver injury control group (Group B). An increase in PCNA and decrease in a-SMA expression level was also observed.CONCLUSION: WeiJia could improve liver function and reduce liver fibrosis

  15. Hepatoprotective activity of Chhit-Chan-Than extract powder against carbon tetrachloride-induced liver injury in rats

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    Yi-Chun Lin

    2014-06-01

    Full Text Available The capability of Chhit-Chan-Than extract powder (CCTEP, 10% aqueous Ocimum gratissimum L. extract to protect against carbon tetrachloride (CCl4-induced oxidative stress and hepatotoxicity in vivo was investigated. Wistar rats were divided into five groups. Group A was a normal control group given only vehicle; Group B, the hepatotoxic group, was injected intraperitoneally twice a week with repeated 8% CCl4/olive oil (0.1 mL/100 g of body weight; Groups C–E, extract-treated groups received CCl4 and different doses of CCTEP (100 mg/kg and 200 mg/kg or silymarin (200 mg/kg of body weight daily by gavage for 8 weeks, respectively. The results showed that the CCl4-induced histopathogical changes may be prevented by CCTEP through reducing the intercellular collogen stack, dropping blood serum alanine aminotransferase and aspartate aminotransferase levels, and restoring the catalase activity and glutathione content. The hepatoprotective properties were further confirmed by the marked improvement in histopathological examination and by quantitative steatosis-fibrosis scoring. The above results suggest that CCTEP is able to prevent the liver inflammation and fibrosis induced by repeated CCl4 administration, and the hepatoprotective effects might be correlated partly with its antioxidant and free radical scavenging effects.

  16. New therapeutic aspect for carvedilol: Antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage

    Energy Technology Data Exchange (ETDEWEB)

    Hamdy, Nadia [Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo (Egypt); El-Demerdash, Ebtehal, E-mail: ebtehal_dm@yahoo.com [Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo (Egypt)

    2012-06-15

    Portal hypertension is a common complication of chronic liver diseases associated with liver fibrosis and cirrhosis. At present, beta-blockers such as carvedilol remain the medical treatment of choice for protection against variceal bleeding and other complications. Since carvedilol has powerful antioxidant properties we assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may add further benefits for its clinical usefulness using a chronic model of carbon tetrachloride (CCl4)-induced hepatotoxicity. Two weeks after CCl4 induction of chronic hepatotoxicity, rats were co-treated with carvedilol (10 mg/kg, orally) daily for 6 weeks. It was found that treatment of animals with carvedilol significantly counteracted the changes in liver function and histopathological lesions induced by CCl4. Also, carvedilol significantly counteracted lipid peroxidation, GSH depletion, and reduction in antioxidant enzyme activities; glutathione-S-transferase and catalase that was induced by CCl4. In addition, carvedilol ameliorated the inflammation induced by CCl4 as indicated by reducing the serum level of acute phase protein marker; alpha-2-macroglobulin and the liver expression of nuclear factor-kappa B (NF-κB). Finally, carvedilol significantly reduced liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cell (HSC) activation marker; alpha smooth muscle actin. In conclusion, the present study provides evidences for the promising antifibrotic effects of carvedilol that can be explained by amelioration of oxidative stress through mainly, replenishment of GSH, restoration of antioxidant enzyme activities and reduction of lipid peroxides as well as amelioration of inflammation and fibrosis by decreasing collagen accumulation, acute phase protein level, NF-κB expression and finally HSC activation. -- Highlights: ► Carvedilol is a beta blocker with antioxidant and antifibrotic

  17. Antioxidant and Protective Effect of Ethyl Acetate Extract of Podophyllum hexandrum Rhizome on Carbon Tetrachloride Induced Rat Liver Injury

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    Showkat Ahmad Ganie

    2011-01-01

    Full Text Available The antioxidant and hepatoprotective activities of ethyl acetate extract was carefully investigated by the methods of DPPH radical scavenging activity, Hydroxyl radical scavenging activity, superoxide radical scavenging activity, hydrogen peroxide radical scavenging activity, and its reducing power ability. All these in vitro antioxidant activities were concentration dependent, which were compared with standard antioxidants such as BHT, α-tocopherol. The hepatoprotective potential of Podophyllum hexandrum extract was also evaluated in male Wistar rats against carbon tetrachloride- (CCl4- induced liver damage. Pretreated rats were given ethyl acetate extract at 20, 30, and 50 mg/kg dose prior to CCl4 administration (1 mL/kg, 1:1 in olive oil. Rats pretreated with P. hexandrum extract remarkably prevented the elevation of serum AST, ALT, LDH, and liver lipid peroxides in CCl4-treated rats. Hepatic glutathione levels were significantly increased by the treatment with the extract in all the experimental groups. The extract at the tested doses also restored the levels of liver homogenate enzymes (glutathione peroxidase, glutathione reductase, superoxide dismutase, and glutathione-S-transferase significantly. This study suggests that ethyl acetate extract of P. hexandrum has a liver-protective effect against CCl4-induced hepatotoxicity and possess in vitro antioxidant activities.

  18. Phytochemical analysis, hepatoprotective and antioxidant activity of Alchornea cordifolia methanol leaf extract on carbon tetrachloride-induced hepatic damage in rats

    Institute of Scientific and Technical Information of China (English)

    Patience O Osadebe; Festus BC Okoye; Philip F Uzor; Nneka R Nnamani; Ijeoma E Adiele; Nkemakonam C Obiano

    2012-01-01

    ABSTRACT Objective:To investigate the hepatoprotective and antioxidant activities ofAlchornea cordifolia (A. cordifolia) leaf extract.Methods: Various solvent fractions of the methanol extract of the leaf of the plantA. cordifolia Mull. Arg (Fam: Euphorbiaceae) were evaluated for hepatoprotective activity by carbon tetrachloride-induced liver damage in rats. The degree of protection was measured by using biochemical parameters such as serum glutamate oxalate transaminase(SGOT/AST), serum glutamate pyruvate transaminase(SGPT/ALT), alkaline phosphatase(ALP) and total bilirubin. Thein vitro antioxidant activity of the extract was also evaluated by the 1, 1-diphenyl-2-picrylhydrazyl(DPPH)free radical scavenging assay. The extract was subjected to preliminary phytochemical screening.Results:The ethyl acetate and chloroform fractions, at a dose of 300mg/kg, produced significant(P<0.05) hepatoprotection by decreasing the activities of the serum enzymes and bilirubin while there were marked scavenging of the DPPH free radicals by the fractions. The effects were comparable to those of the standard drugs used for the respective experiments, silymarin and ascorbic acid. Alkaloids, flavonoids, saponins and tannins were detected in the phytochemical screening.Conclusion: From this study, it was concluded that the plant ofA. cordifolia possesses hepatoprotective as well as antioxidant activities and these activities reside mainly in the ethyl acetate and acetone fractions of methanol leaf extract.

  19. Amelioration of carbon tetrachloride- and paracetamol-induced hepatotoxicity in rats by Ficus dalhousiae

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    Syed Safiullah Ghori

    2014-12-01

    Full Text Available The present study was undertaken to investigate hepatoprotective activity of Ficus dalhousiae leaves ethanolic extract based on its traditional claim. Paracetamol- and carbon tetrachloride-induced hepatotoxicity in albino Wistar rats, experimental models was used for the evaluation. Various biochemical parameters like SGPT, SGOT, serum albumin, alkaline phosphatase, total bilirubin, direct bilirubin and total protein were estimated. Oral treatment with the extract 250 and 500 mg/kg, significantly (p<0.01 altered all the serum marker levels to the normal in both the experimental models. The activity of the extract was comparable to that of standard drug, silymarin (25 mg/kg, p.o.. Histopathological observations also demonstrated protective effect of the test extract on liver anatomy. Overall results suggest that F. dalhousiae possesses in vivo hepatoprotective activity.

  20. Protective Effects of Pleurotus tuber-regium on Carbon- Tetrachloride Induced Testicular Injury in Sprague Dawley Rats

    Science.gov (United States)

    Okolo, Kenneth O.; Siminialayi, Iyeopu M.; Orisakwe, Orish E.

    2016-01-01

    The high rate of male infertility and the meager resources to manage same in sub Saharan Africa have necessitated the search for cost effective and available alternatives. Mushrooms have been used traditionally in folk medicine and as nutraceuticals. This study has investigated the effect of the wild mushroom Pleurotus tuber-regium on carbon tetrachloride (CCl4) deleterious effects on the reproductive system of male rats. Thirty six rats were divided into six groups of six animals each. Group I (negative control) received 10 ml/kg olive oil intraperitoneal weekly in addition to feed and water ad libitum. Group II (positive control) received CCl4 10 ml/kg (30% in Olive oil) weekly. Group III, IV, and V received 100 mg, 20 0mg, and 500 mg P. tuber-regium (33.3% in feed) daily in addition to 10 ml/kg CCl4 weekly. Group VI received 500 mg P. tuber-regium (33.3% in feed) daily. After 4 weeks, sperm motility, epididymal count and vitality were determined. Serum malondialdehyde (MDA), testosterone, Luteinizing hormone (LH), Follicle stimulating hormone (FSH), prolactin and oestradiol were estimated using enzyme-linked immunosorbent assay (ELISA) kits. Histopathologic examinations of the testis were carried out. Carbon tetrachloride significantly reduced the sperm motility (54.33 ± 3.79%), epididymal count (28.73 ± 2.86 × 106/ml, vitality (4.96 ± 0.62), LH (0.88 ± 0.14), FSH (2.04 ± 0.33), and Testosterone (2.02 ± 0.24) when compared with control (89.33 ± 9.01), 91.91 ± 1.92 × 106/ml, 13.12 ± 0.19, 2.74 ± 0.32, 3.64 ± 0.62, and 4.16 ± 0.23, respectively, which were reversed by P. tuber-regium administration. Co-administration of P. tuber-regium plus CCl4 significantly reduced MDA level. P. tuber-regium showed dose dependent ameliorative activity against CCl4 deleterious action on the testis and may be beneficial in the management of male infertility. PMID:28018218

  1. ABHRAK BHASMA MEDIATED ALTERATIONS IN LIVER AND KIDNEY FUNCTIONS IN MALE ALBINO RATS DURING CARBON TETRACHLORIDE INDUCED TOXICITY

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    Teli Parashuram

    2013-10-01

    Full Text Available Abhrak bhasma, an Ayurvedic drug used against many diseases including hepatitis. In present study various doses of abhrak bhasma (10, 20, 30 and 40 mg/kg body wt were tested for hepatoprotective efficacy against carbon tetrachloride (CCl4 intoxicated liver and kidney functions in male albino rat. Administration of CCl4 to the normal rat increased serum levels of AST, ALT, ALP and bilirubin indicated acute damage. Abhrak bhasma treatment counteracted the action of CCl4 on liver and kidney functions. With the administration of increasing doses of abhrak bhasma all activities were dropped progressively and significantly at 40 mg dose as compared with silicate control. Conjugation metabolism and excretion of bilirubin were improved with increasing doses of abhrak bhasma suggesting dose dependent protection of all metabolic steps in bilirubin metabolism. Also CCl4 induced acute toxicity increased serum urea and creatinine content, which was progressively controlled by increasing abhrak bhasma doses. The findings of this study indicated that abhrak bhasma exert dose dependent protective effects in liver and kidneys functions against CCl4 induced toxicity in albino rat.

  2. Nigella sativa improves the carbon tetrachloride-induced lung damage in rats through repression of erk/akt pathway

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    Abdullah Aslan

    2015-08-01

    Full Text Available The objective of this study was to examine whether Nigella sativa plays a protective role against the damage in the lung by administering carbon tetra-chloride (CCl4 to rats. Male Wistar albino (n=28, 8 weeks old rats were divided into 4 groups: a negative control: Normal water consuming group to which no CCl4 and N. sativa was administered; b Positive control: Normal water consuming group to which no CCl4 was administered but N. sativa was administered; c CCl4 Group: Normal water consuming and group to which CCl4 was administered (1.5 mL/kg, ip; d N. sativa plus CCl4 group: CCl4 and N. sativa administered group (1.5 mL/kg, ip. Caspase-3, caspase -9, erk, akt protein syntheses were examined via Western blotting. Malondialdehyde determination in lung tissue was made using spectrophotometer. As a results, malondialdehyde amount was decreased in the CCl4 plus N. sativa group in comparison to CCl4 group whereas caspase-3, caspase-9 was increased and erk, akt had decreased. These results show that N. sativa protects the lung against oxidative damage.

  3. Folic acid and melatonin ameliorate carbon tetrachloride-induced hepatic injury, oxidative stress and inflammation in rats

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    Ebaid Hossam

    2013-02-01

    Full Text Available Abstract This study investigated the protective effects of melatonin and folic acid against carbon tetrachloride (CCl4-induced hepatic injury in rats. Oxidative stress, liver function, liver histopathology and serum lipid levels were evaluated. The levels of protein kinase B (Akt1, interferon gamma (IFN-γ, programmed cell death-receptor (Fas and Tumor necrosis factor-alpha (TNF-α mRNA expression were analyzed. CCl4 significantly elevated the levels of lipid peroxidation (MDA, cholesterol, LDL, triglycerides, bilirubin and urea. In addition, CCl4 was found to significantly suppress the activity of both catalase and glutathione (GSH and decrease the levels of serum total protein and HDL-cholesterol. All of these parameters were restored to their normal levels by treatment with melatonin, folic acid or their combination. An improvement of the general hepatic architecture was observed in rats that were treated with the combination of melatonin and folic acid along with CCl4. Furthermore, the CCl4-induced upregulation of TNF-α and Fas mRNA expression was significantly restored by the three treatments. Melatonin, folic acid or their combination also restored the baseline levels of IFN-γ and Akt1 mRNA expression. The combination of melatonin and folic acid exhibited ability to reduce the markers of liver injury induced by CCl4 and restore the oxidative stability, the level of inflammatory cytokines, the lipid profile and the cell survival Akt1 signals.

  4. High-fat diet plus carbon tetrachloride-induced liver fibrosis is alleviated by betaine treatment in rats.

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    Bingül, İlknur; Aydın, A Fatih; Başaran-Küçükgergin, Canan; Doğan-Ekici, Işın; Çoban, Jale; Doğru-Abbasoğlu, Semra; Uysal, Müjdat

    2016-10-01

    Steatosis, the first lesion in non-alcoholic fatty liver disease (NAFLD), may progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Steatosis predisposes the liver to oxidative stress, inflammation, and cytokines. Betaine (BET) has antioxidant, antiinflammatory and hepatoprotective effects. However, the effects of BET on liver fibrosis development are unknown. Rats were treated with high-fat diet (60% of total calories from fat) for 14weeks. Carbon tetrachloride (0.2mL/kg; two times per week; i.p.) was administered to rats in the last 6weeks with/without commercial food containing BET (2%; w/w). Serum liver function tests and tumor necrosis factor-α, insulin resistance, hepatic triglyceride (TG) and hydroxyproline (HYP) levels and oxidative stress parameters were determined along with histopathologic observations. Alpha-smooth muscle-actin (α-SMA), transforming growth factor-β1 (TGF-β1) and type I collagen (COL1A1) protein expressions and mRNA expressions of matrix metalloproteinase-2 (MMP-2) and its inhibitors (TIMP-1 and TIMP-2) were evaluated. BET decreased TG and HYP levels, prooxidant status and fibrotic changes in the liver. α-SMA, COL1A1 and TGF-β1 protein expressions, MMP-2, TIMP-1, and TIMP-2 mRNA expressions diminished due to BET treatment. BET has an antifibrotic effect and this effect may be related to its antioxidant and antiinflammatory actions together with suppression on HSC activation.

  5. Protective effects of Chaenomeles thibetica extract against carbon tetrachloride-induced damage via the MAPK/Nrf2 pathway.

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    Ma, Bingxin; Wang, Jing; Tong, Jing; Zhou, Gao; Chen, Yuxin; He, Jingsheng; Wang, Youwei

    2016-03-01

    Chaenomeles thibetica, a type of fruit of the genus Chaenomeles, is commonly cultivated and used as Mugua in China and as liquor, candy, and functional food in Tibet. Total phenol, flavonoid, and proanthocyanidin contents were measured in C. thibetica extract (CTE). CTE had a positive effect on free radical scavenging and anti-lipid oxidation in vitro. The protective effects of CTE against carbon tetrachloride (CCl4)-induced oxidative damage in vivo were also measured. The results of antioxidative enzymes indicated that CTE can increase the activities of the catalase, superoxide dismutase, and glutathione contents and reduce the level of malondialdehyde in rats. The levels of alanine aminotransferase, aspartate transaminase, alkaline phosphatase, and total bilirubin were significantly reversed by CTE compared with the elevated levels in the CCl4 group. Besides, CTE could reverse the cell viability of HepG2 inoculated with CCl4via phosphorylation of mitogen-activated protein kinases (MAPKs), activating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and increasing the expression of phase II detoxification enzymes. These effects may expand the applications of C. thibetica and offer alternative food with antioxidant and hepatoprotective functions in the food industry.

  6. Protective effects of neohesperidin dihydrochalcone against carbon tetrachloride-induced oxidative damage in vivo and in vitro.

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    Hu, Lihua; Li, Lingrui; Xu, Demei; Xia, Xiaomin; Pi, Ruxian; Xu, Duo; Wang, Wenchao; Du, Hong; Song, Erqun; Song, Yang

    2014-04-25

    The purpose of this study was to investigate the possible hepatoprotective effects of neohesperidin dihydrochalcone (NHDC) on carbon tetrachloride (CCl4)-induced acute oxidative injury in vivo and in vitro. In a mouse model, intraperitoneal injection of CCl4 resulted in a significant increase in serum aspartate transaminase (AST) and alanine transaminase (ALT) activities. Histopathological examination revealed severe hepatocyte necrosis and destruction of architecture in liver lesions, and immunohistochemical staining illustrated a remarkable enhancement of COX-2 and iNOS expression. The levels of hepatic antioxidant, such as, catalase (CAT), total superoxide dismutase (T-SOD), glutathione peroxidase (GP-X) and glutathione (GSH) were decreased, compared to the control group. However, pretreatment of NHDC for six consecutive days significantly ameliorated these changes. Moreover, Western blotting assay indicated pretreatment with NHDC also down-regulated CCl4-induced protein expressions of NF-κB, IL-6, caspase 3 and caspase 8. In HepG2 cell model, CCl4-treatment caused significant decrease in cell viability, antioxidant activities and GSH level, increase in intracellular reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) level. Interestingly, pretreatment of NHDC effectively relieved CCl4-induced oxidative damage in a dose-dependent manner. In conclusion, NHDC appeared to possess promising anti-oxidative and anti-inflammatory capacities, it is possible to be used as a hepatoprotective agent.

  7. Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation

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    Wen-ying CHOU; Cheng-nan LU; Tsung-hsing LEE; Chia-ling WU; Kung-sheng HUNG; Allan M CONCEJERO; Bruno JAWAN; Cheng-haung WANG

    2006-01-01

    Aim:Liver fibrosis represents a process of healing and scarring in response to chronic liver injury.Effective therapies for liver fibrosis are lacking.Interleukin-10 (IL-10) is a cytokine that downregulates pro-inflammatory responses and has a modulatory effect on hepatic fibrogenesis.The aim of this study was to investigate whether electroporative IL-10 gene therapy has an hepatic fibrolytic effect on mice.Methods:Hepatic fibrosis was induced by administering carbon tetrachloride (CCl4) for 10 weeks in mice.The human IL-10 expression plasmid was delivered via electroporation after hepatic fibrosis was established.Histopathology,reverse transcription polymerase chain reaction (RT-PCR) ,immunoblotting,and gelatin zymography were used to investigate the possible mechanisms of action of IL-10.Results:Human IL-10 gene therapy reversed CCl4-induced liver fibrosis in mice.RT-PCR revealed that IL-10 gene therapy attenuated liver TGF-β1,collagen αl,fibronectin,and cell adhesion molecule mRNA upregulation.Following gene transfer,both the activation of α-smooth muscle actin and cyclooxygenase-2 were significantly attenuated.Furthermore.IL-10 significantly inhibited matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of matrix metalloproteinase (TIMP) activation after CCl4 intoxication.Conclusions:We demonstrated that IL-10 gene therapy attenuated CCl4-induced liver fibrosis in mice.IL-10 prevented upregulated fibrogenic and pro-inflammatory gene responses.Its collagenolytic effect may be attributed to MMP and TIMP modulation.IL-10 gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

  8. Management of carbon tetrachloride-induced acute liver injury in rats by syngeneic hepatocyte transplantation in spleen and peritoneal cavity

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    Charalampos Pilichos; Despina Perrea; Maria Demonakou; Athena Preza; Ismini Donta

    2004-01-01

    AIM: Acute hepatitis may seldom have a fulminant course.In the treatment of this medical emergency, potential liver support measure must provide immediate and sufficient assistance to the hepatic function. The goal of our study was to study the adequacy of hepatocyte transplantation (HCTx) in two different anatomical sites, splenic parenchyma and peritoneal cavity, in a rat model of reversible acute hepatitis induced by carbon tetrachloride (CCl4).METHODS: After CCl4 intoxication, 84 male Wistar rats used as recipients were divided in to four experimental groups accordingly to their treatment: Group A (n=24): intrasplenic transplantation of 10x106 isolated hepatocytes, Group B (n=24):intraperitoneal transplantation of 20xL06 isolated hepatocytes attached on plastic microcarriers, Group C (n= 18): i ntrasplenic injection of 1 mL normal saline (sham-operated controls),Group D (n=18): intraperitoneal injection of 2.5 mL normal saline (sham-operated controls). Survival, liver function tests (LFT) and histology were studied in all four groups, on d 2,5 and 10 post-HCTx.RESULTS: The ten-day survival (and mean survival) in the 4 groups was 72.2% (8.1±3.1), 33.3% (5.4±3.4), 0%(3.1±1.3) and 33.3% (5.4±3.6) in groups A, B, C, D,respectively (PAB<0.05, PAC<0.05, PBD=NS). In the final survivors, LFT (except alkaline phosphatase) and hepatic histology returned to normal, independently of their previous therapy. Viable hepatocytes were identified within splenic parenchyma (in group A on d 2) and both in the native liver and the fatty tissue of abdominal wall (in group B on d 5).CONCLUSION: A significantly better survival of the intrasplenically transplanted animals has been demonstrated.Intraperitoneal hepatocytes failed to promptly engraft. A different timing between liver injury and intraperitoneal HCTx may give better results and merits further investigation.

  9. Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids

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    Cheshchevik, V.T. [Institute for Pharmacology and Biochemistry, National Academy of Sciences of Belarus, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Department of Biochemistry, Yanka Kupala Grodno State University, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Lapshina, E.A.; Dremza, I.K.; Zabrodskaya, S.V. [Institute for Pharmacology and Biochemistry, National Academy of Sciences of Belarus, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Reiter, R.J. [Department of Cellular and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229–3900 (United States); Prokopchik, N.I. [Grodno State Medical University, Gorkogo - 80, 230015 Grodno (Belarus); Zavodnik, I.B., E-mail: zavodnik_il@mail.ru [Institute for Pharmacology and Biochemistry, National Academy of Sciences of Belarus, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Department of Biochemistry, Yanka Kupala Grodno State University, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus)

    2012-06-15

    In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6 g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride – induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p < 0.05). Short-term melatonin treatment (10 mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production. After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl{sub 4} displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl{sub 4}, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage

  10. Puerarin attenuates carbon tetrachloride-induced liver oxidative stress and hyperlipidaemia in mouse by JNK/c-Jun/CYP7A1 pathway.

    Science.gov (United States)

    Ma, Jie-Qiong; Ding, Jie; Zhao, Hai; Liu, Chan-Min

    2014-11-01

    Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. The aim of this study was to investigate the effects of puerarin on hepatic oxidative stress and hyperlipidaemia in mice exposed to carbon tetrachloride (CCl4). Male ICR mice were injected with CCl4 with or without puerarin co-administration (200 and 400 mg/kg intragastrically once-daily) for 8 weeks. Our data showed that puerarin significantly prevented CCl4-induced hepatotoxicity, indicated by both diagnostic indicators of the liver damage (serum aminotransferase levels) and histopathological analysis. Puerarin decreased the thiobarbituric acid reactive substances (TBARS) and the protein carbonyl content (PCO) in the liver of CCl4-treated mice. Puerarin also restored the levels of reduced glutathione (GSH) and total antioxidant capacity (TAC) in the liver. Furthermore, the increase in serum cholesterol, triglycerides and low-density lipoproteins (LDL) induced by CCl4 was effectively suppressed by puerarin. The high-density lipoprotein (HDL) level in the CCl4 treatment mice was also increased by puerarin. Western blot analysis showed that puerarin remarkably inhibited hyperlipidaemia by regulating the expression of phosphorylated Jun N-terminal kinases (JNK), phosphorylated c-Jun protein and cholesterol 7a-hydroxylase (CYP7A1) in the liver of CCl4-treated mice. Altogether, these results suggest that puerarin could protect the CCl4-induced liver injury and hyperlipidaemia by reducing reactive oxygen species S production, renewing the total antioxidant capacity and influencing expression of hepatic lipid biosynthesis and metabolism genes.

  11. Dose response and time course studies on superoxide dismutase as a urinary biomarker of carbon tetrachloride-induced hepatic injury in the Hanover Wistar rat.

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    Smyth, Rosemary; Munday, Michael R; York, Malcolm J; Clarke, Christopher J; Dare, Theo; Turton, John A

    2009-10-01

    Previous studies have shown that the enzyme copper/zinc superoxide dismutase (SOD-1) is increased in the urine of rats with carbon tetrachloride (CCl(4))-induced hepatotoxicity. The present experiments aimed to investigate further the usefulness of urinary SOD-1 as a non-invasive biomarker of liver injury. Two investigations were carried out, a dose response study and a time course study. In the dose response study, rats were given a single dose of CCl(4) at 0 (control), 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40 and 0.80 ml/kg and urine samples collected from 12 to 36 h postdosing. In the time course study, rats were dosed at 0.80 ml/kg CCl(4) and urine sampled at 4, 12, 24 and 36 h postdosing. In both studies, the presence of SOD-1 in the urine was confirmed by Western blotting with an SOD-1 antibody. In the dose response study, serum SOD activity was elevated in all CCl(4)-treated animals and urinary SOD-1 activity was increased 2.2 times at the lowest dose (0.10 ml/kg) and 60.4 times at the highest CCl(4) dose level (0.80 ml/kg). In the time course study, urinary SOD-1 was first detected in samples collected from 4 to 12 h postdosing. We conclude that urinary SOD-1 has potential as a sensitive non-invasive biomarker of CCl(4)-induced hepatocellular injury.

  12. Wu-Chia-Pi Solution Attenuates Carbon Tetrachloride-Induced Hepatic Injury through the Antioxidative Abilities of Its Components Acteoside and Quercetin

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    Ching-Chiung Wang

    2012-12-01

    Full Text Available Wu-Chia-Pi medicated wine, composed nine Chinese medicines soaked in 35% alcohol, is widely used in Asia for its health-promoting functions. However, long-term consumption of alcohol could result in liver dysfunction. In this study, Wu-Chia-Pi solution (WCPS and extract (WCPE were prepared by modification of the principals given by the Committee on Chinese Medicine and Pharmacy in Taiwan. The aim of this study was to explore the protective effect of WCPS against carbon tetrachloride (CCl4-induced liver injury and to clarify its active component(s. Antioxidative effects of the test samples were evaluated via MDA inhibition, catalase activity and DPPH-scavenging assays. HPLC was used to analysis the active components. Results showed that WCPS (1 and 5 mL/kg significantly prevented CCl4-induced liver injury without chronic liver toxicity. Referring to the antioxidative activities, WCPE displayed significant MDA inhibitory and DPPH-scavenging activities with IC50 values of 0.91 ± 0.03 and 0.60 ± 0.04 mg/mL, respectively. Catalase activity was also enhanced by treatment of WCPE, acteoside and quercetin. Therefore, we suggest that acteoside and quercetin are the major contributors to the antioxidative and hepatoprotective activities of WCPS, and a possible mechanism could be mediated through reduction of oxidative stress.

  13. Schisandra Lignan Extract Protects against Carbon Tetrachloride-Induced Liver Injury in Mice by Inhibiting Oxidative Stress and Regulating the NF-κB and JNK Signaling Pathways

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    Chen, Qingshan; Zhan, Qi; Li, Ying; Sun, Sen; Zhao, Liang

    2017-01-01

    Schisandra chinensis (S. chinensis) is a traditional Chinese herbal medicine widely used for the treatment of liver disease, whose main active components are lignans. However, the action mechanisms of the lignans in S. chinensis remain unclear. This study aimed to investigate the protective effect and related molecular mechanism of Schisandra lignan extract (SLE) against carbon tetrachloride- (CCl4-) induced acute liver injury in mice. Different doses of SLE at 50, 100, and 200 mg/kg were administered daily by gavage for 5 days before CCl4 treatment. The results showed that SLE significantly decreased the activities of serum ALT/AST and reduced liver pathologic changes induced by CCl4. Pretreatment with SLE not only decreased the content of MDA but increased SOD, GSH, and GSH-Px activities in the liver, suggesting that SLE attenuated CCl4-induced oxidative stress. The expression levels of inflammatory cytokines TNF-a, IL-1β, and IL-6 were decreased after oral administration of SLE, probably because lignans inhibited the NF-κB activity. Additionally, SLE also inhibited hepatocyte apoptosis by suppressing JNK activation and regulating Bcl-2/Bax signaling pathways. In conclusion, these results suggested that SLE prevented CCl4-induced liver injury through a combination of antioxidative stress, anti-inflammation, and antihepatocyte apoptosis and alleviated inflammation and apoptosis by regulating the NF-κB, JNK, and Bcl-2/Bax signaling pathways.

  14. The molecular mechanisms of the hepatoprotective effect of gomisin A against oxidative stress and inflammatory response in rats with carbon tetrachloride-induced acute liver injury.

    Science.gov (United States)

    Teraoka, Ryutaro; Shimada, Tsutomu; Aburada, Masaki

    2012-01-01

    Oxidative damage and inflammation are implicated in the pathogenesis of liver injury and fibrosis. In the present study, we investigated the molecular mechanism by which gomisin A conferred a hepatoprotective effect, focusing on its antioxidant and anti-inflammatory effects using rats with carbon tetrachloride (CCl(4))-induced acute liver injury. Pretreatment with gomisin A prior to the administration of CCl(4) markedly prevented an increase in alanine aminotransferase, aspartate aminotransferase, and histological hepatic lesions. Gomisin A was also associated with a decrease in hepatic lipid peroxidation, and increased superoxide dismutase activity, suggesting that gomisin A has an antioxidant effect. In addition gomisin A treatment ameliorated mRNA levels of CCl(4)-induced inflammatory mediators, including tumor necrosis factor-α, interleukin-1β and inducible nitric oxide (NO) synthase, and the protein levels of transcriptional upregulator nuclear factor kappa B (NF-κB) and phospho-inhibitor of NF-κB (IκB). Furthermore, α-smooth muscle actin (α-SMA), a myofibroblast marker, was also inhibited by gomisin A treatment. These results suggest that gomisin A inhibits the oxidative stress and activation of NF-κB, leading to down-regulation of pro-inflammatory mediators and amelioration of fibrogenesis.

  15. Effectiveness of cinnamon (Cinnamomum zeylanicum) bark oil in the prevention of carbon tetrachloride-induced damages on the male reproductive system.

    Science.gov (United States)

    Yüce, A; Türk, G; Çeribaşı, S; Güvenç, M; Çiftçi, M; Sönmez, M; Özer Kaya, Ş; Çay, M; Aksakal, M

    2014-04-01

    In this study, it was aimed to investigate the likelihood of detrimental effects of carbon tetrachloride (CCl4 ) on male reproductive system through oxidative stress mechanism and also protective effects of cinnamon bark oil (CBO). For this purpose, 28 healthy male Wistar rats were divided into four groups, seven rats in each. Group 1 received only olive oil daily; group 2 was treated with 100 mg kg(-1) CBO daily; group 3 was treated with only 0.25 ml kg(-1) CCl4 weekly; and group 4 received weekly CCl4 + daily CBO. All administrations were made by intragastric catheter and maintained for 10 weeks. Body and reproductive organ weights, sperm characteristics, testicular oxidative stress markers and testicular apoptosis were examined. CCl4 administration caused significant decreases in body and reproductive organ weights, testicular catalase (CAT) activity, sperm motility and concentration, and significant increases in lipid peroxidation (LPO) level, abnormal sperm rate and apoptotic index along with some histopathological damages compared with the control group. However, significant improvements were observed in absolute weights of testis and epididymis, all sperm quality parameters, LPO level, apoptotic index and testicular histopathological structure following the administration of CCl4 together with CBO when compared to group given CCl4 only. The findings of this study clearly suggest that CBO has protective effect against damages in male reproductive organs and cells induced by CCl4 .

  16. Antioxidant and Prophylactic Effects of Delonix elata L., Stem Bark Extracts, and Flavonoid Isolated Quercetin against Carbon Tetrachloride-Induced Hepatotoxicity in Rats

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    Pradeepa Krishnappa

    2014-01-01

    Full Text Available Delonix elata L. (Ceasalpinaceae, is widely used by the traditional medical practitioners of Karnataka, India, to cure jaundice, and bronchial and rheumatic problems. The objective of this study was to screen the in vitro antioxidant and hepatoprotective activity of the stem bark extracts against CCl4-induced liver damage in rats. Among different stem bark extracts tested, the ethanol extract (DSE has shown significant in vitro antioxidant property in radicals scavenging, metal chelating, and lipid peroxidation inhibition assays. HPLC analysis of the DSE revealed the presence of known antioxidant molecules, namely, gallic acid, ellagic acid, coumaric acid, quercetin, and rutin. Bioassay-guided fractionation of DSE has resulted in the isolation and characterization of quercetin. DSE and quercetin have shown significant prophylactic effects by restoring the liver function markers (AST, ALT, ALP, serum bilirubin, and total protein and antioxidant enzymes (SOD, CAT, GPx, and GST. These results were proved to be hepatoprotective at par with silymarin and well supported by the histological observations of liver sections with distinct hepatic cells, and mild degree of fatty change and necrosis. The results indicated that the DSE and quercetin were significant for prophylactic activity against CCl4-induced liver damage in rats. This activity could be attributed to the antioxidant constituents in the DSE and hence justified the ethnomedicinal claims.

  17. Endogenous hydrogen sulfide is associated with angiotensin II type 1 receptor in a rat model of carbon tetrachloride-induced hepatic fibrosis

    Science.gov (United States)

    FAN, HUI-NING; CHEN, NI-WEI; SHEN, WEI-LIN; ZHAO, XIANG-YUN; ZHANG, JING

    2015-01-01

    The present study aimed to investigate the effects of endogenous hydrogen sulfide (H2S) on the expression levels of angiotensin II type 1 receptor (AGTR1) in a rat model of carbon tetrachloride (CCl4)-induced hepatic fibrosis. A total of 56 Wistar rats were randomly divided into four groups: Normal control group, model group, sodium hydrosulfide (NaHS) group, and DL-propargylglycine (PAG) group. Hepatic fibrosis was induced by CCl4. The rats in the PAG group were intraperitoneally injected with PAG, an inhibitor of cystathionine-γ-lyase (CSE). The rats in the NaHS group were intraperitoneally injected with NaHS. An equal volume of saline solution was intraperitoneally injected into both the control and model groups. All rats were sacrificed at week three or four following treatment. The serum levels of hyaluronidase (HA), laminin protein (LN), procollagen III (PcIII), and collagen IV (cIV) were detected using ELISA. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and albumin (ALB) were detected using an automatic biochemical analyzer. The liver mRNA expression levels of CSE were detected by reverse transcription-quantitative polymerase chain reaction. The liver expression levels of AGTR1 and the plasma expression levels of H2S were detected using western blot analyses. The results indicated that the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly higher in the PAG group, as compared with the model group (P<0.05). Conversely, the expression levels of ALB were significantly lower in the PAG group, as compared with the model group. In addition, the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly lower in the NaHS group, as compared with

  18. (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione protects rats from carbon tetrachloride-induced liver injury and fibrogenesis

    Institute of Scientific and Technical Information of China (English)

    Zhi-Zhi Chen; Li-Juan Chen; Yu-Quan Wei; Zheng-Lin Wang; Chong-Yang Deng; Hao Zheng; Xian-Huo Wang; Liang Ma; Xia Ye; Ying-Hua Ma; Cai-Feng Xie

    2012-01-01

    AIM:To evaluate the hepatoprotective roles of (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (SKLB010) against carbon tetrachloride (CCl4)-induced acute and chronic liver injury and its underlying mechanisms of action.METHODS:In the first experiment,rats were weighed and randomly divided into 5 groups (five rats in each group) to assess the protective effect of SKLB010on acute liver injury.For induction of acute injury,rats were administered a single intraperitoneal injection of 2 mL/kg of 50% (v/v) CCl4 dissolved in olive oil (1∶1).Group 1 was untreated and served as the control group; group 2 received CCl4 for induction of liver injury and served as the model group.In groups 3,4 and 5,rats receiving CCl4 were also treated with SKLB010 at doses of 25,50 and 100 mg/kg,respectively.Blood samples were collected at 6,12 and 24 h after CCl4 intoxication to determine the serum activity of alanine amino transferase.Tumour necrosis factor-α (TNF-α),interleukin-1β (IL-1β) were determined using enzyme-linked immunosorbent assay.At 24 h after CCl4 injection,liver fibrogenesis was evaluated by hematoxylin-eosin (HE) staining and immunohistochemical analyses.Cytokine transcript levels of TNF-α,IL-1β and inducible nitric oxide synthase in the liver tissues of rats were measured using a reverse transcriptase reverse transcription-polymerase chain reaction technique.In the second experiment,rats were randomly divided into 2 groups (15 rats in each group),and liver injury in the CCl4-administered groups was induced by a single intraperitoneal injection of 2 mL/kg of 50% (v/v) CCl4 dissolved in olive oil (1∶1).The SKLB010-treated groups received oral 100 mg/kg SKLB010 before CCl4 administration.Five rats in each group were sacrificed at 2 h,6 h,12 h after CCl4 intoxication and small fortions of livers were rapidly frozen for extraction of total RNA,hepatic proteins and glutathione (GSH) assays.In the hepatic fibrosis model group,rats were randomly divided into 2

  19. Establishment of carbon tetrachloride-induced acute liver injury model in mice%四氯化碳致小鼠急性肝损伤动物模型建立方法的研究

    Institute of Scientific and Technical Information of China (English)

    周琼; 刘芳萍; 刘颖姝; 赵玉林; 李昌文; 李睿; 张秀英

    2012-01-01

    通过对染毒途径、剂量和时间的研究,建立四氯化碳(CCl4)致小鼠急性肝损伤模型.采取腹腔注射和灌胃两种途径给予小鼠1% CCl4,染毒后24h检测血清转氨酶含量,并观察肝脏病变.结果显示,灌胃组比腹腔注射组小鼠血清转氨酶变化个体差异小,肝脏病变明显,病灶分布均匀,且与实际中毒途径一致,故采用灌胃方法进行确定染毒剂量及时间试验.分别以0.125%、0.25%、0.35%、0.5%的CCl4给小鼠灌胃,染毒24h后检测血清转氨酶含量,确定最佳染毒剂量.以该浓度给小鼠灌胃,分别于染毒后2、6、12、16、20、24、28、32、48h检测小鼠血清转氨酶含量.结果表明,灌胃0.35% CCl4,小鼠血清转氨酶升高与对照组相比差异极显著(P<0.01),此浓度灌胃后,20h血清转氨酶含量显著升高(P<0.01),24h达到最高值,与对照组相比差异极显著(P<0.01).因此,以0.35%四氯化碳,按0.1mL·10g-1体重灌胃,染毒24h,可建立较理想的小鼠急性肝损伤模型.%Established the model of carbon tetrachloride-induced acute liver injury in mice by investigating the optimal exposure pathway, dose and time. Mice were prepared with 1% CCU by intraperitoneal injection and gavage respectively. Serum transaminase levels were detected and liver lesions were examined after 24 h. The results showed that individual difference of serum transaminase level in gavage group was smaller than intraperitoneal injection group, liver lesions were more uniform. Optimal dose and time was investigated by gavage because it has the same poisoning way with reality. Mice were given carbon tetrachloride in oil solution by gavage, with concentration of 0.125%, 0.25%, 0.35% and 0.5%. Detected serum transaminase levels after 24 h to measure optimal exposure dose. Serum transaminase levels was detected at 2,6,12,16, 20, 24, 28, 32, 48 h after mice were expoed to optimal dose of CCU. The results showed that mice received 0.35% CCU

  20. Potentiation of carbon tetrachloride hepatotoxicity by pentosan polysulfate in rats.

    Science.gov (United States)

    Zim, M C A; Silveira, T R; Schwartsmann, G; Cerski, T; Motta, A

    2002-11-01

    Few data are available in the literature regarding the effect of pentosan polysulfate (PPS) on normal and fibrotic rat livers. In addition, the combination of PPS and carbon tetrachloride (CCl4) has not been studied so far. The objective of this study was to assess the effect of PPS on rat livers treated or not with CCl4 for the induction of liver fibrosis. The study consisted of four stages: 1) hepatic fibrosis induction with CCl4 (N = 36 rats); 2) evaluation of the effect of PPS on CCl4-induced hepatic fibrosis (N = 36 rats); 3) evaluation of the effect of higher doses of PPS in combination with CCl4 (N = 50 rats); 4) evaluation of the presence of an enzymatic inductor effect by PPS (N = 18 rats) using the sodium pentobarbital test which indirectly evaluates hepatic microsomal enzyme activity in vivo. Adult (60 to 70 days) male Wistar rats weighing 180 to 220 g were used. All animals receiving 0.5 ml 8% CCl4 (N = 36) developed hepatic fibrosis, and after 8 weeks they also developed cirrhosis. No delay or prevention of hepatic fibrosis was observed with the administration of 5 mg/kg PPS (N = 8) and 1 mg/kg PPS (N = 8) 1 h after the administration of CCl4, but the increased hepatotoxicity resulting from the combination of the two substances caused massive hepatic necrosis in most rats (N = 45). PPS (40 mg/kg) alone caused hepatic congestion only after 8 weeks, but massive hepatic necrosis was again observed in association with 0.5 ml CCl4 after 1 to 4 weeks of treatment. Unexpectedly, sleeping time increased with time of PPS administration (1, 2, or 3 weeks). This suggests that PPS does not function as an activator of the hepatic microsomal enzymatic system. Further studies are necessary in order to clarify the unexpected increase in hepatotoxicity caused by the combination of CCl4 and high doses of PPS, which results in massive hepatic necrosis.

  1. Potentiation of carbon tetrachloride hepatotoxicity by pentosan polysulfate in rats

    Directory of Open Access Journals (Sweden)

    Zim M.C.A.

    2002-01-01

    Full Text Available Few data are available in the literature regarding the effect of pentosan polysulfate (PPS on normal and fibrotic rat livers. In addition, the combination of PPS and carbon tetrachloride (CCl4 has not been studied so far. The objective of this study was to assess the effect of PPS on rat livers treated or not with CCl4 for the induction of liver fibrosis. The study consisted of four stages: 1 hepatic fibrosis induction with CCl4 (N = 36 rats; 2 evaluation of the effect of PPS on CCl4-induced hepatic fibrosis (N = 36 rats; 3 evaluation of the effect of higher doses of PPS in combination with CCl4 (N = 50 rats; 4 evaluation of the presence of an enzymatic inductor effect by PPS (N = 18 rats using the sodium pentobarbital test which indirectly evaluates hepatic microsomal enzyme activity in vivo. Adult (60 to 70 days male Wistar rats weighing 180 to 220 g were used. All animals receiving 0.5 ml 8% CCl4 (N = 36 developed hepatic fibrosis, and after 8 weeks they also developed cirrhosis. No delay or prevention of hepatic fibrosis was observed with the administration of 5 mg/kg PPS (N = 8 and 1 mg/kg PPS (N = 8 1 h after the administration of CCl4, but the increased hepatotoxicity resulting from the combination of the two substances caused massive hepatic necrosis in most rats (N = 45. PPS (40 mg/kg alone caused hepatic congestion only after 8 weeks, but massive hepatic necrosis was again observed in association with 0.5 ml CCl4 after 1 to 4 weeks of treatment. Unexpectedly, sleeping time increased with time of PPS administration (1, 2, or 3 weeks. This suggests that PPS does not function as an activator of the hepatic microsomal enzymatic system. Further studies are necessary in order to clarify the unexpected increase in hepatotoxicity caused by the combination of CCl4 and high doses of PPS, which results in massive hepatic necrosis.

  2. The hepatotoxicity of multi-walled carbon nanotubes in mice

    Energy Technology Data Exchange (ETDEWEB)

    Ji Zongfei; Zhang Danying; Shen Xizhong; Dong Ling [Department of Gastroenterology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Li Ling; Deng Xiaoyong; Wu Minhong; Liu Yuanfang, E-mail: xydeng@shu.edu.c, E-mail: dltalk@tom.co [Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai 200444 (China)

    2009-11-04

    The hepatotoxicity of two types of multi-walled carbon nanotubes (MWCNTs), acid-oxidized MWCNTs (O-MWCNTs) and Tween-80-dispersed MWCNTs (T-MWCNTs), were investigated with Kunming mice exposed to 10 and 60 mg kg{sup -1} by intravenous injection for 15 and 60 d. Compared with the PBS group, the body-weight gain of the mice decreased and the level of total bilirubin and aspartate aminotransferase increased in the MWCNT-exposed group with a significant dose-effect relationship, while tumor necrosis factor alpha level did not show significant statistical change within 60 d. Spotty necrosis, inflammatory cell infiltration in portal region, hepatocyte mitochondria swelling and lysis were observed with a significant dose-effect relationship in the MWCNT groups. Liver damage of the T-MWCNT group was more severe than that of the O-MWCNT group according to the Roenigk classification system. Furthermore, T-MWCNTs induce slight liver oxidative damage in mice at 15 d, which was recovered at 60 d. Part of the gene expressions of mouse liver in the MWCNT groups changed compared to the PBS group, including GPCRs (G protein-coupled receptors), cholesterol biosynthesis, metabolism by cytochrome P450, natural-killer-cell-mediated cytotoxicity, TNF- {alpha}, NF-{kappa}B signaling pathway, etc. In the P450 pathway, the gene expressions of Gsta2 (down-regulated), Cyp2B19 (up-regulated) and Cyp2C50 (down-regulated) had significant changes in the MWCNT groups. These results show that a high dose of T-MWCNTs can induce hepatic toxicity in mice while O-MWCNTs seem to have less toxicity.

  3. The hepatotoxicity of multi-walled carbon nanotubes in mice

    Science.gov (United States)

    Ji, Zongfei; Zhang, Danying; Li, Ling; Shen, Xizhong; Deng, Xiaoyong; Dong, Ling; Wu, Minhong; Liu, Yuanfang

    2009-11-01

    The hepatotoxicity of two types of multi-walled carbon nanotubes (MWCNTs), acid-oxidized MWCNTs (O-MWCNTs) and Tween-80-dispersed MWCNTs (T-MWCNTs), were investigated with Kunming mice exposed to 10 and 60 mg kg-1 by intravenous injection for 15 and 60 d. Compared with the PBS group, the body-weight gain of the mice decreased and the level of total bilirubin and aspartate aminotransferase increased in the MWCNT-exposed group with a significant dose-effect relationship, while tumor necrosis factor alpha level did not show significant statistical change within 60 d. Spotty necrosis, inflammatory cell infiltration in portal region, hepatocyte mitochondria swelling and lysis were observed with a significant dose-effect relationship in the MWCNT groups. Liver damage of the T-MWCNT group was more severe than that of the O-MWCNT group according to the Roenigk classification system. Furthermore, T-MWCNTs induce slight liver oxidative damage in mice at 15 d, which was recovered at 60 d. Part of the gene expressions of mouse liver in the MWCNT groups changed compared to the PBS group, including GPCRs (G protein-coupled receptors), cholesterol biosynthesis, metabolism by cytochrome P450, natural-killer-cell-mediated cytotoxicity, TNF- α, NF-κB signaling pathway, etc. In the P450 pathway, the gene expressions of Gsta2 (down-regulated), Cyp2B19 (up-regulated) and Cyp2C50 (down-regulated) had significant changes in the MWCNT groups. These results show that a high dose of T-MWCNTs can induce hepatic toxicity in mice while O-MWCNTs seem to have less toxicity.

  4. Comprehensive characterization of serum clinical chemistry parameters and the identification of urinary superoxide dismutase in a carbon tetrachloride-induced model of hepatic fibrosis in the female Hanover Wistar rat.

    Science.gov (United States)

    Smyth, Rosemary; Munday, Michael R; York, Malcolm J; Clarke, Christopher J; Dare, Theo; Turton, John A

    2007-10-01

    Carbon tetrachloride (CCl(4)) was used to induce liver fibrosis in the rat. Using this model, we have identified changes in serum and urinary clinical chemistry parameters, and characterized histopathological lesions in the liver. Two experiments were conducted. In Experiment 1, rats were dosed at six levels of CCl(4) (0.06-0.36 ml/kg) twice weekly for 6 weeks, followed by a 6-week non-dosing recovery period (week 12). Livers were removed for histology at 6 and 12 weeks and serum parameters analysed. In Experiment 2, rats were given seven dose levels of CCl(4) (0.4-1.0 ml/kg) twice weekly for 6 weeks, followed by a 6-week recovery period (week 12); urine samples were analysed at 3, 6, 9 and 12 weeks using one-dimensional sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Liver fibrosis was evident at 6 weeks in Experiments 1 and 2, and the activity of serum enzymes (including alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase) was increased. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis (Experiment 2) revealed a protein band at 18.4 kDa in urine from rats treated with CCl(4), not present in control urine, which was identified as copper/zinc superoxide dismutase (Cu/Zn SOD). Western blotting revealed that SOD was increased in urine from rats treated with CCl(4) at 3 and 6 weeks, but not at 9 and 12 weeks. We conclude that Cu/Zn SOD is a urinary marker of hepatic necrosis, but not hepatic fibrosis.

  5. Effect of Mallotus Philippensis Muell.-Arg leaves against hepatotoxicity of Carbon tetrachloride in rats

    OpenAIRE

    Ramakrishna S; Geetha K.M,; Bhaskar gopal P.V.V.S,; Ranjit kumar P; Charan Madav. P,; Umachandar. L

    2011-01-01

    Liver Toxicity is a major health problem of worldwide proportions. Herbal medicines derived from plant extracts are being increasingly utilized to treat a wide variety of clinical diseases. In the present study MEMP leaves is used to screen the hepatoprotective activity. Hepatotoxicity was induced in experimental animals by administration of carbon tetra chloride (CCl4) (25ml/kg, i.p.). Silymarin (25 mg/kg, p.o.) was used as the standard. Functional parameters like onset of sleep and duration...

  6. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat

    OpenAIRE

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate ...

  7. Sida rhombifolia ssp. retusa seed extract inhibits DEN induced murine hepatic preneoplasia and carbon tetrachloride hepatotoxicity.

    Science.gov (United States)

    Poojari, Radhika; Gupta, Sanjay; Maru, Girish; Khade, Bharat; Bhagwat, Sanjay

    2009-01-01

    Sida rhombifolia ssp. retusa is a well established drug in the Ayurvedic system of medicine used for antirheumatism and antiasthmatism. Inhibitory effects of S. rhombifolia ssp. retusa seed extract on DEN induced hepatocellular preneoplastic foci and carbon tetrachloride (CCl4) induced hepatotoxicity was investigated in rats. Rats received DEN, 1ppm/g b.w. in drinking water for 6 weeks or CCl(4), 0.7 ml/kg i.p. once a week for 4 weeks and seed extract 50 mg, 100 mg/kg b.w. orally prior, during and after exposure to DEN/CCl4 for 20 or 5 weeks, respectively. Treatment with seed extract significantly inhibited the increase in DEN/CCl(4) induced activities of pre-cancerous marker enzymes; gamma-glutamyl transpeptidase, glutathione-S-transferase, hepatotoxicity marker enzymes; glutamate pyruvate transaminase, glutamate oxaloacetate transaminase and alkaline phosphatase as well as lipid peroxidase. Depleted glutathione, protein and albumin levels were restored. Also, histopathological and transmission electron microscopic studies showed prevention of cellular degenerative changes. The chemopreventive and hepatoprotective potentials of seed extract are due to free radical scavenging activity and restoration of cellular structural integrity.

  8. Effect of Mallotus Philippensis Muell.-Arg leaves against hepatotoxicity of Carbon tetrachloride in rats

    Directory of Open Access Journals (Sweden)

    Ramakrishna.S,

    2011-02-01

    Full Text Available Liver Toxicity is a major health problem of worldwide proportions. Herbal medicines derived from plant extracts are being increasingly utilized to treat a wide variety of clinical diseases. In the present study MEMP leaves is used to screen the hepatoprotective activity. Hepatotoxicity was induced in experimental animals by administration of carbon tetra chloride (CCl4 (25ml/kg, i.p.. Silymarin (25 mg/kg, p.o. was used as the standard. Functional parameters like onset of sleep and duration of sleep, Biochemical Parameters like serum glutamic oxaloacetic transaminase (SGOT, serum glutamic pyruvic transaminase (SGPT, serum alkaline phosphatase (SALP, total bilirubin and direct bilirubin were measured. Cytotoxicity of CCl4 was estimated by quantitating the release of malondialdehyde (MDA. The activity of tissue antioxidant enzymes namely super oxide dismutase (SOD, catalase (CAT, and the level of total protein (TP were also measured. Histopathological evaluation of liver sections was also done. CCl4 administration in rats elevated the levels of SGPT, SGOT, SALP and bilirubin. Administration of MEMP significantly (P<0.001 prevented this increase. The activity of anti-oxidant enzymes in carbon tetrachloride (CCl4 group was decreased and these enzyme levels were significantly (p<0.001 increased in Mallotus philippensis leaves groups. Histopathological studies revealed that the concurrent administration of MEMP with CCl4 exhibited protection of liver tissue, which further evidenced the above results. Thestudy confirmed the hepatoprotective activity of MEMP, which may be attributed to its antioxidant property.

  9. Hepatoprotective activity of LIV-first against carbon tetra chloride-induced hepatotoxicity in albino rats

    Directory of Open Access Journals (Sweden)

    Lima T

    2010-01-01

    Full Text Available Liver toxicity is a major health problem of worldwide proportions. Herbal medicines derived from plant extracts are being increasingly utilized to treat a wide variety of clinical diseases. In the present study, LIV-first (16.3 mg/kg, p.o. was used to screen the hepatoprotective activity. Hepatotoxicity was induced in experimental animals by administration of carbon tetrachloride (CCl 4 (1 ml/kg, i.p. Silymarin (25 mg/kg,p.o. was used as the standard. Biochemical parameters like serum glutamate oxaloacetate transaminase (SGOT, serum glutamate pyruvate transaminase (SGPT, alkaline phosphatase (ALP and serum bilirubin were measured. Cytotoxicity of CCl 4 was estimated by quantitating the release of malondialdehyde. The activity of tissue antioxidant enzymes namely superoxide dismutase, catalase and the level of total protein and glutathione were also measured. Histopathological evaluation of liver sections was also done. CCl 4 administration in rats elevated the levels of SGPT, SGOT, ALP and bilirubin. Administration of LIV-first significantly ( P< 0.01 prevented this increase. The activity of anti-oxidant enzymes in carbon tetrachloride CCl 4 -treated group was decreased and these enzyme levels were significantly ( P< 0.05 increased in LIV-first-treated groups. Histopathological studies revealed that the concurrent administration of CCl 4 with the extract exhibited protection of the liver tissue, which further evidenced the above results. The study confirmed the hepatoprotective activity of LIV-first, which may be attributed to its antioxidant property.

  10. Prophylactic effect of four prescriptions of traditional Chinese medicine on α-naphthylisothiocyanate and carbon tetrachloride induced toxicity in rats%中医四方剂对异硫氰酸α-萘酯及四氯化碳诱发的大鼠肝损伤的预防作用

    Institute of Scientific and Technical Information of China (English)

    林国瑞; 陈荣洲; 曹伟; 林俊清; 林昭庚; 蔡金川

    2001-01-01

    目的:探讨四种中医方剂对实验性肝损伤的作用.方法:事先给予四磨饮(SMY)、桂枝茯苓丸(GFW)、泻青丸(XQW)及四逆散(SNS)的水提取物,对异硫氰酸α-萘酯(ANIT)、四氯化碳(CCl4)诱发的肝损伤,进行预防保肝评估,包括生化指标、肝组织脂质过氧化及组织病理.结果:大鼠给予ANIT后,总胆红素(TBI)、碱性磷酸酶(ALP)、谷草转氨酶(GOT)、谷丙转氨酶(GPT)皆有明显升高,组织病理显示胆道郁阻及局部坏死.四磨饮、泻青丸及四逆散在生化指标及病理观察上皆有显著的预防效果.在四氯化碳诱发的肝损伤实验中,四方剂对肝功能生化指标与肝组织脂质过氧化及病理变化等,皆显示出预防效果.结论:虽然异硫氰酸α-萘酯、四氯化碳的肝损伤机制不同,但此四方都有不同程度的保肝作用,且其作用是由多重机制来完成的.方剂处方均由君臣佐使的配合来设计,显示对不同毒物的多重保护作用.%AIM: To study the prophylactic effects of four Chinese traditional prescriptions against experimental liver injury. METHODS: Liver toxins, a-naphthylisothiocyanate (ANIT), and carbon tetrachloride (CCl4) were used to induce acute liver injury. Simo Yin (SMY), Guizhi Fuling Wan (GFW), Xieqing Wan (XQW), and Sini San (SNS) were fed (500 mg/kg, in saline, po ) to the rats before toxin administration. All the animals were killed 48 h after toxin insulted. Serum index of liver function and hepatic lipid peroxidation (LPO) were estimated. Histopathological observation was conducted simultaneously. RESULTS: The rars treated with ANIT exhibited elevations of serum total bilirubin (TBI),alkaline phosphatase ( ALP ), glutamate-oxalatetransaminase ( GOT ), glutamate-pyruvate-transaminase (GPT), as well as cholestasis and parenchyma necrosis. In rats, challenged with ANIT, receiving the pretreatment of prescriptions of SMY, XQW, and SNS, the biochemical and morphological parameters of liver injury

  11. In vitro and in vivo hepatoprotective and antioxidant effects of sily-marin against carbon tetrachloride-induced hepatocyte damage in crucian carp Carassius auratus%水飞蓟素对四氯化碳致鲫肝(细胞)损伤的保护和抗氧化作用

    Institute of Scientific and Technical Information of China (English)

    贾睿; 曹丽萍; 杜金梁; 徐跑; 殷国俊

    2013-01-01

    We evaluated the hepatoprotective and antioxidant effects of silymarin (SM) against carbon tetrachlo-ride (CCl4)-induced hepatocyte and liver injury in crucian carp (carassius auratus) in vitro and in vivo. In vitro, 100, 300, and 600 μg/mL silymarin were added to carp primary hepatocytes before (pre-treatment), after (post-treatment), or both before and after(pre- and post-treatment) incubation of the hepatocytes with 8 mmol/L CCl4 in culture medium. We then measured lactate dehydrogenase (LDH), glutamate pyruvate transaminase (GPT), glutamate oxalate transaminase (GOT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels. In vivo, crucian carp were fed a diet containing one of three concentrations of silymarin [0.1, 0.5, or 1 g/kg (diet)] for 60 d. Each fish was then given a single intraperitoneal injection of CCl4 (30%in arachis oil), and 72 h after the injection, we collected blood and liver samples from each fish. We measured the serum biochemical indices and liver tissue indices described above. Silymarin improved cell viability and decreased GPT, GOT, LDH, MDA, and SOD activ-ity. Administration of silymarin at 0.5 and 1 g/kg diet for 60 d prior to CCl4 intoxication significantly decreased GPT, GOT, and LDH activity, increased levels of total protein and albumin in the serum, and increased SOD, glu-tathione peroxidase, catalase, glutathione, total antioxidant capacity, and MDA formation in liver tissue. However, these parameters, except for LDH, were not significantly altered in fish fed 0.1 g silymarin per kg diet. Our data suggest that silymarin exhibits a protective effect against CCl4-induced hepatotoxicity in fish, which is likely re-lated to its antioxidant activity. We suggest that silymarin may be used as a hepatoprotective agent against fish liver diseases.%  为了评价水飞蓟素(Silymarin, SM)对鲫(Cyprinus carpio)肝(细胞)的保护和抗氧化作用,分别从体外和体内两个方面探讨其作用效果。在体外,利用8

  12. Observation of the hepatoprotective and antioxidant activities of Trianthema decandra Linn. (Vallai sharunnai roots on carbon tetrachloride-treated rats

    Directory of Open Access Journals (Sweden)

    G. Balamurugan

    2008-06-01

    Full Text Available The present study was carried out to observe the hepatoprotective effect and antioxidant activity of the ethanol extract of the roots of Trianthema decandra Linn. (200 and 400 mg/kg in rats treated with carbon tetrachloride for 8 weeks. Extract at the tested doses restored the levels of all serum (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin and total protein and liver homogenate enzymes (glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase significantly. Histology demonstrated profound steatosis degeneration and nodule formation were observed in the hepatic architecture of carbon tetrachloride treated rats which were found to acquire near-normalcy in extract plus carbon tetrachloride administrated rats, and supported the biochemical observations. This study suggests that ethanol extract of T. decandra has a liver protective effect against carbon tetrachloride- induced hepatotoxicity and possess antioxidant activities.

  13. Lygodium flexuosum extract down regulates the expression of proinflammatory cytokines in CCl4 -induced hepatotoxicity

    Institute of Scientific and Technical Information of China (English)

    Pallara Janardhanan Wills; Velikkakathu Vasumathi Asha

    2012-01-01

    Objective:To examine the downregulation of proinflammatory cytokines in a time dependant manner on carbon tetrachloride induced toxicity in experimental animals.Methods:CCl4(150 μL/100 g) was dissolved in corn oil(1:1 v/v%) and administered orally.GroupI was treated as normal control and received corn oil on8th day.GroupII was toxic control and was given a single dose ofCCl4 on8th days.GroupIII wastreated withLygodium flexuosum(L. flexuosum)n-hexane extract(200 mg/kg) for8 days and on8th day a single dose ofCCl4 was received.GroupIV(negative control) receivedL. flexuosumn-hexane extract(200 mg/kg) alone for8 days.Results:Treatment withn-hexane extract prior to the administration ofCCl4 significantly prevented an increase in serumAST,ALT,LDH activity and lipid peroxidation and prevented the depletion of glutathione (GSH).Rats treated withL. flexuosum had reduced mRNA levels ofTGF-β1,TNF-α andIL-1βgenes in liver ofCCl4 intoxicated rats when compared toCCl4 control as evidenced byRT-PCR. Conclusions:The data suggest that L. flexuosum, a widely available fern, significantly reduces CCl4 induced acute hepatotoxicity by down-regulating the expression of pro-inflammatory cytokines in rats.

  14. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat.

    Science.gov (United States)

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (Psesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes.

  15. Therapeutic detoxification of quercetin against carbon tetrachloride-induced acute liver injury in mice and its mechanism%槲皮素对四氯化碳引起的小鼠急性肝损伤治疗作用及其机理

    Institute of Scientific and Technical Information of China (English)

    Jia-qi ZHANG; Liang SHI; Xi-ning XU; Si-chong HUANG; Bin LU; Li-li JI; Zheng-tao WANG

    2014-01-01

    This study observes the therapeutic detoxification of quercetin, a wel-known flavonoid, against carbon tetrachloride (CCl4) induced acute liver injuryin vivo and explores its mechanism. Quercetin decreased CCl4-increased serum activities of alanine and aspartate aminotransferases (ALT/AST) when orally taken 30 min after CCl4 intoxica-tion. The results of a histological evaluation further evidenced the ability of quercetin to protect against CCl4-induced liver injury. Quercetin decreased the CCl4-increased malondialdehyde (MDA) and reduced the glutathione (GSH) amounts in the liver. It also reduced the enhanced immunohistochemical staining of the 4-hydroxynonenal (4-HNE) in the liver induced by CCl4. Peroxiredoxin (Prx) 1, 2, 3, 5, 6, thioredoxin reductase 1 and 2 (TrxR1/2), thioredoxin 1 and 2 (Trx1/2), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) al play critical roles in maintaining celular redox homeostasis. Real-time polymerase chain reaction (PCR) results demonstrated that quercetin reversed the decreased mRNA expression of al those genes induced by CCl4. In conclusion, our results demonstrate that quercetin ameliorates CCl4-induced acute liver injuryin vivo via aleviating oxidative stress injuries when oraly taken after CCl4 intoxication. This protection may be caused by the elevation of the antioxidant capacity induced by quercetin.

  16. Potentiation of carbon tetrachloride hepatotoxicity and lethality in type 2 diabetic rats.

    Science.gov (United States)

    Sawant, Sharmilee P; Dnyanmote, Ankur V; Shankar, Kartik; Limaye, Pallavi B; Latendresse, John R; Mehendale, Harihara M

    2004-02-01

    There is a need for well characterized and economical type 2 diabetic model that mimics the human disease. We have developed a type 2 diabetes rat model that closely resembles the diabetic patients and takes only 24 days to develop robust diabetes. Nonlethal doses of allyl alcohol (35 mg/kg i.p.), CCl(4) (2 ml/kg i.p.), or thioacetamide (300 mg/kg i.p.) yielded 80 to 100% mortality in diabetic rats. The objective of the present study was to investigate two hypotheses: higher CCl(4) bioactivation and/or inhibited compensatory tissue repair were the underlying mechanisms for increased CCl(4) hepatotoxicity in diabetic rats. Diabetes was induced by feeding high fat diet followed by a single dose of streptozotocin on day 14 (45 mg/kg i.p.) and was confirmed on day 24 by hyperglycemia, normoinsulinemia, and oral glucose intolerance. Time course studies (0-96 h) of CCl(4) (2 ml/kg i.p.) indicated that although initial liver injury was the same in nondiabetic and diabetic rats, it progressed only in the latter, culminating in hepatic failure, and death. Hepatomicrosomal CYP2E1 protein and activity, lipid peroxidation, glutathione, and (14)CCl(4) covalent binding to liver tissue were the same in both groups, suggesting that higher bioactivation-based injury is not the mechanism. Inhibited tissue repair resulted in progression of injury and death in diabetic rats, whereas in the nondiabetic rats robust tissue repair resulted in regression of injury and survival after CCl(4) administration. These studies show high sensitivity of type 2 diabetes to model hepatotoxicants and suggest that CCl(4) hepatotoxicity is potentiated due to inhibited tissue repair.

  17. Genetically graded activation of Nrf2 protects mice against carbon tetrachloride-induced hepatotoxicity%Nrf2抗氧化损伤通路在CCl4所致小鼠肝毒性中的保护作用

    Institute of Scientific and Technical Information of China (English)

    陆远富; Connie Wu; 刘杰; Curtis Dean Klaassen

    2015-01-01

    目的 观察核转录相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)抗氧化损伤通路对四氯化碳(CCl4)所致小鼠肝毒性的保护作用.方法 选取Nrt2-null、Wild-type、Keap1-KD、Keapl-HKO小鼠,按基因型分为4组,分别给予40 mg/kg CCl4腹腔注射,腹腔注射生理盐水(10 mL/kg)作对照,16 h后收集血浆和肝组织样本,检测血中谷丙转氨酶(alanine transaminase,ALT)和乳酸脱氢酶(lactic dehydrogenase,LDH)活性以及肝组织中丙二醛(malondialdehyde,MDA)含量;HE染色观察肝组织病理学变化,Real-time PCR和Western blot法检测相关基因表达.结果 CCl4增加Nrf2-null组和Wild-type组血中ALT、LDH活性及肝组织MDA含量,同时造成肝组织病理损伤,而在Keap1-KD组和Keap1-HKO组影响不明显;Nrf2因子靶基因(Nqo1和Gclc)在CCl4的诱导表达逐渐增高(顺序为Nrf2-null、Wild-type、Keapl-KD、Keap1-HKO),继而使炎症因子、内质网应激基因、细胞凋亡基因、细胞坏死基因的表达(mKC、MIP-2、IL-1β、TNFα、Gadd45、Chop10、Bax、Caspase3、Mcl、Noxa)按Nrf2-null、Wild-type、Keap1-KD、Keap1-HKO顺序逐渐下降.结论 Nrf2因子激活保护CCl4所致小鼠肝损伤反应.

  18. Toll-Like Receptor 3 Gene Deficiency Aggravates Carbon Tetrachloride-Induced Liver Fibrosis in Mice%Toll样受体3基因缺陷促进四氯化碳诱导的小鼠肝纤维化损伤

    Institute of Scientific and Technical Information of China (English)

    薛如意; 张丹瑛; 吴昊; 刘韬韬; 董玲; 沈锡中

    2016-01-01

    使肝组织中炎性因子 TNF‐α、IL‐6和 MCP‐1以及促纤维化分子TGF‐β、TIMP1和PDGFR表达升高。结论:TLR3基因缺陷可促进四氯化碳诱导的肝纤维化小鼠肝组织中的胶原沉积和肝星状细胞激活,促进肝组织炎性因子释放,使肝促纤维化分子上调。以上提示,T L R3是肝纤维化病理过程中的一个保护性基因。%Objective:To investigate the effect of Toll‐like receptor 3(TLR3) gene deficiency on the degree of liver fibrosis in mouse model of carbon tetrachloride(CCl4 )‐induced liver fibrosis .Methods :A total of 20 wild‐type male mice and 20 male mice with TLR3 gene deficiency (TLR3‐/‐) were divided into wild‐type control group and wild‐type model group ,TLR3‐/‐ control group and TLR3‐/‐ model group ,respectively ,with 10 mice in each group .The control group was injected with corn‐oil by intraperitoneal injection while the model group was injected with CCl4 by intraperitoneal injection .After 8 weeks ,blood sample wascollectedandserumlevelofalanineaminotransferase(ALT),aspartatetransaminase(AST),totalbilirubin(TBIL),and albumin(Alb) was analyzed by automatic biochemical analyzer .And the degree of collagen deposition in liver tissue was evaluated by Masson trichrome staining .And the activation of hepatic stellate cells was detected by immunohistochemistry staining of α‐smooth muscle actin(α‐SMA).And hydroxyproline content of liver tissue was detected with detection kit . Furthermore ,real‐time fluorescence polymerase chain reaction was used to detect the expression of liver fibrotic marker type I collagen ,and inflammatory cytokines including tumor necrosis factor‐alpha (TNF‐α) , interleukin‐6 (IL‐6 ) and monocyte chemotactic protein‐1(MCP‐1) ,as well as pro‐fibrotic molecule including transforming growth factor‐beta (TGF‐β) ,tissue inhibitor of metalloproteinase 1(TIMP1) and platelet‐derived growth factor receptor(PDGFR) .Results:TLR3 gene deficiency had no

  19. Modulatory effect of Mangifera indica against carbon tetrachloride induced kidney damage in rats.

    Science.gov (United States)

    Awodele, Olufunsho; Adeneye, Adejuwon Adewale; Aiyeola, Sheriff Aboyade; Benebo, Adokiye Senibo

    2015-12-01

    There is little scientific evidence on the local use of Mangifera indica in kidney diseases. This study investigated the reno-modulatory roles of the aqueous stem bark extract of Mangifera indica (MIASE) against CCl4-induced renal damage. Rats were treated intragastrically with 125, 250 and 500 mg/kg/day MIASE for 7 days before and after the administration of CCl4 (3 ml/kg of 30% CCl4, i.p.). Serum levels of electrolytes (Na+, K+, Cl(-), HCO3(-)), urea and creatinine were determined. Renal tissue reduced glutathione (GSH), malondialdehyde (MDA), catalase (CAT), superoxide (SOD) activities were also assessed. The histopathological changes in kidneys were determined using standard methods. In CCl4 treated rats the results showed significant (pMangifera indica may present a great prospect for drug development in the management of kidney disease with lipid peroxidation as its etiology.

  20. Hepatoprotective activity of Haridradi ghrita on carbon tetrachloride-induced liver damage in rats.

    Science.gov (United States)

    Satturwar, P M; Fulzele, S V; Joshi, S B; Dorle, A K

    2003-12-01

    Haridradi ghrita, a ghee based polyherbal formulation, (50, 100, 200 and 300 mg/kg) significantly lowered marker enzymes (SGPT, SGOT, ALP) and bilirubin in serum and liver peroxide, superoxide dismutase and catalase in liver homogenate following CCl4 (0.7 ml/kg, ip) toxicity. The protective effect was further supported by reversal of CCl4 induced histological changes. The results demonstrate significant hepatoprotective action of H. ghrita in CCl4 damaged rats.

  1. Campomanesia adamantium (Myrtaceae fruits protect HEPG2 cells against carbon tetrachloride-induced toxicity

    Directory of Open Access Journals (Sweden)

    Thaís de Oliveira Fernandes

    2015-01-01

    Full Text Available Campomanesia adamantium (Myrtaceae is an antioxidant compounds-rich Brazilian fruit popularly known as gabiroba. In view of this, it was evaluated the hepatoprotective effects of pulp (GPE or peel/seed (GPSE hydroalcoholic extracts of gabiroba on injured liver-derived HepG2 cells by CCl4 (4 mM. The results showed the presence of total phenolic in GPSE was (60% higher when compared to GPE, associated with interesting antioxidant activity using DPPH·− assay. Additionally, HPLC chromatograms and thin layer chromatography of GPE and GPSE showed the presence of flavonoids. Pretreatment of HepG2 cells with GPE or GPSE (both at 800–1000 μg/mL significantly (p < 0.0001 protected against cytotoxicity induced by CCl4. Additionally, the cells treated with both extracts (both at 1000 μg/mL showed normal morphology (general and nuclear contrasting with apoptotic characteristics in the cells only exposed to CCl4. In these experiments, GPSE also was more effective than GPE. In addition, CCl4 induced a marked increase in AST (p < 0.05 and ALT (p < 0.0001 levels, while GPE or GPSE significantly (p < 0.0001 reduced these levels, reaching values found in the control group. In conclusion, the results suggest that gabiroba fruits exert hepatoprotective effects on HepG2 cells against the CCl4-induced toxicity, probably, at least in part, associated with the presence of antioxidant compounds, especially flavonoids.

  2. Long-term treatment with shengmai san-derived herbal supplement (Wei Kang Su) enhances antioxidant response in various tissues of rats with protection against carbon tetrachloride hepatotoxicity.

    Science.gov (United States)

    Leong, Pou Kuan; Chen, Na; Chiu, Po Yee; Leung, Hoi Yan; Ma, Chung Wah; Tang, Qing Tao; Ko, Kam Ming

    2010-04-01

    Wei Kang Su (WKS) is a commercial herbal product based on a Chinese herbal formula, Shengmai San. Here, we investigated the effects of long-term treatment with WKS on mitochondrial antioxidant status and functional ability, as well as heat shock protein (Hsp) 25/70 production, in various tissues of rats. WKS treatment enhanced mitochondrial antioxidant status and ATP generation capacity, as well as Hsp 25/70 production in various rat tissues. WKS treatment suppressed plasma reactive oxygen metabolite levels and protected against carbon tetrachloride hepatotoxicity in rats. Long-term WKS treatment may prevent diseases by enhancing the resistance of mitochondria to oxidative stress.

  3. Long-term hepatotoxicity of polyethylene-glycol functionalized multi-walled carbon nanotubes in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Danying; Ji Zongfei; Shen Xizhong; Dong Ling; Gu Taoying [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032 (China); Deng Xiaoyong; Wu Minghong; Liu Yuanfang, E-mail: dltalk@tom.com, E-mail: mhwu@staff.shu.edu.cn [Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai 200444 (China)

    2010-04-30

    The toxicity of polyethylene-glycol functionalized (PEGylated) multi-walled carbon nanotubes (MWCNTs) and non-PEGylated MWCNTs in vivo was evaluated and compared. Mice were exposed to MWCNTs by intravenous injection. The activity level of glutathione, superoxide dismutase and gene expression in liver, as well as some biochemical parameters and the tumor necrosis factor alpha level in blood were measured over 2 months. The pathological and electron micrographic observations of liver evidently indicate that the damage caused by non-PEGylated MWCNTs is slightly more severe than that of PEGylated MWCNTs, which means that PEGylation can partly, but not substantially, improve the in vivo biocompatibility of MWCNTs.

  4. Multi walled carbon nano tubes induced hepatotoxicity in Swiss albino mice.

    Science.gov (United States)

    Awasthi, Kumud Kant; John, P J; Awasthi, Anjali; Awasthi, Kamlendra

    2013-01-01

    In the present study, multi walled carbon nano tubes (MWCNTs) were synthesized using chemical vapour deposition (CVD) technique. Swiss albino mice were orally administered with single dose of 60 and 100 mg/kg body weight of purified and functionalized MWCNTs suspended in water. The mice were autopsied on 7, 14, 21 and 28 days post exposure. Liver was taken out and part of it fixed in Bouin's solution for histopathological examinations. The remaining part was immersed in cold saline, blotted dry, weighed quickly and homogenized in ice cold buffer. The activity of superoxide dismutase (SOD) and catalase (CAT) was immediately measured in the supernatant. The MWCNTs in liver led to pathological changes, including injury to macrophages, cellular swelling, unspecific inflammation, spot necrosis and blood coagulation. Estimation of SOD and CAT showed altered levels in the experimental groups as compared to controls. Therefore, MWCNTs from manufactured and combustion sources in the environment can have adverse effects on human health.

  5. Hepatoprotective activity of the methanolic extract of Fagonia indica Burm in carbon tetra chloride induced hepatotoxicity in albino rats

    Institute of Scientific and Technical Information of China (English)

    I.M. Bagban; S.P. Roy; A.Chaudhary; S. K. Das; K.J. Gohil; K.K. Bhandari

    2012-01-01

    Objective: To investigate hepatoprotective activity of the methanolic extract of Fagonia indica Burm. on CCl4 induced hepatotoxicity in albino rats. Methods: Animals in Group 1 served as vehicle control, Group 2 served as hepatotoxin (CCl4 2ml/kg, s.c) treated group, Group 3 served as standard (Silymarin 50mg/kg, p.o.) treated group. Group4 and 5 served as methanolic extract of Fagonia indica (MEFI) in different doses (200 mg/kg and 400 mg/kg b.w., p.o).The degree of protection was determined by measuring levels of biochemical marker like SGOT, SGPT, ALP, Bilirubin (Total & Direct) and Cholesterol. The histopathological studies also show the hepatic protection of the test extracts. Results: The levels of the biochemical parameters such as SGPT, SGOT, ALP, Total bilirubin, Direct bilirubin and Cholesterol were significantly increased in CCl4 treated rats when compared with the normal group (P<0.05), but the MEFI (400 mg/kg, bw) treated rats showed maximum reduction of SGOT (114.83±1.51), SGPT (164.33±1.25), ALP (154.83±1.53), Total bilirubin (1.55±0.01), Direct bilirubin (0.65±0.009) and Cholesterol (193.00±1.06) in a significant manner. Histopathological studies also reveal the hepatoprotection property of MEFI in a dose dependent manner. Conclusions: These results suggest that MEFI in different doses showed significant hepatoprotective activity against CCl4 induced hepatotoxicity and this might be due to the presence of flavonoids and tannins. Further research is sought to explore the exact mechanism of action and phytoconstituents responsible for the pharmacological response.

  6. Protective role of Cupressuflavone from Cupressus macrocarpa against carbon tetrachloride-induced hepato- and nephrotoxicity in mice.

    Science.gov (United States)

    Al-Sayed, Eman; Abdel-Daim, Mohamed M

    2014-12-01

    The hepatoprotective and nephroprotective activity of cupressuflavone isolated from Cupressus macrocarpa was investigated against CCl4-induced toxicity in mice. Cupressuflavone was administered (40, 80, and 160 mg/kg/day) for five days. CCl4 was administered (0.5 mL/kg intraperitoneally) at the end of the experiment. A substantial increase (p < 0.001) in the levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, total bilirubin, cholesterol, creatinine, uric acid, urea, and malondialdehyde was observed in the CCl4-treated group compared to the normal control group. In contrast, a significant reduction (p < 0.001) in glutathione and superoxide dismutase contents as well as the total protein level was evident in the CCl4-intoxicated mice. Cupressuflavone pretreatment markedly inhibited the CCl4-induced increase in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, cholesterol, creatinine, uric acid, urea, and malondialdehyde levels in a dose-dependent manner (p < 0.001 at all the tested doses). In addition, a significant (p < 0.001) and dose-dependent decrease in the total bilirubin levels was evident by cupressuflavone pretreatment (80 and 160 mg/kg/day) when compared to the CCl4-intoxicated group. Furthermore, cupressuflavone administration significantly increased the activity of antioxidant parameters glutathione and superoxide dismutase as well as the serum protein levels (p < 0.001 at all the tested doses) in a dose-dependent manner. Histological observations confirmed the strong hepato- and nephroprotective activity. These findings suggest that cupressuflavone could exert a beneficial effect against oxidative stress by enhancing the antioxidant defense status, reducing lipid peroxidation, and protecting against the pathological changes induced by CCl4 in the liver and kidney tissues. The structure of cupressuflavone was identified by NMR, UV, and HRESI-MS/MS spectral data.

  7. Studies of single-walled carbon nanotubes-induced hepatotoxicity by NMR-based metabonomics of rat blood plasma and liver extracts

    Science.gov (United States)

    Lin, Bencheng; Zhang, Huashan; Lin, Zhiqing; Fang, Yanjun; Tian, Lei; Yang, Honglian; Yan, Jun; Liu, Huanliang; Zhang, Wei; Xi, Zhuge

    2013-05-01

    The toxicological effects of single-walled carbon nanotubes (SWCNTs) were investigated after intratracheal instillation in male Wistar rats over a 15-day period using metabonomic analysis of 1H (nuclear magnetic resonance) NMR spectra of blood plasma and liver tissue extracts. Concurrent liver histopathology examinations and plasma clinical chemistry analyses were also performed. Significant changes were observed in clinical chemistry features, including alkaline phosphatase, total protein, and total cholesterol, and in liver pathology, suggesting that SWCNTs clearly have hepatotoxicity in the rat. 1H NMR spectra and pattern recognition analyses from nanomaterial-treated rats showed remarkable differences in the excretion of lactate, trimethylamine oxide, bilineurin, phosphocholine, amylaceum, and glycogen. Indications of amino acid metabolism impairment were supported by increased lactate concentrations and decreased alanine concentrations in plasma. The rise in plasma and liver tissue extract concentrations of choline and phosphocholine, together with decreased lipids and lipoproteins, after SWCNTs treatment indicated a disruption of membrane fluidity caused by lipid peroxidation. Energy, amino acid, and fat metabolism appeared to be affected by SWCNTs exposure. Clinical chemistry and metabonomic approaches clearly indicated liver injury, which might have been associated with an indirect mechanism involving nanomaterial-induced oxidative stress.

  8. Evaluation of silymarin and / or ginger effect on induced hepatotoxicity by carbon tetrachloride in male albino rats

    Directory of Open Access Journals (Sweden)

    Hassan H. A.* and EL-Gendy A. M

    2003-09-01

    Full Text Available Liver disease appears to be increase. Part of this increase may be due to our frequent contact with chemicals and other environmental pollutants. The amount of medicne consumed has increased greatly which could be danger to the liver. The hepatoprotective flavonoid, silymarin (7.56 mg/Kg b. wt. and ginger (Zingiber officinale (1% of diet for 4 weeks were used to ameliorate the liver injury in rats intoxicated with carbon tetrachloride (CCL4 , single acute dose 4 ml/ Kg b. wt. of 50% v/v CCL4 in olive oil, subcutaneous. The obtained results showed that CCL4 decreased serum and liver total protein and albumin. Also reduced glutathione content. The antioxidant enzymes; glutathione-S-transferase, superoxide dismutase and catalase activity decreased in the liver of CCL4 toxicity group. On the other hand, CCL4 toxicity increased serum and liver bilirubin, total lipid and total cholestertol levels. In addition, liver function (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase and liver lipid peroxidation content showed significant increase in the CCL4 treated group. Previous parameters turned back to normal values in carbon tetrachloride intoxicated rats after treating with silymarin and/ or ginger for one month. Meanwhile, the most interesting effect was induced by a combination of silymarin and ginger. Hence, the present findings will provide a potential scope for future use of ginger for the treatment of liver disorders.

  9. In vivo antioxidant and hepatoprotective potential of Glycyrrhiza glabra extract on carbon tetra chloride (CCl4 induced oxidative-stress mediated hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Varsha Sharma

    2014-02-01

    Results: The results suggest that, the crude extract of root of G. glabra at the doses of 300 and 600mg/kg body wt. expressed significant hepatoprotective potential against CCl4 induced oxidative stress mediated hepatotoxicity in student ‘t’ test (p [Int J Res Med Sci 2014; 2(1.000: 314-320

  10. Ameliorative and antidyslipidemic potentials of aqueous leaf extract of Gongronema latifolium in CCl4 carbon tetrachloride-induced oxidative stress rats

    Directory of Open Access Journals (Sweden)

    Asiat Na’Allah

    2016-10-01

    Full Text Available Objective: To investigate the effect of leaf aqueous extract from Gongronema latifolium (G. latifolium on CCl4 induced-oxidative stress in Wistar rat. This effect was assessed by measuring liver marker enzymes activity, analyzing the antioxidant parameters, lipid profile estimation and lipid peroxidation by-product following CCl4 induced-oxidative stress. Methods: Milled G. latifolium leaves were subjected to aqueous extraction and the filtrate was evaporated between 40–60 °C under reduced pressure and a calculated volume of the leaf extract was administered at a dose of 500 mg/kg body weight. Thirty-five rats were grouped into seven groups of 5 animals each namely; control and experimental groups. The experimental groups were treated with 2.0 mL/kg body weight CCl4, 25 mg/kg body weight/ day silymarin (a standard hepatoprotective antioxidant, 500 mg/kg body weight aqueous extract of G. latifolium leaves were administered to the CCl4 treated rats for 21 days. Results: Administration of the extract and silymarin increase significantly (P < 0.05 in liver marker enzyme (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase activities in serum, liver and kidney in the treated groups when compared with untreated groups. The antioxidant parameters (catalase, peroxidase and glutathione S-transferase were significantly elevated (P < 0.05 in animals treated with the extract and silymarin in comparison with untreated groups. CCl4 induced oxidative stress mediated variations in total cholesterol, triacylglycerides, high-density lipoprotein cholesterol, low density lipoprotein cholesterol and very low-density lipoprotein cholesterol were restored significantly (P < 0.05 by the extract. Conclusions: The result obtained from this study indicated the antioxidant and antidyslipidemic potentials of the aqueous extract of G. latifolium leaves.

  11. Enrichment and purification of total flavonoids from Cortex Juglandis Mandshuricae extracts and their suppressive effect on carbon tetrachloride-induced hepatic injury in Mice.

    Science.gov (United States)

    Zhao, Pan; Qi, Chao; Wang, Gang; Dai, Xinpeng; Hou, Xiaohong

    2015-12-15

    In the present work, a simple and efficient chromatographic separation method was developed for preparative separation and enrichment of total flavonoids (TFs) from Cortex Juglandis Mandshuricae (CJM) extracts and then the protective effect of TFs against CCl4-induced acute liver injury in mice was investigated. Enrichment and purification of TFs from CJM extracts were studied using six macroporous resins and HPD-750 resin was selected as the best resin according to its adsorption and desorption properties. The operating parameters of resin column chromatography were optimized. Under the optimal conditions, TFs from CJM with purity larger than 50% were produced and their antioxidant activity was further evaluated in vitro. The mice were orally administrated with the purified TFs for seven days and then given CCl4 (0.3%, 10mL/kg i.p.). The results showed that TFs of CJM significantly attenuated the activities of serum aspartate transaminase (AST) and alanine transaminase (ALT) compared with model group, as well as the relative liver weight. Histopathological observation also revealed that TFs reduced the incidence of liver lesions and improved hepatocyte abnormality. Moreover, oral administration of TFs significantly enhanced antioxidant enzyme activities (superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)) and decreased the content of malondialdehyde (MDA). Histopathological and biochemical results elicited that TFs of CJM had significant hepatoprotective activity comparable to the standard silymarin. This is the first time to reveal the protective actions of the TFs from CJM against CCl4-induced liver damage in mice and this natural product should be developed as a new drug for treatment of live injury in future.

  12. Ameliorative and antidyslipidemic potentials of aqueous leaf extract ofGongronema latifoliumin CCl4 carbon tetrachloride-induced oxidative stress rats

    Institute of Scientific and Technical Information of China (English)

    Asiat NaAllah; Aliu Babajide Sanusi; Hamdala AjokeOwoniyi; Abdulhakeem Olarewaju Sulyman; Jubril Olayinka Akolade

    2016-01-01

    Objective:To investigate the effect of leaf aqueous extract fromGongronema latifolium (G. latifolium) on CCl4 induced-oxidative stress in Wistar rat. This effect was assessed by measuring liver marker enzymes activity, analyzing the antioxidant parameters, lipid profile estimation and lipid peroxidation by-product following CCl4 induced-oxidative stress. Methods: MilledG. latifolium leaves were subjected to aqueous extraction and the filtrate was evaporated between 40–60°C under reduced pressure and a calculated volume of the leaf extract was administered at a dose of 500 mg/kg body weight. Thirty-five rats were grouped into seven groups of 5 animals each namely; control and experimental groups. The experimental groups were treated with 2.0 mL/kg body weight CCl4, 25 mg/kg body weight/day silymarin (a standard hepatoprotective antioxidant), 500 mg/kg body weight aqueous extract ofG. latifolium leaves were administered to the CCl4 treated rats for 21 days. Results: Administration of the extract and silymarin increase significantly (P < 0.05) in liver marker enzyme (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase) activities in serum, liver and kidney in the treated groups when compared with untreated groups. The antioxidant parameters (catalase, peroxidase and glutathioneS-transferase) were significantly elevated (P < 0.05) in animals treated with the extract and silymarin in comparison with untreated groups. CCl4 induced oxidative stress mediated variations in total cholesterol, triacylglycerides, high-density lipoprotein cholesterol, low density lipoprotein cholesterol and very low-density lipoprotein cholesterol were restored significantly (P < 0.05) by the extract. Conclusions: The result obtained from this study indicated the antioxidant and antidyslipidemic potentials of the aqueous extract ofG. latifolium leaves.

  13. Herbal and dietary supplement hepatotoxicity.

    Science.gov (United States)

    Navarro, Victor J

    2009-11-01

    Herbal and dietary supplements (HDS) are commonly used in the United States and throughout the world. The Dietary Supplement Health and Education Act and public standards set through the U.S. Pharmacopeia provide regulatory framework for these products. These regulations help to ensure the safety of grandfathered and new HDS coming onto the market, and the opportunity to identify and take action against unsafe products that have been distributed. The clinical patterns of presentation and severity of HDS-associated hepatotoxicity can be highly variable, even for the same product. In addition, accurate causality assessment in cases of suspected HDS hepatotoxicity is confounded by infrequent ascertainment of product intake by healthcare providers, under-reporting of HDS use by patients, the ubiquity of HDS and the complexity of their components, and the possibility for product adulteration. Additional measures to prevent HDS-induced hepatotoxicity include greater consumer and provider awareness, increased spontaneous reporting, and reassessment of regulations regarding the manufacturing, distribution, and marketing of these products.

  14. Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity.

    Science.gov (United States)

    Sun, Jinchun; Slavov, Svetoslav; Schnackenberg, Laura K; Ando, Yosuke; Greenhaw, James; Yang, Xi; Salminen, William; Mendrick, Donna L; Beger, Richard

    2014-07-01

    It has been estimated that 10% of acute liver failure is due to "idiosyncratic hepatotoxicity". The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride), two idiosyncratic hepatotoxicants (felbamate and dantrolene), and three non-hepatotoxicants (meloxicam, penicillin and metformin). Male Sprague-Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h), 7 (24 h) and 20 (6 h and 24 h) metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics) may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting.

  15. HEPATOPROTECTIVE EFFECT OF LGI ON CARBON TERACHLORID AND ALCOHOL HEPATOTOXICITY%利加隆对实验性肝损害的干预作用

    Institute of Scientific and Technical Information of China (English)

    李丽娟; 田学明; 范宗江

    2000-01-01

    目的:了解抗氧化剂利加隆(LGL)对实验性肝损害的干预作用,并探讨其作用机制。方法: 四氯化碳(CL4)及低浓度酒精诱导Wistor大鼠肝损害模型.部分动物在染毒同时给予LGL治疗,观察 不同时相治疗组与非治疗大鼠血ALT、肝组织MDA含量及肝超微结构改变的差异。结果:CCL4及酒精 染毒后,各时相点非治疗组大鼠血ALT较正常对照组明显升高(P<0.01),同时相点治疗组ALT较非 治疗组明显降低(P<0.01):各非治疗组肝组织MDA含量较正常对照组明显升高(P<0.01),同时相 点治疗组肝组织MDA含量较非治疗组明显降低(P<0.01)。MDA含量变化与ALT含量变化呈正相 关,γ=0.76(P<0.01)。LGL治疗组可见肝细胞再生,肝超微结构改变较非治疗组明显减轻。结论:抗氧 化剂LGL能减轻CCL4及低剂量酒精引起的肝损害.这种治疗作用可能是通过其抗脂质过氧化反应、 抗炎性反应、抑制炎性细胞因子的产生及活性的作用而发挥的。%Objective: To study hepatoprotective effect of LGL, an anti-oxidizing agent, on experimental hepatic injury.Method: Carbon teiachlorid (CCL4) and alcohol at low concentration were used to induce hepatic injury model in Wistar rats for 3, 6 and 9 weeks, respectively. Some of these rats were treated coincidentally with LGL (treated group) and the others belonged to toxic group. The changes of alanine aminotransferase (ALT) in blood, malondialhyde (MDA) in hepatic tissues and hepatic ultramicrostructure of both groups were observed. Result: The levels of ALT ans MDA of the toxic group were higher at the three phases than those of the treated group and normal group (P< 0. 01). ALTlevel of the treated group was a little higher than that of the normal group and MDA levels between both groups were not different significantly. MDA level was positively correlated with ALT level (γ=0. 76). Regeneration of hepatic cells was observed

  16. Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Jinchun Sun

    2014-07-01

    Full Text Available It has been estimated that 10% of acute liver failure is due to “idiosyncratic hepatotoxicity”. The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride, two idiosyncratic hepatotoxicants (felbamate and dantrolene, and three non-hepatotoxicants (meloxicam, penicillin and metformin. Male Sprague–Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h, 7 (24 h and 20 (6 h and 24 h metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting.

  17. Biochemical effects of Calotropis procera on hepatotoxicity

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    Ali Ismaiel Ali Abd Alrheam

    2015-12-01

    Full Text Available Introduction: Calotropis procera commonly known as Sodom apple is a 6-meter high shrub that belongs to the Aclepiadaceae plant family and is commonly found in West Africa and other tropical places. In Saudi Arabia the plant is commonly used in traditional medicine for the treatment of variety of diseases including fever, constipation, muscular spasm and joint pain. Aim: In the present study C. procera were investigated for the hepatoprotective activity. Material and Methods: Carbon tetrachloride is used to produce hepatotoxicity. Forty two male albino rats, weighting 150-200 gm divided into seven groups, each consisted of 6 rats. Carbon tetrachloride 2ml/kg was administered twice a week to all of the groups of animals except group I, which served as control and given the normal saline. Group II served as Carbon tetrachloirde control. Group III received Silymarin at 100 mg/kg/day dose, Group IV received aqueous leaves extracts C. procera 200mg/kg, Group V received chloroform leaves extracts C. procera 200mg/kg, Group VI received ethanol leaves extracts C. procera 200 mg/kg, Group VII received latex of C. procera 200mg/kg. The effect of aqueous, chloroform, ethanol leaves extract and latex C. procera on biochemical parameters of liver was measured. Results: The results showed that the aqueous, chloroform, ethanol leaves extract and latex C. procera produced significant decrease in Acid phosphatase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Total protein, Albumin and total bilirubin levels compared to the CCL4 treated group II. Conclusion: Calotropis procera appears to to have hepatoprotective activity and these may be due to enrich of the plant by phytoconstituents that activate and in hence a pharmacological response of different parts of the body and this study need further studies to shows the complete properties of the plant. [Biomed Res Ther 2015; 2(12.000: 446-453

  18. Anabolic androgenic steroid-induced hepatotoxicity.

    Science.gov (United States)

    Bond, Peter; Llewellyn, William; Van Mol, Peter

    2016-08-01

    Anabolic androgenic steroids (AAS) have been abused for decades by both professional and amateur athletes in order to improve physical performance or muscle mass. AAS abuse can cause adverse effects, among which are hepatotoxic effects. These effects include cholestatic icterus and possibly peliosis hepatis and hepatocellular carcinoma or adenoma. In particular, 17α-alkylated AAS appear to be hepatotoxic, whereas nonalkylated AAS appear not to be. The 17α-alkyl substitution retards hepatic metabolism of the AAS rendering it orally bioavailable. The mechanism responsible for the hepatotoxicity induced by 17α-alkylated AAS remains poorly understood. However, oxidative stress has been repeatedly shown to be associated with it. In this manuscript we present a hypothesis which describes a potential mechanism responsible for AAS-induced hepatotoxicity, based on several observations from the literature which suggest oxidative stress being a causal factor.

  19. A review of methotrexate-associated hepatotoxicity.

    Science.gov (United States)

    Bath, Roopjeet K; Brar, Navkiran K; Forouhar, Faripour A; Wu, George Y

    2014-10-01

    Methotrexate is effective not only in treating psoriasis and rheumatoid arthritis but also various other disorders. The use of methotrexate has been somewhat limited by concerns regarding its adverse effects, including its potential for hepatotoxicity. The purpose of this article is to provide an overview of methotrexate-associated hepatotoxicity, including risk factors, pathogenesis and recommendations for monitoring it by US, UK and European guidelines, as well as providing a brief overview of its mechanism of action and of high-dose methotrexate.

  20. Calcium transport, thiol status, and hepatotoxicity following N-nitrosodimethylamine exposure in mice

    Energy Technology Data Exchange (ETDEWEB)

    Reitman, F.A.; Berger, M.L.; Minnema, D.J.; Shertzer, H.G.

    1988-01-01

    The hepatotoxicant N-nitrosodimethylamine (NDMA) is presumed to exert toxicity through reactive metabolites. NDMA is similar in this respect to numerous other hepatotoxicants, for which hepatotoxicity is also associated with a rapid depletion of soluble and/or protein thiols, and an inhibition of calcium transport systems. The authors examined the hypothesis that hepatotoxicity for NDMA is preceded by thiol depletion and/or inhibition of calcium transport in isolated liver subcellular fractions. Centrizonal liver necrosis in mice was evident at 24 but not at 12 h subsequent to intraperitoneal administration of 40 mg NDMA/kg. Hepatotoxicity was not preceded by depletion of liver protein-free sulfhydryls, nor by protein sulfhydryl depletion in liver whole homogenate, microsomal, or plasma membrane fractions. NDMA-mediated toxicity was also not preceded by inhibition of calcium uptake capability by microsomal, mitochondrial, or plasma membrane fractions. In contrast, carbon tetrachloride produced the expected rapid decrease in microsomal calcium uptake capability, followed by a centrizonal necrosis that was maximal at about 24 h. These studies suggest that the mechanism of NDMA hepatotoxicity may differ from that of a number of other hepatotoxicants (e.g., carbon tetrachloride, acetaminophen, bromobenzene) for which toxicity is also mediated through reactive metabolites.

  1. Hepatotoxicity and the present herbal hepatoprotective scenario

    Directory of Open Access Journals (Sweden)

    Priyankar Dey

    2013-01-01

    Full Text Available Most of the metabolic and physiological processes of our body as well as the detoxification of various drugs and xenobiotic chemicals occur in the liver. During this detoxification process, the reactive chemical intermediates damage the liver severely. There are several commercially available drugs, consumption of which results in idiosyncratic drug reaction mediated hepatotoxicity. Drug induced hepatotoxicity is a burning problem in this regard and several drugs are withdrawn from the market due to their hepatotoxic nature. Today, worldwide search of non-hepatotoxic drugs, especially potent hepatoprotective drugs have led towards the screening of numerous herbal products. Pharmaceutical companies and scientific communities have started to consider the therapeutic efficiency of the plant-based hepatoprotective remedies. Different herbs are mentioned in various ethnopharmacological practices possessing hepatoprotective capacities and around the globe, such herbs are still used by people to cure certain liver diseases. Therefore, we have documented the various aspects of hepatotoxicity and an overview on the current scenario of the hepatoprotective herbal remedies.

  2. Mechanisms underlying the hepatotoxic effects of ecstasy.

    Science.gov (United States)

    Carvalho, Márcia; Pontes, Helena; Remião, Fernando; Bastos, Maria L; Carvalho, Félix

    2010-08-01

    3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a worldwide illegally used amphetamine-derived designer drug known to be hepatotoxic to humans. Jaundice, hepatomegaly, centrilobular necrosis, hepatitis and fibrosis represent some of the adverse effects caused by MDMA in the liver. Although there is irrefutable evidence of MDMA-induced hepatocellular damage, the mechanisms responsible for that toxicity remain to be thoroughly clarified. One well thought-of mechanism imply MDMA metabolism in the liver into reactive metabolites as responsible for the MDMA-elicited hepatotoxicity. However, other factors, including MDMA-induced hyperthermia, the increase in neurotransmitters efflux, the oxidation of biogenic amines, polydrug abuse pattern, and environmental features accompanying illicit MDMA use, may increase the risk for liver complications. Liver damage patterns of MDMA in animals and humans and current research on the mechanisms underlying the hepatotoxic effects of MDMA will be highlighted in this review.

  3. Current and emerging biomarkers of hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Yang X

    2012-08-01

    Full Text Available Xi Yang, William F Salminen, Laura K SchnackenbergDivision of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USAAbstract: Drug-induced liver injury (DILI is of great concern to human health. Generally, liver function and injury is evaluated based upon clinical signs, a select group of serum clinical biomarkers, and occasionally liver biopsies. While alanine aminotransferase, the most commonly used biomarker of hepatocellular injury, is a sensitive marker of liver injury, it is not necessarily specific for liver injury. Furthermore, alanine aminotransferase levels may not always correlate with the extent of injury. Therefore, new hepatotoxicity biomarkers are needed that are more predictive and specific indicators of liver injury and altered function. In addition, no current biomarker provides prognostic information about ultimate outcome once injury occurs, and any new biomarker filling this need is desperately needed. The omics technologies, including genomics, proteomics, and metabolomics, are being used in preclinical animal studies as well as clinical studies to evaluate markers of hepatotoxicity in easily obtained biofluids, such as urine and serum. Recently, the evaluation of circulating microRNAs in urine and blood has also shown promise for the identification of novel, sensitive markers of liver injury. This review evaluates the current status of proposed biomarkers of hepatotoxicity from the omics platforms, as well as from analysis of microRNAs. A brief description of the qualification of proposed biomarkers is also given.Keywords: biomarkers, hepatotoxicity, metabolomics, microRNA, proteomics, transcriptomics

  4. Hepatotoxicity Induced by "the 3Ks": Kava, Kratom and Khat.

    Science.gov (United States)

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Zaami, Simona; Ricci, Serafino; Giorgetti, Raffaele; Terranova, Daniela; Busardò, Francesco P; Marinelli, Enrico

    2016-04-16

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by "the 3Ks", while trying to clarify the numerous aspects that still need to be addressed.

  5. A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide

    OpenAIRE

    Shih, Tung-Yuan; Pai, Chien-Yi; Yang, Ping; Chang, Wen-Liang; Wang, Ning-Chi; Hu, Oliver Yoa-Pu

    2013-01-01

    Relatively little is known about the hepatotoxicity of pyrazinamide (PZA). PZA requires activation by amidase to form pyrazinoic acid (PA). Xanthine oxidase then hydroxylates PA to form 5-hydroxypyrazinoic acid (5-OH-PA). PZA can also be directly oxidized to form 5-OH-PZA. Before this study, it was unclear which metabolic pathway or PZA metabolites led to hepatotoxicity. This study determines whether PZA metabolites are responsible for PZA-induced hepatotoxicity. PZA metabolites were identifi...

  6. Large animal hepatotoxic and nephrotoxic plants.

    Science.gov (United States)

    Oladosu, L A; Case, A A

    1979-10-01

    The hepatotoxic and nephrotoxic plants of large domestic animals have been reviewed. The most important ones are those widely distributed as weeds over pastures, negelcted forests and grasslands, those used as ornamentals, the nitrate concentrating forage crops, and the cyanophoric plants. Crotolaria spp, the ragwort (Senecia jacobaea), the lantana spp. and heliotopum are common hepatoxic plants. Amaranthus retroflexus, Datura stramonium, Solanum rostratum, and the castor oil plant (Ricinus communis) are nephrotoxic plants.

  7. Black Cohosh Hepatotoxicity with Autoimmune Hepatitis Presentation

    Science.gov (United States)

    Franco, Diana L.; Kale, Santosh; Lam-Himlin, Dora M.; Harrison, M. Edwyn

    2017-01-01

    Herbal medicines have been used for the treatment of various ailments since time immemorial. Black cohosh (BC) is well known for the treatment of postmenopausal symptoms, with conflicting evidence supporting its safety and benefits. We present a rare case of BC-induced autoimmune hepatitis (AIH) with hepatotoxicity in a 69-year-old female. To our knowledge, this represents the third case of BC-induced AIH. PMID:28203134

  8. Alpha methyldopa induced hepatotoxicity in pregnancy

    Directory of Open Access Journals (Sweden)

    Padmasri Ramalingappa

    2014-06-01

    Full Text Available We report a case of gestational hepatitis due to alpha-methyldopa and briefly review the literature on alpha-methyldopa-induced hepatotoxicity in pregnancy. A 32 year old woman, primigravida with 34 weeks of gestation with pre eclampsia, presented with symptoms of nausea, dark coloured urine and jaundice. She was on alpha methyldopa (Aldomet 250 mg thrice a day since the last five weeks. Laboratory investigations revealed raised bilirubin, serum aspartate transaminases and serum alanine transaminases. Platelets were normal. Peripheral smear did not show haemolysis. With the exclusion of viral, haemolytic and obstructive causes, drug induced jaundice was considered as a differential diagnosis. Alpha methyldopa was withdrawn and replaced with nifedipine for her pre eclampsia treatment. Her repeat bilirubin level done two weeks later showed a drop. She went into labour at 38 weeks and delivered vaginally. In postpartum follow up her liver tests returned to normal in two weeks, about six weeks after stopping methyldopa. Hepatotoxicity should be considered as one of the adverse drug reaction of alpha methyldopa. It is not possible at present to predict which patients will develop liver disease following the administration of this drug. An awareness of the possibility of methyldopa induced hepatotoxicity should be present in the clinician's mind and liver function tests should be done at regular intervals. The occasional occurrence of this harmful side effect is not a contraindication to the use of this antihypertensive agent. [Int J Reprod Contracept Obstet Gynecol 2014; 3(3.000: 805-807

  9. A Systematic Strategy for Screening and Application of Specific Biomarkers in Hepatotoxicity Using Metabolomics Combined With ROC Curves and SVMs.

    Science.gov (United States)

    Li, Yubo; Wang, Lei; Ju, Liang; Deng, Haoyue; Zhang, Zhenzhu; Hou, Zhiguo; Xie, Jiabin; Wang, Yuming; Zhang, Yanjun

    2016-04-01

    Current studies that evaluate toxicity based on metabolomics have primarily focused on the screening of biomarkers while largely neglecting further verification and biomarker applications. For this reason, we used drug-induced hepatotoxicity as an example to establish a systematic strategy for screening specific biomarkers and applied these biomarkers to evaluate whether the drugs have potential hepatotoxicity toxicity. Carbon tetrachloride (5 ml/kg), acetaminophen (1500 mg/kg), and atorvastatin (5 mg/kg) are established as rat hepatotoxicity models. Fifteen common biomarkers were screened by multivariate statistical analysis and integration analysis-based metabolomics data. The receiver operating characteristic curve was used to evaluate the sensitivity and specificity of the biomarkers. We obtained 10 specific biomarker candidates with an area under the curve greater than 0.7. Then, a support vector machine model was established by extracting specific biomarker candidate data from the hepatotoxic drugs and nonhepatotoxic drugs; the accuracy of the model was 94.90% (92.86% sensitivity and 92.59% specificity) and the results demonstrated that those ten biomarkers are specific. 6 drugs were used to predict the hepatotoxicity by the support vector machines model; the prediction results were consistent with the biochemical and histopathological results, demonstrating that the model was reliable. Thus, this support vector machine model can be applied to discriminate the between the hepatic or nonhepatic toxicity of drugs. This approach not only presents a new strategy for screening-specific biomarkers with greater diagnostic significance but also provides a new evaluation pattern for hepatotoxicity, and it will be a highly useful tool in toxicity estimation and disease diagnoses.

  10. Evaluation of hepatoprotective activity of Bergamot orange in rats

    OpenAIRE

    Karaca, Mehmet; İLHAN, Fatma; Altan, Hasan; Him, Aydın; TÜTÜNCÜ, Mehmet; Özbek, Hanefi

    2012-01-01

    Abstract. Essential oil extract of Bergamot orange (BO) was investigated for its hepatoprotective effect on carbon tetrachloride-induced hepatotoxicity in rats. Six different groups were established. Silibinin was used as the reference agent. BO significantly reduced the serum ALT level when compared to CCl4 group while it did not affect the serum AST level. The histopathological findings did not show any significant difference between the BO and CCl4 groups. The results suggest that BO has a...

  11. Statin Hepatotoxicity: Is it a Real Concern?

    Science.gov (United States)

    Sikka, Pranav; Saxena, K. K.; Kapoor, Seema

    2011-01-01

    Statins are the most effective and widely used drugs for treating dyslipidemia, a major risk factor for coronary heart disease. These are one of the safest hypolipidemic drugs but many patients are advised to discontinue statins for the fear of hepatotoxicity. Despite a lack of evidence that statins cause liver diseases, many physicians are reluctant to start statins in patients with an out-of-range liver enzymes value and this reluctance to initiate or interrupt the therapy with statins leads to dyslipidemia and its grave consequences. Further, there are some reports showing an additional benefit of statins in reducing cardiovascular events in patients with abnormal liver function tests. PMID:22567196

  12. Statin Hepatotoxicity: Is it a Real Concern?

    Directory of Open Access Journals (Sweden)

    Pranav Sikka

    2011-01-01

    Full Text Available Statins are the most effective and widely used drugs for treating dyslipidemia, a major risk factor for coronary heart disease. These are one of the safest hypolipidemic drugs but many patients are advised to discontinue statins for the fear of hepatotoxicity. Despite a lack of evidence that statins cause liver diseases, many physicians are reluctant to start statins in patients with an out-of-range liver enzymes value and this reluctance to initiate or interrupt the therapy with statins leads to dyslipidemia and its grave consequences. Further, there are some reports showing an additional benefit of statins in reducing cardiovascular events in patients with abnormal liver function tests.

  13. Lead hepatotoxicity: Selected aspects of pathobiochemistry

    Directory of Open Access Journals (Sweden)

    Mateusz Labudda

    2013-08-01

    Full Text Available Lead (Pb that belongs to heavy metals is one of the major pollution components of the environment. Occupational and environmental exposure to lead can cause its absorption by the body and consequently exert toxic effects in the liver. In this paper biochemical determinants of hepatotoxicity caused by lead are presented. Generation of reactive oxygen species, disturbances in the cellular antioxidant system, lipid peroxidation, inhibition of enzymatic proteins and intercellular signaling are also discussed. Med Pr 2013;64(4:565–568

  14. Comparison of cytoprotective effects of saponins isolated from leaves of Aralia elata Seem. (Araliaceae) with synthesized bisdesmosides of oleanoic acid and hederagenin on carbon tetrachloride-induced hepatic injury.

    Science.gov (United States)

    Saito, S; Ebashi, J; Sumita, S; Furumoto, T; Nagamura, Y; Nishida, K; Isiguro, I

    1993-08-01

    Glycosylations of 3-O-(2,3,4-tri-O-acetyl-alpha-L-rhamnopyranosyl(1-->2)- 3,4-di-O-acetyl-alpha-L-arabinopyranosyl)-23-O-acetylhederageni n (15) with mono- (16), di- (17) and trisaccharide bromide (18) gave the bisdesmoside peracetates 19, 20 and 22, respectively, which were treated with 5% KOH in MeOH to give the bisdesmosides 25-27. Hydrolysis of the glycosides 6 and 9 having beta-D-glucopyranose as a terminal sugar component with beta-glucosidase in acetate buffer (pH 4.7) gave compounds 28 and 29, respectively. Cytoprotective effects of the synthesized triterpenoidal saponins against CCl4-induced hepatic injury were compared with those of saponins isolated from the leaves of Aralia elata Seem. (Araliaceae) using isolated hepatocytes from rat liver. Although the monodesmosides 1-4 having neutral sugar components only at the O-3 position on the aglycones showed no cytoprotective effect, bisdesmosides having sugar components at both the O-3 and O-28 positions on the aglycones had potent effects, even when the species of the sugar components were different. The bisdesmosides 10, 11, and 27 having five monosaccharides in the molecules exhibited the most potent cytoprotective effects.

  15. [Herbals and herbal nutritional products hepatotoxicity].

    Science.gov (United States)

    Mengual-Moreno, Edgardo; Lizarzábal-García, Maribel; Hernández-Rincón, Ileana; Barboza-Nobrega, María De Freitas

    2015-09-01

    Herbs and other botanicals have been used in different cultures with medicinal and dietary purposes for centuries. Contrary to the belief of being natural and safe products, their hepatotoxic potential is recognized in several studies worldwide, and represent a health problem that deserves greater attention. The reported prevalence of hepatotoxicity associated with botanicals is variable and depends on various factors such as population, period and design of the study. There have been reports of a total of 60 products with herbal medicinal and dietary purposes, which may cause liver damage; however, the pathophysiological mechanisms involved are not fully elucidated. Their clinical and histological features, not unlike liver injury associated with drugs in most patients, have a pattern of hepatocellular injury. Diagnosis is by exclusion, and represents a clinical challenge. It is essential the clinical suspicion and the differential diagnosis with other acute and chronic conditions. Hence, future researches are aimed at improving existing diagnostic methods and introducing new toxicological, genetic and immunological technologies. Treatment is complex and presents a challenge for the specialist, as there are no antidotes. Management based on the discontinued use of the product and in the symptomatic treatment, decreases the progression to an acute fulminant hepatic failure.

  16. Rutin Attenuates Hepatotoxicity in High-Cholesterol-Diet-Fed Rats.

    Science.gov (United States)

    AlSharari, Shakir D; Al-Rejaie, Salim S; Abuohashish, Hatem M; Ahmed, Mohamed M; Hafez, Mohamed M

    2016-01-01

    Background and Objective. High-cholesterol diet (HCD) intends to increase the oxidative stress in liver tissues inducing hepatotoxicity. Rutin is a natural flavonoid (vitamin p) which is known to have antioxidative properties. The aim of the present study was to investigate the potential effects of Rutin on hypercholesterolemia-induced hepatotoxicity in rats. Materials and Methods. Male Wistar rats were divided into four groups: G-I control, G-II Rutin, G-III HCD, and G-IV Rutin + HCD. The liver functions and lipid profile were used to evaluate the HCD-induced hepatotoxicity. Quantitative real time-PCR was carried out to evaluate the expression levels of genes in TGF-β/Smad signaling pathway. Results. Rutin in combination with HCD showed a significant protective effect against hepatotoxicity. HCD caused significant increase in the mRNA expression of transforming growth factor beta (TGF-β), Mothers Against Decapentaplegic Homolog 2 (Smad-2), Mothers Against Decapentaplegic Homolog 4 (Smad-4), Bcl-2-binding component 3 (Bbc3), caspase-3, P53 and Interleukin-6 (IL-6) and decrease in the expression levels of Cyclin depended kinase inhibitor (P21) and Interleukin-3 (IL-3) in hepatic cells. Conclusion. TGF-β/Smad signaling pathway is involved in HCD-induced hepatotoxicity and Rutin inhibits the hepatotoxicity via suppressing this pathway. Therefore, Rutin might be considered as a protective agent for hepatotoxicity.

  17. Rutin Attenuates Hepatotoxicity in High-Cholesterol-Diet-Fed Rats

    Directory of Open Access Journals (Sweden)

    Shakir D. AlSharari

    2016-01-01

    Full Text Available Background and Objective. High-cholesterol diet (HCD intends to increase the oxidative stress in liver tissues inducing hepatotoxicity. Rutin is a natural flavonoid (vitamin p which is known to have antioxidative properties. The aim of the present study was to investigate the potential effects of Rutin on hypercholesterolemia-induced hepatotoxicity in rats. Materials and Methods. Male Wistar rats were divided into four groups: G-I control, G-II Rutin, G-III HCD, and G-IV Rutin + HCD. The liver functions and lipid profile were used to evaluate the HCD-induced hepatotoxicity. Quantitative real time-PCR was carried out to evaluate the expression levels of genes in TGF-β/Smad signaling pathway. Results. Rutin in combination with HCD showed a significant protective effect against hepatotoxicity. HCD caused significant increase in the mRNA expression of transforming growth factor beta (TGF-β, Mothers Against Decapentaplegic Homolog 2 (Smad-2, Mothers Against Decapentaplegic Homolog 4 (Smad-4, Bcl-2-binding component 3 (Bbc3, caspase-3, P53 and Interleukin-6 (IL-6 and decrease in the expression levels of Cyclin depended kinase inhibitor (P21 and Interleukin-3 (IL-3 in hepatic cells. Conclusion. TGF-β/Smad signaling pathway is involved in HCD-induced hepatotoxicity and Rutin inhibits the hepatotoxicity via suppressing this pathway. Therefore, Rutin might be considered as a protective agent for hepatotoxicity.

  18. Proteomic investigation of signatures for geniposide-induced hepatotoxicity.

    Science.gov (United States)

    Wei, Junying; Zhang, Fangbo; Zhang, Yi; Cao, Chunyu; Li, Xianyu; Li, Defeng; Liu, Xin; Yang, Hongjun; Huang, Luqi

    2014-12-05

    Evaluating the safety of traditional medicinal herbs and their major active constituents is critical for their widespread usage. Geniposide, a major active constituent with a defined structure from the traditional medicinal herb Gardenia jasminoides ELLIS fruit, exhibits remarkable anti-inflammatory, antiapoptotic, and antifibrotic properties and has been used in a variety of medical fields, mainly for the treatment of liver diseases. However, geniposide-induced hepatotoxicity and methods for the early detection of hepatotoxicity have yet to be reported. In this study, geniposide-induced hepatotoxicity was investigated. In addition, candidate biomarkers for the earlier detection of geniposide-induced hepatotoxicity were identified using a label-free quantitative proteomics approach on a geniposide overdose-induced liver injury in a rat model. Using an accurate intensity-based, absolute quantification (iBAQ)-based, one-step discovery and verification approach, a candidate biomarker panel was easily obtained from individual samples in response to different conditions. To determine the biomarkers' early detection abilities, five candidate biomarkers were selected and tested using enzyme-linked immunosorbent assays (ELISAs). Two biomarkers, glycine N-methyltransferase (GNMT) and glycogen phosphorylase (PYGL), were found to indicate hepatic injuries significantly earlier than the current gold standard liver biomarker. This study provides a first insight into geniposide-induced hepatotoxicity in a rat model and describes a method for the earlier detection of this hepatotoxicity, facilitating the efficient monitoring of drug-induced hepatotoxicity.

  19. Silymarin nanoparticle prevents paracetamol-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Das S

    2011-06-01

    Full Text Available Suvadra Das, Partha Roy, Runa Ghosh Auddy, Arup MukherjeeDepartment of Chemical Technology, University of Calcutta, Kolkata, West Bengal, IndiaAbstract: Silymarin (Sm is a polyphenolic component extracted from Silybum marianum. It is an antioxidant, traditionally used as an immunostimulant, hepatoprotectant, and dietary supplement. Relatively recently, Sm has proved to be a valuable chemopreventive and a useful antineoplastic agent. Medical success for Sm is, however, constrained by very low aqueous solubility and associated biopharmaceutical limitations. Sm flavonolignans are also susceptible to ion-catalyzed degradation in the gut. Proven antihepatotoxic activity of Sm cannot therefore be fully exploited in acute chemical poisoning conditions like that in paracetamol overdose. Moreover, a synchronous delivery that is required for hepatic regeneration is difficult to achieve by itself. This work is meant to circumvent the inherent limitations of Sm through the use of nanotechnology. Sm nanoparticles (Smnps were prepared by nanoprecipitation in polyvinyl alcohol stabilized Eudragit RS100® polymer (Rohm Pharma GmbH, Darmstadt, Germany. Process parameter optimization provided 67.39% entrapment efficiency and a Gaussian particle distribution of average size 120.37 nm. Sm release from the nanoparticles was considerably sustained for all formulations. Smnps were strongly protective against hepatic damage when tested in a paracetamol overdose hepatotoxicity model. Nanoparticles recorded no animal death even when administered after an established paracetamol-induced hepatic necrosis. Preventing progress of paracetamol hepatic damage was traced for an efficient glutathione regeneration to a level of 11.3 µmol/g in hepatic tissue due to Smnps.Keywords: silymarin, paracetamol, nanoparticle, glutathione, mouse hepatotoxicity

  20. Possible hepatotoxicity of chronic marijuana usage

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    Paulo Borini

    Full Text Available CONTEXT: Hepatotoxicity is a potential complication from the usage of various illicit drugs, possibly consequent to their liver metabolism, but information on this is scarce in the medical literature. OBJECTIVE: To study the occurrence of clinical and laboratory hepatic alterations in chronic marijuana users, from the use of marijuana on its own or in association with other legal or illicit drugs. TYPE OF STUDY: transversal study SETTING: Hospital Espírita de Marília, Marília, São Paulo, Brazil PARTICIPANTS: The study was made among 123 patients interned in the Hospital Espírita de Marília from October 1996 to December 1998, divided into 3 groups: 26 (21% using only marijuana, 83 (67.5% using marijuana and crack, and 14 (11.4% consuming marijuana and alcohol. PROCEDURES AND MAIN MEASUREMENTS: Patients were examined clinically with special emphasis on types of drugs used, drug intake route, age when consumption began, length and pattern of usage, presence of tattooing, jaundice, hepatomegaly and splenomegaly. Serum determinations of total proteins, albumin, globulin, total and fractions of bilirubin, aspartate (AST and alanine (ALT aminotransferases, alkaline phosphatase (AP, gamma-glutamyltransferase and prothrombin activity were performed. RESULTS: Among users of only marijuana, hepatomegaly was observed in 57.7% and splenomegaly in 73.1%, and slightly elevated AST (42.3%, ALT (34.6% and AP (53.8%. The three groups did not differ significantly in the prevalence of hepatomegaly, splenomegaly and hepatosplenomegaly. The group using both marijuana and alcohol showed the highest prevalence of alterations and highest levels of aminotransferases. Mean AP levels were above normal in all groups. CONCLUSIONS: Chronic marijuana usage, on its own or in association with other drugs, was associated with hepatic morphologic and enzymatic alterations. This indicates that cannabinoids are possible hepatotoxic substances.

  1. A Rare Side Effect of Metformin: Metformin-Induced Hepatotoxicity

    OpenAIRE

    2007-01-01

    Metformin is an oral hypoglycemic agent that is commonly used in the treatment of type 2 diabetes mellitus. While metformin-associated metabolic acidosis is a widely recognized side effect of this drug, metformin-induced hepatotoxicity has been rarely reported in the literature. We present herein the case of a 52-year-old male in whom metformin-associated lactic acidosis and metformin-induced hepatotoxicity developed.

  2. Noninvasive biomarkers for acute hepatotoxicity induced by 1,3-dichloro-2-propanol: hyperpolarized 13C dynamic MR spectroscopy.

    Science.gov (United States)

    Kim, Gwang-Won; Oh, Chang-Hyun; Kim, Jong-Choon; Yoon, Woong; Jeong, Yong-Yeon; Kim, Yun-Hyeon; Kim, Jae-Kyu; Park, Jin-Gyoon; Kang, Heoung-Keun; Jeong, Gwang-Woo

    2016-02-01

    The purpose of this study was to investigate the cellular metabolite change for acute hepatotoxicity induced by 1,3-dichloro-2-propanol (1,3-DCP) in rats and its correlations with the enzyme levels. In order to induce acute hepatotoxicity, a single subcutaneous injection of 1,3-DCP (80 mg/kg) was given to six male Sprague-Dawley rats. Hyperpolarized (13)C dynamic magnetic resonance spectroscopy (MRS) was performed on rat liver following injection of hyperpolarized [1-(13)C] pyruvate. The levels of serum aspartate am inotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) in the 1,3-DCP treated rats were significantly increased as compared with those in normal rats. In the dynamic (13)C MR spectra, the ratios of [1-(13)C] lactate to the total carbon and [1-(13)C] alanine to the total carbon in the 1,3-DCP treated rats were significantly increased, and there were positive correlations between cellular metabolic changes and enzyme levels. The levels of [1-(13)C] lactate and [1-(13)C] alanine are potentially considered as important biomarkers for the 1,3-DCP-induced acute hepatotoxicity.

  3. Mecanismos de hepatotoxicidade Mechanisms of hepatotoxicity

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    Marcelo Chiara Bertolami

    2005-10-01

    Full Text Available Hepatopatia relacionada ao uso de drogas hipolipemiantes tem sido definida como um dano celular (aumento das enzimas AST e ALT sem alterações colestáticas (aumento de bilirrubinas e/ou fosfatase alcalina. Seis mecanismos são propostos para a hepatopatia: 1. Reações de alta energia no citocromo P450 comprometendo a homeostase do cálcio com a ruptura de fibrilas intracelulares e lise de hepatócitos. 2. Disfunção de proteínas transportadoras relacionadas com o fluxo de ácidos biliares (mecanismo proposto para a toxicidade hepática dos fibratos. 3. Reações imunes geradas pela formação de metabólitos das drogas hipolipemiantes formados no fígado. 4. Hepatoxicidade promovida por células T com inflamação adicional mediada por neutrófilos. 5. Apoptose mediada por TNF e Fas (imune-mediada. 6. Estresse oxidativo gerado por dano a organelas intracelulares. Ainda, idade avançada, consumo excessivo de álcool, altas doses de drogas hipolipemiantes, interação com outros fármacos, e doença hepática ativa prévia podem aumentar a hepatotoxidade.Liver disease following the use of hypolipidemic drugs has been reported as a cellular damage (increases in AST or ALT enzymes without cholestatic alterations (bilirubin and or alkaline phosphatase increases. Six mechanisms were proposed for hepatotoxicity : 1. High energy reactions on P450 cytochrome impairing calcium homestasis with rupture of intracellular fibrils and hepatocyte lysis. 2. Impairment of transporter proteins related to the bile acids flux (mechanism proposed for fibrate liver toxicity. 3. Immune reactions due to the formation of metabolites linked to enzymes following liver metabolism of hypolipidemic drugs. 4. Hepatotoxicity by T cells with additional inflammation mediated by neutrophils. 5. Apoptosis mediated by TNF and Fas (immune mediated. 6. Oxidative stress due to damage of intracellular organelles. In addition, advanced age, alcohol in excess, high doses of

  4. Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

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    Nesreen E.M. Mohammed

    2016-11-01

    Conclusion: Amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

  5. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

    OpenAIRE

    Flaminia Pantano; Roberta Tittarelli; Giulio Mannocchi; Simona Zaami; Serafino Ricci; Raffaele Giorgetti; Daniela Terranova; Busardò, Francesco P.; Enrico Marinelli

    2016-01-01

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, lea...

  6. Protective effect of Livactine against CCl4 and paracetamol induced hepatotoxicity in adult Wistar rats

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    Candasamy Mayuren

    2010-10-01

    Full Text Available Background: Liver disease has become one of the serious health problems as it is exposed to many kinds of xenobiotics and therapeutic agents. Moreover the rapidly growing morbidity and mortality from liver disease are attributable to the increasing number of chemical compounds and environmental pollution. Unfortunately, so far, in the modern era of medicine there is no specific treatment to counter the menacing impact of these dreaded diseases. Many polyherbal formulations are used widely to treat these disorders. Livactine is a polyherbal formulation and is claimed to be useful in jaundice and biliary dysfunctions. Most of these formulations do not have standard and approved reports stating their pharmacological action or therapeutic efficacy. Therefore, there is a need for experimental confirmation of the pharmacological effects of this formulation. The rationale behind the selection of carbon tetrachloride is due to its free radical mechanism based liver injury, and paracetamol is consumed widely by the human population and it is also a potential liver hazard. Aim: To evaluate the anti-hepatotoxic activity of Livactine against carbon tetrachloride & paracetamol induced toxicity in rats. Material and Methods: Albino rats of Wistar strain were used to evaluate the hepatoprotective activity of Livactine against carbon tetrachloride & paracetamol induced toxicity. Liver damage was assessed by estimating various biochemical parameters such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, lactate dehydrogenase, alkaline phosphatase, acid phosphatase, total bilirubin, and total protein. The results of the rats treated with Livactine were compared with that of Liv-52.Results: Livactine showed significant dose dependent hepatoprotective effect by reducing elevated serum enzyme levels when compared to that of Liv-52.Conclusion: Our findings confirm that the formulation was found to be effective pharmacologically at

  7. Protective effect of Livactine against CCl4 and paracetamol induced hepatotoxicity in adult Wistar rats

    Directory of Open Access Journals (Sweden)

    Candasamy Mayuren.

    2010-01-01

    Full Text Available Background : Liver disease has become one of the serious health problems as it is exposed to many kinds of xenobiotics and therapeutic agents. Moreover the rapidly growing morbidity and mortality from liver disease are attributable to the increasing number of chemical compounds and environmental pollution. Unfortunately, so far, in the modern era of medicine there is no specific treatment to counter the menacing impact of these dreaded diseases. Many polyherbal formulations are used widely to treat these disorders. Livactine is a polyherbal formulation and is claimed to be useful in jaundice and biliary dysfunctions. Most of these formulations do not have standard and approved reports stating their pharmacological action or therapeutic efficacy. Therefore, there is a need for experimental confirmation of the pharmacological effects of this formulation. The rationale behind the selection of carbon tetrachloride is due to its free radical mechanism based liver injury, and paracetamol is consumed widely by the human population and it is also a potential liver hazard. Aim: To evaluate the anti-hepatotoxic activity of Livactine against carbon tetrachloride & paracetamol induced toxicity in rats. Material and Methods: Albino rats of Wistar strain were used to evaluate the hepatoprotective activity of Livactine against carbon tetrachloride & paracetamol induced toxicity. Liver damage was assessed by estimating various biochemical parameters such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, lactate dehydrogenase, alkaline phosphatase, acid phosphatase, total bilirubin, and total protein. The results of the rats treated with Livactine were compared with that of Liv-52. Results: Livactine showed significant dose dependent hepatoprotective effect by reducing elevated serum enzyme levels when compared to that of Liv-52. Conclusion: Our findings confirm that the formulation was found to be effective pharmacologically

  8. Experimental models of hepatotoxicity related to acute liver failure

    Science.gov (United States)

    Maes, Michaël; Vinken, Mathieu; Jaeschke, Hartmut

    2015-01-01

    Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. PMID:26631581

  9. DIFFERENT MODELS OF HEPATOTOXICITY AND RELATED LIVER DISEASES: A REVIEW

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    Singh Robin

    2012-07-01

    Full Text Available The liver is among the most complex and important organs in the human body. Its primary function is to control the flow and safety of substances absorbed from the digestive system before distribution of these substances to the systemic circulatory system. Hepatotoxicity implies chemical-driven liver damage. Chemicals that cause liver injury are called hepatotoxins. Hepatic injury leads to disturbances in transport function of hepatocytes resulting in leakage of plasma membrane thereby causing an increased enzyme level in serum. There are many diseases that are related with hepatotoxicity caused by certain chemicals or hepatotoxins. Herbal medicines are great demand in various chemicals and drugs disordered hepatic, the developed world for primary health care because of their efficacy, safety, lesser side effects and narrow therapeutic window. This review focus on liver, its function, liver diseases and different models of hepatotoxicity.

  10. The chronic hepatotoxicity assessment of the herbal formula Zishen Yutai pill.

    Science.gov (United States)

    Xing, Xiaoyan; Deng, Xuehong; Shi, Jinjin; Zhang, Meishuang; Sun, Guibo; Tang, Shimin; Huang, Qiuling; Sun, Xiaobo

    2017-02-01

    Zishen Yutai pill (ZYP) is an oriental herbal formula, while hepatotoxicity assessment of ZYP was rarely evaluated. Therefore, our aim is to re-evaluate its hepatotoxicity in both normal and carbon tetrachloride (CCl4) induced chronic liver injury rats. In the normal model, two doses of ZYP (1.575 and 9.450 g kg(-1) d(-1); i.e. 1 × , 6 × clinical doses) were given orally to rats for 24 weeks. In the chronic liver injury model, 10% CCl4 was administered to rats abdominally twice a week at a dose of 5 mL kg(-1) for 12 consecutive weeks. Administration time started from 4 weeks after the beginning of CCl4 treatment. Toxicological parameters included mortality, body weight, food consumption, clinical signs, biochemical parameters, gross observation, organ weight, necropsy findings and histopathology were monitored. In the normal model, we found no any mortality or abnormality in clinical signs, relative liver weight, biochemical parameters and histopathology in ZYP treatment groups. In the chronic liver injury model, liver damage related parameter such as ALT was elevated at the high dose of ZYP treatment in contrast to the CCl4-treated group (P rats and 9.450 g kg(-1) d(-1) ZYP in the injury rats.

  11. Rutin Attenuates Hepatotoxicity in High-Cholesterol-Diet-Fed Rats

    OpenAIRE

    AlSharari, Shakir D.; Al-Rejaie, Salim S.; Abuohashish, Hatem M.; Ahmed, Mohamed M.; Hafez, Mohamed M

    2016-01-01

    Background and Objective. High-cholesterol diet (HCD) intends to increase the oxidative stress in liver tissues inducing hepatotoxicity. Rutin is a natural flavonoid (vitamin p) which is known to have antioxidative properties. The aim of the present study was to investigate the potential effects of Rutin on hypercholesterolemia-induced hepatotoxicity in rats. Materials and Methods. Male Wistar rats were divided into four groups: G-I control, G-II Rutin, G-III HCD, and G-IV Rutin + HCD. The li...

  12. Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation.

    Science.gov (United States)

    Frenzel, Christian; Teschke, Rolf

    2016-04-27

    Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.

  13. Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation

    Directory of Open Access Journals (Sweden)

    Christian Frenzel

    2016-04-01

    Full Text Available Herb induced liver injury (HILI and drug induced liver injury (DILI share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM rarely causes elevated liver tests (LT. However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.

  14. Hepatoprotective activity of aqueous extract of Portulaca oleracea in combination with lycopene in rats

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    M Anusha

    2011-01-01

    Full Text Available Objective : To investigate the hepatoprotective activity of the aqueous extract of the aerial parts of Portulaca oleracea (P. oleracea in combination with lycopene against carbon tetrachloride induced hepatotoxicity in rats. Materials and Methods : Hepatotoxicity was induced in male Wistar rats by intraperitoneal injection of carbon tetrachloride (0.1 ml/kg b.w for 14 days. The aqueous extract of P. oleracea in combination with lycopene (50 mg/kg b.w was administered to the experimental animals at two selected doses for 14 days. The hepatoprotective activity of the combination was evaluated by the liver function marker enzymes in the serum [aspartate transaminases (AST, alanine transaminases (ALT, alkaline phosphatase (Alk.P, total bilirubin (TB, total protein (TP and total cholesterol (TC], pentobarbitone induced sleeping time (PST and histopathological studies of liver. Results : Both the treatment groups showed hepatoprotective effect against carbon tetrachloride induced hepatotoxicity by significantly restoring the levels of serum enzymes to normal which was comparable to that of silymarin group. Besides, the results obtained from PST and histopathological results also support the study. Conclusions : The oral administration of P. oleracea in combination with lycopene significantly ameliorates CCl 4 hepatotoxicity in rats.

  15. Hepatotoxicity induced by cyproterone acetate: A report of three cases

    Institute of Scientific and Technical Information of China (English)

    Ioanna Savidou; Melanie Deutsch; Aspasia S Soultati; Dimitrios Koudouras; Georgia Kafiri; Spyridon P Dourakis

    2006-01-01

    Cyproterone acetate (CPA) is a steroidal synthetic progestagen and anti-androgenic compound widely administered in prostate cancer which has been evidentially correlated with a severe hepatotoxic potency.Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after CPA administration. Patients were treated with CPA at the doses of 200-300 mg/d for malignant prostate disease for 3-12 mo prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis)were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. The current article highlights the hepatotoxic potency of a widely administered therapeutic agent and illustrates the importance of clinical surveillance especially in patients with previous hepatic diseases. Three relevant cases are reported and a review of the published literature is made.

  16. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism.

    Science.gov (United States)

    Yan, Xinmiao; Kang, Hong; Feng, Jun; Yang, Yiyan; Tang, Kailin; Zhu, Ruixin; Yang, Li; Wang, Zhengtao; Cao, Zhiwei

    2016-03-07

    Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  17. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism

    Directory of Open Access Journals (Sweden)

    Xinmiao Yan

    2016-03-01

    Full Text Available Pyrrolizidine Alkaloids (PAs are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1 and glutathione peroxidase 1 (GPX1 targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  18. Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2.

    Science.gov (United States)

    Adams, M L; Pierce, R H; Vail, M E; White, C C; Tonge, R P; Kavanagh, T J; Fausto, N; Nelson, S D; Bruschi, S A

    2001-11-01

    Mitochondria play an important role in the cell death induced by many drugs, including hepatotoxicity from overdose of the popular analgesic, acetaminophen (APAP). To investigate mitochondrial alterations associated with APAP-induced hepatotoxicity, the subcellular distribution of proapoptotic BAX was determined. Based on the antiapoptotic characteristics of BCL-2, we further hypothesized that if a BAX component was evident then BCL-2 overexpression may be hepatoprotective. Mice, either with a human bcl-2 transgene (-/+) or wild-type mice (WT; -/-), were dosed with 500 or 600 mg/kg (i.p.) APAP or a nonhepatotoxic isomer, N-acetyl-m-aminophenol (AMAP). Immunoblot analyses indicated increased mitochondrial BAX-beta content very early after APAP or AMAP treatment. This was paralleled by disappearance of BAX-alpha from the cytosol of APAP treated animals and, to a lesser extent, with AMAP treatment. Early pathological evidence of APAP-induced zone 3 necrosis was seen in bcl-2 (-/+) mice, which progressed to massive panlobular necrosis with hemorrhage by 24 h. In contrast, WT mice dosed with APAP showed a more typical, and less severe, centrilobular necrosis. AMAP-treated bcl-2 (-/+) mice displayed only early microvesicular steatosis without progression to extensive necrosis. Decreased complex III activity, evident as early as 6 h after treatment, correlated well with plasma enzyme activities at 24 h (AST r(2) = 0.89, ALT r(2) = 0.87) thereby confirming a role for mitochondria in APAP-mediated hepatotoxicity. In conclusion, these data suggest for the first time that BAX may be an early determinant of APAP-mediated hepatotoxicity and that BCL-2 overexpression unexpectedly enhances APAP hepatotoxicity.

  19. PROTECTIVE EFFECT OF Solanum Pubescens LINN ON CCL4 INDUCED HEPATOTOXICITY IN ALBINO RATS

    Directory of Open Access Journals (Sweden)

    M.Pushpalatha

    2012-01-01

    Full Text Available Ethanol extract of Solanum pubescens Linn was evaluated for hepato protective and antioxidant activities in rats. The plant extract (500mg/kg/day showed a remarkable hepatoprotective and antioxidant activity against Carbon tetrachloride (CCl4-induced hepatotoxicity as judged from the serum marker enzymes and antioxidant levels in liver tissues. CCl4 induced a significant rise in aspartate amino transferase (AST, alanine amino transferase (ALT, alkaline phosphatase (ALP, total bilirubin, LPO with a reduction of total protein, superoxide dismutase (SOD, catalase, and reduced glutathione (GSH. Treatment of rats with plant extract (500 mg/kg significantly (P<0.01 altered serum marker enzymes and antioxidant levels to near normal against CCl4 - treated rats. The activity of the extract at dose of 500 mg/kg was comparable to the standard drug, Silymarin (50 mg/kg, p.o.. Histopathological examination of the liver tissues supported the hepatoprotective activity of plant.

  20. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

    Directory of Open Access Journals (Sweden)

    Flaminia Pantano

    2016-04-01

    Full Text Available The 3Ks (kava, kratom and khat are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed.

  1. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

    Science.gov (United States)

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Zaami, Simona; Ricci, Serafino; Giorgetti, Raffaele; Terranova, Daniela; Busardò, Francesco P.; Marinelli, Enrico

    2016-01-01

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed. PMID:27092496

  2. Hepatoprotective Potential of Prosopis farcta Beans Extracts against Acetaminophen-induced Hepatotoxicity in Wister Rats

    OpenAIRE

    Akram Asadollahi; Hadi Sarir; Arash Omidi; Mohammad Bagher Montazar Torbati

    2014-01-01

    Background: Hepatotoxicity by acetaminophen is the most frequent cause of acute liver failure in many countries. Prosopis farcta beans extract (PFE) has some antioxidant property and may alleviate hepatotoxicity. Therefore, the aim of this study was to evaluate effects of PFE against acetaminophen-induced hepatotoxicity. Methods: Thirty-six male Wistar albino rats weighing 220 ± 30 g were distributed into six groups. Two groups were pretreated with PFE (50 and 75 mg/kg) for 7 days before ...

  3. Proteomics Investigations of Drug-Induced Hepatotoxicity in HepG2 Cells

    OpenAIRE

    Van Summeren, Anke; Renes, Johan; Bouwman, Freek G.; Noben, Jean-Paul; van Delft, Joost H. M.; Kleinjans, Jos C.S.; Mariman, Edwin C. M.

    2011-01-01

    Unexpected hepatotoxicity is one of the major reasons of drugs failing in clinical trials. This emphasizes the need for new screening methods that address toxicological hazards early in the drug discovery process. Here, proteomics techniques were used to gain further insight into the mechanistic processes of the hepatotoxic compounds. Drug-induced hepatotoxicity is mainly divided in hepatic steatosis, cholestasis, or necrosis. For each class, a compound was selected, respectively amiodarone, ...

  4. Hepatotoxicity by Drugs: The Most Common Implicated Agents.

    Science.gov (United States)

    Björnsson, Einar S

    2016-02-06

    Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab.

  5. Hepatotoxicity by Drugs: The Most Common Implicated Agents

    Directory of Open Access Journals (Sweden)

    Einar S. Björnsson

    2016-02-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov. According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab.

  6. The Possible Efficacy of Artichoke in Fluconazole Related Hepatotoxicity

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    Hüseyin Kurt

    2014-01-01

    Full Text Available Although fluconazole related hepatotoxicity (FRH is rare, mortal acute hepatic necrosis and jaundice were reported in immunocompromised states such as acquired immunodeficiency syndrome (AIDS and bone marrow transplant (BMT. We present a case of a patient with multiple sclerosis who developed hepatotoxicity with the use of a single 150 mg fluconazole tablet for fungal vaginitis, 10 days after methylprednisolone pulse treatment. Our patient’s alanine aminotransferase (ALT and aspartate aminotransferase (AST levels were decreased, 1200 U/L and 800 U/L, respectively, and bilirubin levels were consistent at 37 mg/dL. Artichoke which has anticholestatic and antioxidant properties was used by our patient. She consumed a 30 mg artichoke leaf extract tea 3 times a day. The bilirubin levels significantly declined at the end of the first week and all liver function tests were normalized within 2 months.

  7. Exacerbation of acetaminophen hepatotoxicity by the anthelmentic drug fenbendazole.

    Science.gov (United States)

    Gardner, Carol R; Mishin, Vladimir; Laskin, Jeffrey D; Laskin, Debra L

    2012-02-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8-12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole.

  8. Propylthiouracil Hepatotoxicity Seen with Jaundice and its Treatment by Steroids

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    Oguzhan Aksu

    2014-08-01

    Full Text Available Propylthiouracil (PTU is widely used in the treatment of hyperthyroidism and rarely leads to hepatotoxicity by an unknown mechanism. The hepatic damage caused by propylthiouracil is generally subclinical, but very rarely, it may be associated with severe liver injury and submassive hepatic necrosis. Although discontinuing of the drug result in full recovery in most cases, hyperbilirubinemia and liver damage may increasingly continue in spite of discontinuation of the drug.

  9. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus

    OpenAIRE

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Objective: Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Materials and Methods: Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were ad...

  10. Effect of coriander on thioacetamide-induced hepatotoxicity in rats.

    Science.gov (United States)

    Moustafa, Abdel Halim A; Ali, Ehab Mostafa M; Moselhey, Said S; Tousson, Ehab; El-Said, Karim S

    2014-08-01

    Thioacetamide (TAA) is a potent hepatotoxin that causes centrilobulal necrosis and nephrotoxic damage following acute administration. Prolonged exposure to TAA can result in bile duct proliferation and liver cirrhosis histologically similar to that caused due to viral hepatitis infection. Coriander in food increases the antioxidant content, acting as a natural antioxidant and inhibiting undesirable oxidation processes. The present study investigated the antioxidant activity of Coriandrum sativum on TAA-induced hepatotoxicity in the male rats. Phenolic content and antioxidant activity were evaluated in the coriander leaves and seeds. Forty-eight adult male rats were divided into four groups. Group I (control), group II (TAA injected rats), group III (TAA injected rats fed coriander leaves) and group IV (TAA injected rats fed coriander seeds). The results revealed that serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were significantly increased in the groups II, III and IV as compared to the normal control. Oxidative stress in the group II was manifested by a significant rise in nitric oxide (NO), thiobarbituric acid reactive substance (TBARS) levels and myloperoxidase (MPO) activities in the liver tissues as compared with the control group. Rats fed with coriander leaves and seeds showed a decrease in the serum ALT, AST and ALP activities and in the liver NO and TBARS levels as compared to the group II. Histopathological study revealed that coriander feeding attenuated TAA-induced hepatotoxicity in the rats. In conclusion, coriander leaves attenuate hepatotoxicity induced by TAA more than that of seeds due to the higher content of phenolic compounds and antioxidants in the leaves of coriander. Liver of rats intoxicated with TAA exhibited advanced CIRRHOSIS: in the form of macronodular and micronodular structure surrounded by fibrous tissue. Treatment with coriander leaves and seeds helps in improving

  11. A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity

    Science.gov (United States)

    Patel, Suraj J; Luther, Jay; Bohr, Stefan; Iracheta-Vellve, Arvin; Li, Matthew; King, Kevin R; Chung, Raymond T; Yarmush, Martin L

    2016-01-01

    Objectives: Acetaminophen (APAP)-induced hepatotoxicity is a major cause of morbidity and mortality. The current pharmacologic treatment for APAP hepatotoxicity, N-acetyl cysteine (NAC), targets the initial metabolite-driven injury but does not directly affect the host inflammatory response. Because of this, NAC is less effective if given at later stages in the disease course. Resolvins, a novel group of lipid mediators shown to attenuate host inflammation, may be a therapeutic intervention for APAP hepatotoxicity. Methods: The temporal patterns of liver injury and neutrophil activation were investigated in a murine model of APAP hepatotoxicity. In addition, the effect of neutrophil depletion and resolvin administration on the severity of liver injury induced by APAP was studied. In vitro studies to investigate the mechanism of resolvin effect on hepatocyte injury and neutrophil adhesion were performed. Results: We demonstrate that hepatic neutrophil activation occurs secondary to the initial liver injury induced directly by APAP. We also show that neutrophil depletion attenuates APAP-induced liver injury, and administration of resolvins hours after APAP challenge not only attenuates liver injury, but also extends the therapeutic window eightfold compared to NAC. Mechanistic in vitro analysis highlights resolvins' ability to inhibit neutrophil attachment to endothelial cells in the presence of the reactive metabolite of APAP. Conclusions: This study highlights the ability of resolvins to protect against APAP-induced liver injury and extend the therapeutic window compared to NAC. Although the mechanism for resolvin-mediated hepatoprotection is likely multifactorial, inhibition of neutrophil infiltration and activation appears to play an important role. PMID:26986653

  12. Hepatotoxicity of NONI juice: Report of two cases

    Institute of Scientific and Technical Information of China (English)

    Vanessa Stadlbauer; Peter Fickert; Carolin Lackner; Jutta Schmerlaib; Peter Krisper; Michael Trauner; Rudolf E Stauber

    2005-01-01

    NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses.No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed. The first patient underwent successful liver transplantation while the second patient recovered spontaneously after cessation of NONI juice.A 29-year-old man with previous toxic hepatitis associated with small doses of paracetamol developed sub-acute hepatic failure following consumption of 1.5 L NONI juice over 3 wk necessitating urgent liver transplantation. A 62-year-old woman without evidence of previous liver disease developed an episode of self-limited acutehepatitis following consumption of 2 L NONI juice for over 3 mo. The most likely hepatotoxic components of Morinda citrifolia were anthraquinones. Physicians should be aware of potential hepatotoxicity of NONI juice.

  13. Antioxidant modulation of nevirapine induced hepatotoxicity in rats.

    Science.gov (United States)

    Awodele, Olufunsho; Popoola, Temidayo; Rotimi, Kunle; Ikumawoyi, Victor; Okunowo, Wahab

    2015-03-01

    HIV/AIDS related mortality has been dramatically reduced by the advent of antiretroviral therapy (ART). However, ART presents with associated adverse effects. One of such adverse effects is hepatotoxicity observed with nevirapine (NVP) containing ART. Since previous studies showed that NVP hepatotoxicity may be due to oxidative stress via generation of oxidative radicals, this study sought to evaluate the protective effects of antioxidants in alleviating NVP induced hepatotoxicity. Rats were divided into 6 groups with 8 animals per group and received doses of the antioxidants jobelyn (10.7 mg/kg/day), vitamin C (8 mg/kg/day), vitamin E (5 mg/kg/day) and/or NVP (6 mg/kg/day) for 60 days. The animals were sacrificed on day 61 by cervical dislocation, blood samples were collected for biochemical and hematological examination. The liver of the sacrificed animals was weighed and subjected to histopathological examination. There was a statistically significant (prats. A significantly (prats showed no visible pathology across the groups. Observations from this study suggest a potentially positive modulatory effect of antioxidants and may be indicative for the inclusion of antioxidants in nevirapine containing ART.

  14. Methotrexate Hepatotoxicity; the Danger Not to Be Ignored

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    M Baghbanian

    2013-06-01

    Full Text Available Introduction: Methotrexate is used increasingly for treatment of some diseases such as rheumatoid arthritis, psoriasis and Crohn. Bone marrow suppression, mucocutaneous lesions, pneumonitis, and hepatotoxicity are major side effects of this drug. Since methotrexate toxicity is dose dependent and is usually administered with low dose via a weekly regimen, its side effects are not commonly seen. But due to long term prescription of this drug over the recent years especially for rheumatoid arthritis, growing cases of methotrexate hepatotoxicity are referred to Gastroenterologist. High dose of drug, high age, alcohol consumption, renal failure and preexisting liver disease are main risk factors for this toxicity. In this study, in addition to presenting two cases with cirrhosis and two cases with hepatitis linked to methotrexate, the clinical aspects on this field are discussed. Conclusions: Methotrexate hepatotoxicity is not a theoretical issue that can be ignored because it can lead to cirrhosis and liver failure. We can prevent the onset of this growing side effect with appropriate patient selection and investigating the patients’ liver function before and during Methotrexate therapy. Periodic testing the liver enzymes is used for monitoring the liver condition, but because interpretation of these tests is sometimes difficult, liver biopsy is needed in particular cases.

  15. Hepatotoxic potential of asarones: In vitro evaluation of hepatotoxicity and quantitative determination in herbal products

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    Dhavalkumar Narendrabha Patel

    2015-02-01

    Full Text Available α and β asarones are natural constituents of some aromatic plants, especially species of the genus Acorus. In addition to beneficial properties of asarones, genotoxicity and carcinogenicity are also reported. Due to potential toxic effects of β-asarone, a limit of exposure from herbal products of approximately 2 μg/kg body weight/day has been set temporarily until a full benefit/risk assessment has been carried out by the European Medicines Agency. Therefore, it is important to monitor levels of β-asarone in herbal products. In this study, we developed a simple, rapid and validated GC-MS method for quantitative determination of asarones and applied it in 20 pediatric herbal products after detecting high concentrations of β-asarone in a product suspected to be implicated in hepatotoxicity in a 3 month old infant. Furthermore, targeted toxicological effects were further investigated in human hepatocytes (THLE-2 cells by employing various in vitro assays, with the goal of elucidating possible mechanisms for the observed toxicity. Results showed that some of the products contained as much as 4 to 25 times greater amounts of β-asarone than the recommended levels. In 4 of 10 samples found to contain asarones, the presence of asarones could not be linked to the labeled ingredients, possibly due to poor quality control. Cell-based investigations in THLE2 cells confirmed the cytotoxicity of -asarone (IC50 = 40.0 ± 2.0 µg/mL which was associated with significant lipid peroxidation and glutathione depletion. This observed cytotoxicity effect is likely due to induction of oxidative stress by asarones. Overall, the results of this study ascertained the usability of this GC-MS method for the quantitative determination of asarones from herbal products, and shed light on the importance of controlling the concentration of potentially toxic asarones in herbal products to safeguard consumer safety. Further investigations of the toxicity of asarones are

  16. Hepatotoxicity of antiretrovirals in patients with human immunodeficiency virus and viral hepatitis coinfections

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    P Parenti

    2012-11-01

    Full Text Available Background: Antiretroviral drugs used to treat HIV may cause hepatotoxicity. The high prevalence of persons with chronic hepatitis B or C coinfected, raised aminotransferases have many causes and neither specific markers is a indicator of liver injury, difficulties in interpreting the hepatotoxicity. Objective: We evaluated hepatotoxicity in HIV/HCV- and/or HBV-coinfected patients, risk factors and severity. Methods: Prospective study of HIV-1 patients with start HAART in Hospital Provincial del Centenario from Rosario, Argentina. Patients were classified into two groups, HCV and/or HBV coinfected vs. no coinfected. The major endpoint was hepatotoxicity defined as Benichou's Score within the first 6 months. This score is among the few validated, but little used in clinical practice. Secondary endpoints were risk factors and severity of hepatotoxicity. Results: 140 patients were included, 39% coinfected and 61% no coinfected. Females were similar in both groups; 21% and 27% respectively. The hepatotoxicity within the first 6 month was 44.3%, 75% in coinfected patients and 25% in no-coinfected. RR 3.97 (95% confidence interval 2.34–6.75, p<0.0001. The hepatotoxicity was associated with the use of illicit drugs and alcohol, symptoms, high level aminotransferases previous to HAART and NNRTI+PI. 3% of hepatotoxicity was severe. Conclusions: 44% of HIV patients experienced hepatotoxicity, 75% in coinfected vs 25% in no coinfected. The relative risk of hepatoxocity was almost 4 times higher among in chronic hepatitis-coinfected patients, compared with those with HIV non-coinfected. In multivariate analysis, the risk factors were illicit drugs, alcohol, symptoms, high level aminotransferases and NRTI+PI. Only 3% of hepatotoxicity was severe. The Benichou's Score is better than level of aminotransferase for evaluated hepatotoxicity, so it would be recommended for use in clinical practice.

  17. Croton zehntneri Essential oil prevents acetaminophen-induced acute hepatotoxicity in mice

    OpenAIRE

    Maria Goretti R. Queiroz; José Henrique L. Cardoso; Tomé, Adriana R; Roberto C. P. Lima Jr.; Jamile M. Ferreira; Daniel F. Sousa; Felipe C. Lima; Campos, Adriana R.

    2008-01-01

    Hepatoprotective activity of Croton zehntneri Pax & Hoffman (Euphorbiaceae) leaf essential oil (EOCz) was evaluated against single dose of acetaminophen-induced (500 mg/kg, p.o.) acute hepatotoxicity in mice. EOCz significantly protected the hepatotoxicity as evident from the activities of serum glutamate pyruvate transaminase (GPT), serum glutamate oxaloacetate transaminase (GOT) activities, that were significantly (p

  18. Hepatotoxicity during Treatment for Tuberculosis in People Living with HIV/AIDS

    Science.gov (United States)

    Araújo-Mariz, Carolline; Lopes, Edmundo Pessoa; Acioli-Santos, Bartolomeu; Maruza, Magda; Montarroyos, Ulisses Ramos; Ximenes, Ricardo Arraes de Alencar; Lacerda, Heloísa Ramos; Miranda-Filho, Demócrito de Barros; de Albuquerque, Maria de Fátima P. Militão

    2016-01-01

    Hepatotoxicity is frequently reported as an adverse reaction during the treatment of tuberculosis. The aim of this study was to determine the incidence of hepatotoxicity and to identify predictive factors for developing hepatotoxicity after people living with HIV/AIDS (PLWHA) start treatment for tuberculosis. This was a prospective cohort study with PLWHA who were monitored during the first 60 days of tuberculosis treatment in Pernambuco, Brazil. Hepatotoxicity was considered increased levels of aminotransferase, namely those that rose to three times higher than the level before initiating tuberculosis treatment, these levels being associated with symptoms of hepatitis. We conducted a multivariate logistic regression analysis and the magnitude of the associations was expressed by the odds ratio with a confidence interval of 95%. Hepatotoxicity was observed in 53 (30.6%) of the 173 patients who started tuberculosis treatment. The final multivariate logistic regression model demonstrated that the use of fluconazole, malnutrition and the subject being classified as a phenotypically slow acetylator increased the risk of hepatotoxicity significantly. The incidence of hepatotoxicity during treatment for tuberculosis in PLWHA was high. Those classified as phenotypically slow acetylators and as malnourished should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis. The use of fluconazole should be avoided during tuberculosis treatment in PLWHA. PMID:27332812

  19. Contaminant hepatotoxins as culprits for kava hepatotoxicity--fact or fiction?

    Science.gov (United States)

    Teschke, Rolf; Sarris, Jerome; Lebot, Vincent

    2013-03-01

    The culprit of kava hepatotoxicity will continue to remain a mystery in humans, if the underlying reaction is of idiosyncratic, unpredictable, and dose-independent nature due potentially to some metabolic aberration in a few individuals emerging from kava use. In addition, kava hepatotoxicity is presently not reproducible experimentally in preclinical models, as demonstrated by studies showing whole kava extracts are not hepatotoxic. This led us to propose our 'working hypothesis' that contaminant hepatotoxins including moulds might have caused rare kava hepatotoxicity in humans. Further studies are now warranted to proof or disproof our working hypothesis, because kava hepatotoxicity possibly based on contaminant hepatotoxins could be a preventable disease. In the meantime, however, for minimizing toxicity risk in kava users, a pragmatic approach should focus on the medicinal use of an aqueous extract derived from peeled rhizomes and roots of a non-mouldy noble kava cultivar, limited to maximum 250-mg kavalactones daily for acute or intermittent use.

  20. Reference genes for real-time PCR quantification of microRNAs and messenger RNAs in rat models of hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    María N Lardizábal

    Full Text Available Hepatotoxicity is associated with major changes in liver gene expression induced by xenobiotic exposure. Understanding the underlying mechanisms is critical for its clinical diagnosis and treatment. MicroRNAs are key regulators of gene expression that control mRNA stability and translation, during normal development and pathology. The canonical technique to measure gene transcript levels is Real-Time qPCR, which has been successfully modified to determine the levels of microRNAs as well. However, in order to obtain accurate data in a multi-step method like RT-qPCR, the normalization with endogenous, stably expressed reference genes is mandatory. Since the expression stability of candidate reference genes varies greatly depending on experimental factors, the aim of our study was to identify a combination of genes for optimal normalization of microRNA and mRNA qPCR expression data in experimental models of acute hepatotoxicity. Rats were treated with four traditional hepatotoxins: acetaminophen, carbon tetrachloride, D-galactosamine and thioacetamide, and the liver expression levels of two groups of candidate reference genes, one for microRNA and the other for mRNA normalization, were determined by RT-qPCR in compliance with the MIQE guidelines. In the present study, we report that traditional reference genes such as U6 spliceosomal RNA, Beta Actin and Glyceraldehyde-3P-dehydrogenase altered their expression in response to classic hepatotoxins and therefore cannot be used as reference genes in hepatotoxicity studies. Stability rankings of candidate reference genes, considering only those that did not alter their expression, were determined using geNorm, NormFinder and BestKeeper software packages. The potential candidates whose measurements were stable were further tested in different combinations to find the optimal set of reference genes that accurately determine mRNA and miRNA levels. Finally, the combination of MicroRNA-16/5S Ribosomal RNA and

  1. Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity.

    Science.gov (United States)

    Castellino, Stephen; O'Mara, Michael; Koch, Kevin; Borts, David J; Bowers, Gary D; MacLauchlin, Christopher

    2012-01-01

    Lapatinib (Tykerb, Tyverb) is an important orally active dual tyrosine kinase inhibitor efficacious in combination therapy for patients with progressive human epidermal receptor 2-overexpressing metastatic breast cancer. However, clinically significant liver injury, which may be associated with lapatinib metabolic activation, has been reported. We describe the metabolism and excretion of [(14)C]lapatinib in six healthy human volunteers after a single oral dose of 250 mg and the potential relationships between metabolism and clinical hepatotoxicity. Overall, elimination showed high intersubject variability, with fecal elimination being the predominant pathway, representing a median of 92% of the dose with lapatinib as the largest component (approximate median 27% of the dose). In plasma, approximately 50% of the observed radioactivity was attributed to metabolites. Analysis of a 4-h pooled plasma extract identified seven metabolites related by an N- and α-carbon oxidation cascade. Fecal metabolites derived from three prominent pathways: N- and α-carbon oxidation, fluorobenzyl oxidative cleavage, and hydroxypyridine formation. Several of the lapatinib metabolites can undoubtedly be linked to reactive species such as aldehydes or quinone imines. In addition to the contribution of these potentially reactive metabolites as suspects in clinical liver injury, the role of other disposition factors, including interaction with drug transporters, pharmacogenetics, or magnitude of the therapeutic dose, should not be discounted.

  2. Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity.

    Science.gov (United States)

    Yohe, Herbert C; O'Hara, Kimberley A; Hunt, Jane A; Kitzmiller, Tamar J; Wood, Sheryl G; Bement, Jenna L; Bement, William J; Szakacs, Juliana G; Wrighton, Steven A; Jacobs, Judith M; Kostrubsky, Vsevolod; Sinclair, Peter R; Sinclair, Jacqueline F

    2006-06-01

    The objective of this study was to determine whether Toll-like receptor 4 (TLR4) has a role in alcohol-mediated acetaminophen (APAP) hepatotoxicity. TLR4 is involved in the inflammatory response to endotoxin. Others have found that ethanol-mediated liver disease is decreased in C3H/HeJ mice, which have a mutated TLR4 resulting in a decreased response to endotoxin compared with endotoxin-responsive mice. In the present study, short-term (1 wk) pretreatment with ethanol plus isopentanol, the predominant alcohols in alcoholic beverages, caused no histologically observed liver damage in either C3H/HeJ mice or endotoxin-responsive C3H/HeN mice, despite an increase in nitrotyrosine levels in the livers of C3H/HeN mice. In C3H/HeN mice pretreated with the alcohols, subsequent exposure to APAP caused a transient decrease in liver nitrotyrosine formation, possibly due to competitive interaction of peroxynitrite with APAP producing 3-nitroacetaminophen. Treatment with APAP alone resulted in steatosis in addition to congestion and necrosis in both C3H/HeN and C3H/HeJ mice, but the effects were more severe in endotoxin-responsive C3H/HeN mice. In alcohol-pretreated endotoxin-responsive C3H/HeN mice, subsequent exposure to APAP resulted in further increases in liver damage, including severe steatosis, associated with elevated plasma levels of TNF-alpha. In contrast, alcohol pretreatment of C3H/HeJ mice caused little to no increase in APAP hepatotoxicity and no increase in plasma TNF-alpha. Portal blood endotoxin levels were very low and were not detectably elevated by any of the treatments. In conclusion, this study implicates a role of TLR4 in APAP-mediated hepatotoxicity.

  3. Green Tea Extract-induced Acute Hepatotoxicity in Rats.

    Science.gov (United States)

    Emoto, Yuko; Yoshizawa, Katsuhiko; Kinoshita, Yuichi; Yuki, Michiko; Yuri, Takashi; Yoshikawa, Yutaka; Sayama, Kazutoshi; Tsubura, Airo

    2014-10-01

    Although green tea is considered to be a healthy beverage, hepatotoxicity associated with the consumption of green tea extract has been reported. In the present study, we characterized the hepatotoxicity of green tea extract in rats and explored the responsible mechanism. Six-week-old IGS rats received a single intraperitoneal (ip) injection of 200 mg/kg green tea extract (THEA-FLAN 90S). At 8, 24, 48 and 72 hrs and 1 and 3 months after exposure, liver damage was assessed by using blood-chemistry, histopathology, and immunohistochemistry to detect cell death (TUNEL and caspase-3) and proliferative activity (PCNA). Analyses of malondialdehyde (MDA) in serum and the liver and of MDA and thymidine glycol (TG) by immunohistochemistry, as oxidative stress markers, were performed. Placental glutathione S-transferase (GST-P), which is a marker of hepatocarcinogenesis, was also immunohistochemically stained. To examine toxicity at older ages, 200 mg/kg green tea extract was administered to 18-wk-old female rats. In 6-wk-old rats, 12% of males and 50% of females died within 72 hrs. In 18-wk-old rats, 88% died within 72 hrs. The serum levels of aspartate aminotransferase, alanine aminotransferase and/or total bilirubin increased in both males and females. Single-cell necrosis with positive signs of TUNEL and caspase-3 was seen in perilobular hepatocytes from 8 hrs onward in all lobular areas. PCNA-positive hepatocytes increased at 48 hrs. MDA levels in the serum and liver tended to increase, and MDA- and TG-positive hepatocytes were seen immunohistochemically. GST-P-positive hepatocellular altered foci were detected in one female rat at the 3-month time point. In conclusion, a single injection of green tea extract induced acute and severe hepatotoxicity, which might be associated with lipid peroxidation and DNA oxidative stress in hepatocytes.

  4. Quantitative Phytochemical Estimation and Evaluation of Hepatoprotective Activity of Methanolic Extract of Dendrobium ovatum (L. Kraenzl. Whole Plant against CCl4 Induced Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Seru Ganapaty

    2013-09-01

    Full Text Available A large number of populations suffer due to various reasons from hepatic diseases of unknown origin. The development of antihepatotoxic drugs being a major thrust area has drawn the attention of workers in the field of natural product research because synthetic drugs may cause serious side effects. The present research was aimed to study the in vivo hepatoprotective activity of methanolic extract of Dendrobium ovatum (L. Kraenzl. Whole plant, which was used traditionally in Chittoor and Khammam districts of Andhra Pradesh, by carbon tetrachloride (CCl4 induced hepatotoxicity animal model and standard drug silymarin. The level of serum aspartate aminotransferase (SGOT, alanine aminotransferase (SGPT, alkaline phosphatase (ALP and total bilirubin (T. BILI. were determined to assay hepatotoxicity. CCl4 administration caused severe hepatic damage in rats as evidenced by elevated serum SGOT, SGPT, ALP and T. BILI. Levels. The D. ovatum and silymarin administration prevented the toxic effect of CCl4 on the above serum parameters in both preventive and curative models. The present study concludes that, methanolic extract of D. ovatum has significant hepatoprotective activity against CCl4 induced hepatotoxicity, which support folkloric utilization and further confirmed by the histological investigation. The observed activity may be associated with its high bioactive compounds including flavonoids, alkaloids, triterpenoids, glycosides, steroids and carbohydrates.

  5. Amelioration of SD rats acute liver injury model induced by carbon tetrachloride%CCl4致SD大鼠急性肝损伤模型制作的改进

    Institute of Scientific and Technical Information of China (English)

    张旻; 唐晓鹏; 李代强; 童敏; 王文龙

    2004-01-01

    Objective: The purpose of this study was to optimize carbon tetrachloride-induced hepatotoxicity in the rat with respect to dose and time course. Method: Carbon tetrachloride with different dosage was given to SD rats by abdominal injection. Rat ALT and AST in serum were analyzed 48 h and rats liver were observed with routine pathology technique, to determine mice liyers' functional and morphological changes after administration. Results: The serum level of ALT and AST increased significantly in 3A~7A CCl4 groups compared with the control group (P<0.05 or P<0.01). The pathological changes in can be seen in every ccl4 group, the damnification degree of liver cells were remarkably aggravated with the control group. Deceased rats were seen in 6A and 7A group. Conclusion: Ameliorated acute liver injury model of mice was established, which has definite liver injury with lower mortality rate and less damnification to other organs, can be used for the mechanism and treatment research of acute liver injury.%目的本文筛选CCl4致SD大鼠急性肝损伤模型的最佳给药浓度和剂量,追踪观察模型大鼠肝损伤后修复过程.方法本文采用随机对照分组的研究方法,对不同的SD大鼠模型组给予不同剂量的CCl4一次性腹腔注射.给药后48h检测大鼠血清ALT,AST.各组随机处死一只SD大鼠,取肝组织制成病理切片镜下观察.追踪观察筛选后的CCl4模型大鼠肝组织病理变化恢复情况.结果本实验发现3A-7A组的ALT,AST较对照组明显升高(P<0.05或P<0.01),随着CCl4的剂量的增加,大鼠肝组织的病理损伤加重,6A和7A组可见自然死亡大鼠.结论本试验筛选了CCl4致SD大鼠急性肝损伤模型的较好CCl4的剂量.该模型肝损伤明显,死亡率低,对其他重要脏器影响小,可作为急性肝损伤研究的较好模型.

  6. Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats.

    Science.gov (United States)

    Jacevic, Vesna; Djordjevic, Aleksandar; Srdjenovic, Branislava; Milic-Tores, Vukosava; Segrt, Zoran; Dragojevic-Simic, Viktorija; Kuca, Kamil

    2017-03-16

    Doxorubicin (DOX), commonly used antineoplastic agent, affects bone marrow, intestinal tract and heart, but it also has some hepatotoxic effects. Main mechanism of its toxicity is the production of free reactive oxygen species. Polyhidroxilated C60 fullerene derivatives, fullerenol nanoparticles (FNP), act as free radical scavengers in in vitro systems. The aim of the study was to investigate potential FNP protective role against DOX-induced hepatotoxicity in rats. Experiments were performed on adult male Wistar rats. Animals were divided into five groups: (1) 0.9% NaCl (control), (2) 100mg/kg ip FNP, (3) 10mg/kg DOX iv, (4) 50mg/kg ip FNP 30min before 10mg/kg iv DOX, (5) 100mg/kg ip FNP 30min before 10mg/kg iv DOX. A general health condition, body and liver weight, TBARS level and antioxidative enzyme activity, as well as pathohistological examination of the liver tissue were conducted on days 2 and 14 of the study. FNP, applied alone, did not alter any examinated parameters. However, when used as a pretreatment it significantly increased survival rate, body and liver weight, and decreased TBARS level, antioxidative enzyme activity and hepatic damage score in DOX-treated rats. FNP administered at a dose of 100mg/kg significantly attenuated effects of doxorubicin administered in a single high dose in rats, concerning general condition, body and liver weight, lipid peroxidation level and antioxidative enzyme activity as well as structural alterations of the hepatic tissue.

  7. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

    Directory of Open Access Journals (Sweden)

    Miren García-Cortés

    2016-04-01

    Full Text Available Dietary supplements (DS are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™ while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang. Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  8. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics.

    Science.gov (United States)

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J

    2016-04-09

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  9. Lipoic acid attenuates Aroclor 1260-induced hepatotoxicity in adult rats.

    Science.gov (United States)

    Aly, Hamdy A A; Mansour, Ahmed M; Hassan, Memy H; Abd-Ellah, Mohamed F

    2016-08-01

    The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase-3 & -9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260-induced liver injury. Lipoic acid could protect rats against Aroclor 1260-induced hepatotoxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913-922, 2016.

  10. Hepatotoxic Alterations Induced by Inhalation of Trichloroethylene (TCE) in Rats

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective Trichloroethylene (TCE) is one of the most potent organic unsaturated solvents being used in dry cleaning, metal degreasing, thinner for paints varnishes and electroplating, etc. and has been reported to be a hepatotoxicant through oral and dermal exposure. However, its inhalation toxicity data is very limited in the literature due to the fact that the exposure levels associated with these effects were usually not reported. Hence, inhalation toxicity study was carried out for hepatotoxic studies. Method Inhalation toxicity studies was carried out by exposing rats to TCE for 8, 12 and 24 weeks in a dynamically operated whole body inhalation chamber. Sham treated control rats were exposed to compressed air in the inhalation chamber for the same period. Results Significant increase in liver weight (liver enlargement) appearance of necrotic lesions with fatty changes and marked necrosis were observed after longer duration (12 and 24 weeks) of TCE exposure. The lysosomal rupture resulted in increased activity of acid and alkaline phosphatase alongwith reduced glutathione content and total increased sulfhydryl content in liver tissue. Conclusion TCE exposure through Inhalation route induces hepatotoxicity in terms of marked necrosis with fatty changes and by modulating the lysosomal enzymes.

  11. Gadolinium chloride pretreatment ameliorates acute cadmium-induced hepatotoxicity.

    Science.gov (United States)

    Kyriakou, Loukas G; Tzirogiannis, Konstantinos N; Demonakou, Maria D; Kourentzi, Kalliopi T; Mykoniatis, Michael G; Panoutsopoulos, Georgios I

    2013-08-01

    Cadmium is a known industrial and environmental pollutant. It causes hepatotoxicity upon acute administration. Features of cadmium-induced acute hepatoxicity encompass necrosis, apoptosis, peliosis and inflammatory infiltration. Gadolinium chloride (GdCl3) may prevent cadmium-induced hepatotoxicity by suppressing Kupffer cells. The effect of GdCl3 pretreatment on a model of acute cadmium-induced liver injury was investigated. Male Wistar rats 4-5 months old were injected intraperitoneally with normal saline followed by cadmium chloride (CdCl2; 6.5 mg/kg) or GdCl3 (10 mg/kg) followed by CdCl2 (6.5 mg/kg; groups I and II, respectively). Rats of both the groups were killed at 9, 12, 16, 24, 48 and 60 h after cadmium intoxication. Liver sections were analyzed for necrosis, apoptosis, peliosis and mitoses. Liver regeneration was also evaluated by tritiated thymidine incorporation into hepatic DNA. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also determined. Hepatic necrosis, hepatocyte and nonparenchymal cell apoptosis and macroscopic and microscopic types of peliosis hepatis were minimized by gadolinium pretreatment. Serum levels of AST and ALT were also greatly diminished in rats of group II. Tritiated thymidine incorporation into hepatic DNA was increased in gadolinium pretreatment rats. Kupffer cell activation was minimal in both the groups of rats. Gadolinium pretreatment attenuates acute cadmium-induced liver injury in young Wistar rats, with mechanisms other than Kupffer cell elimination.

  12. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus

    Science.gov (United States)

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Objective: Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Materials and Methods: Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were administered with 25, 50 and 75 mg/kg body weight blend of sunset yellow, metanil yellow and tartrazine for 30 days. Hepatotoxicity in rats treated with a blend of these food colors was studied by assessing parameters such as serum total protein, serum albumin, serum alkaline phosphatase (ALP) as well as hepatic malondialdehyde (MDA). The activity of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were assessed. Results: Significantly increased concentrations of serum total protein, serum albumin, serum ALP and hepatic MDA and significantly lowered levels of SOD, reduced GSH and CAT in the liver tissue of treated animals were observed when compared with control animals. The alteration in the liver includes necrosis of hepatocytes, infiltration and vacuolation. Conclusion: The result indicates that consumption of food color in diet induces liver tissue damage. The used doses of food color were mostly attributable to hepatocellular damage and drastic alteration in antioxidant defense system. PMID:26862277

  13. Gene expression profiling reveals potential key pathways involved in pyrazinamide-mediated hepatotoxicity in Wistar rats.

    Science.gov (United States)

    Zhang, Yun; Jiang, Zhenzhou; Su, Yijing; Chen, Mi; Li, Fu; Liu, Li; Sun, Lixin; Wang, Yun; Zhang, Shuang; Zhang, Luyong

    2013-08-01

    Pyrazinamide (PZA) is an important sterilizing prodrug that shortens the duration of tuberculosis therapy. However, hepatotoxicity has been reported during clinical trials investigating PZA. To determine the hepatotoxic effects of PZA in vivo and to further investigate the underlying cellular mechanism, we profiled the gene expression patterns of PZA-treated rat livers by microarray analysis. Wistar rats of both sexes were orally administered PZA at doses of 0.5, 1.0 and 2.0 g kg(-1) for 28 days. Body weight, absolute and relative liver weight, biochemical analysis, histopathology, oxidative stress parameters in liver homogenates and changes in global transcriptomic expression were evaluated to study the hepatotoxic effects of PZA. Our results confirm the dose-dependent and sex-related hepatotoxicity of PZA. Female rats were more sensitive to PZA-induced hepatotoxicity than males. Furthermore, changes in the activity of major antioxidant enzymes and nonenzymatic antioxidants (superoxide dismutase, total antioxidant capacity, glutathione and malondialdehyde), indicating the development of oxidative stress, were more significant in the PZA-treated group. PZA-induced gene expression changes were related to pathways involved in drug metabolism, peroxisome proliferator-activated receptor (PPAR) signaling, oxidative stress and apoptosis. Real-time polymerase chain reaction confirmed the regulation of selected genes involved in PZA-hepatotoxicity (Ephx1, Cyp2b1, Gstm1, Gstp1, Fabp7, Acaa1, Cpt-1b, Cyp8b1, Hmox1 and Ntrk1). We observed for the first time that these genes have effects on PZA-induced hepatotoxicity. In addition, drug metabolism and PPAR signaling pathways may play an important role in PZA hepatotoxicity. Taken together, these findings will be useful for future PZA hepatotoxicity studies.

  14. Nanoemulsified ethanolic extract of Pyllanthus amarus Schum & Thonn ameliorates CCl4 induced hepatotoxicity in Wistar rats.

    Science.gov (United States)

    Deepa, V; Sridhar, R; Goparaju, A; Reddy, P Neelakanta; Murthy, P Balakrishna

    2012-11-01

    Phyllanthus amarus (PA) is commonly used in traditional medicine for hepatoprotectivity. The major limitation is that, treatment requires a large quantity of herbal extract for a longer duration. Aim of the present study was to encapsulate ethanolic plant extract for sustained release of constituents in intestine and facilitate maximum absorption. The efficacy was compared for the hepatoprotective activity of nanoencapsulated ethanolic extract of P. amarus (NPA) and PA in carbon tetrachloride (CCl4) induced hepatotoxic male rats. Based on total phenol content (TPC), the loading efficiency of nanocapsules was 89% (pH 7.0) and optimum concentration was 2:18 (mg/mL) for plant extract: olive oil. Scanning electron microscopy (SEM) showed a spherical morphology, photon correlation spectroscopy (PCS) identified mean particle diameter as 213 nm and Fourier transform infrared spectroscopy (FT-IR) revealed that the phytoconstituents were stable. An oral dose of NPA (20 mg/kg body wt.) showed a better hepatoprotective activity than PA (100 mg/kg body wt.) and also repeated dose oral toxicity proved to be safe. These biochemical assessments were supported by rat biopsy examinations. In conclusion, the nanoemulsification method may be applied for poor water-soluble ethanolic herbal extracts to reduce the dosage and time.

  15. Hepatotoxic microcystin removal using pumice embedded monolithic composite cryogel as an alternative water treatment method.

    Science.gov (United States)

    Gurbuz, Fatma; Ceylan, Şeyda; Odabaşı, Mehmet; Codd, Geoffrey A

    2016-03-01

    Microcystins are the most commonly encountered water-borne cyanotoxins which present short- and long-term risks to human health. Guidelines at international and national level, and legislation in some countries, have been introduced for the effective health risk management of these potent hepatotoxic, tumour-promoters. The stable cyclic structure of microcystins and their common production by cyanobacteria in waterbodies at times of high total dissolved organic carbon content presents challenges to drinking water treatment facilities, with conventional, advanced and novel strategies under evaluation. Here, we have studied the removal of microcystins using three different forms of pumice particles (PPs), which are embedded into macroporous cryogel columns. Macroporous composite cryogel columns (MCCs) are a new generation of separation media designed to face this challenging task. Three different MCCs were prepared by adding plain PPs, Cu(2+)-attached PPs and Fe(3+)-attached PPs to reaction media before the cryogelation step. Column studies showed that MCCs could be successfully used as an alternative water treatment method for successful microcystin removal.

  16. Leflunomide for the treatment of rheumatoid arthritis in clinical practice - Incidence and severity of hepatotoxicity

    NARCIS (Netherlands)

    van Roon, EN; Jansen, TLTA; Houtman, NM; Spoelstra, P; Brouwers, JRBJ

    2004-01-01

    Objective: Leflunomide is a novel disease modifying antirheumatic drug (DMARD). Because of reports on possible hepatotoxicity and adaptations in the recommendations for monitoring liver function during leflunomide treatment, we conducted a study to evaluate the incidence and severity of hepatotoxici

  17. A study of effect of Nigella sativa oil in paracetamol induced hepatotoxicity in albino rats

    Directory of Open Access Journals (Sweden)

    Manik S. Ghadlinge

    2014-06-01

    Conclusion: This study demonstrated that NS oil has hepatoprotective effect. NS oil administration can prevent or reverse the hepatotoxicity induced by paracetamol. [Int J Basic Clin Pharmacol 2014; 3(3.000: 539-546

  18. Nrf2 protects against furosemide-induced hepatotoxicity.

    Science.gov (United States)

    Qu, Qiang; Liu, Jie; Zhou, Hong-Hao; Klaassen, Curtis D

    2014-10-01

    Furosemide is a diuretic drug, but its reactive intermediates lead to acute liver injury in mice. Given the essential role of Nrf2 as a cellular defense regulator, we investigated whether Nrf2 would protect against furosemide-induced liver injury using the Nrf2 "gene-dose response" mouse model (Nrf2-null with Nrf2 knock-out, wild-type with normal expression of Nrf2, Keap1-KD with enhanced Nrf2 activation and Keap1-HKO mice with maximum Nrf2 activation). Twenty-four hours after furosemide administration (250mg/kg, i.p.), serum ALT activities and histopathological analysis indicated severe hepatotoxicity in Nrf2-null and WT mice, but significantly less in the Nrf2-overexpressing Keap1-KD and Keap1-HKO mice. Furosemide increased the mRNA of genes involved in the acute phase response (hemeoxygenase-1 and metallothionein-1), ER stress (C/Ebp-homologous protein and Growth arrest and DNA-damage-inducible protein), inflammatory cytokine (interleukin 1 beta), chemokines (macrophage inflammatory protein 2 and mouse keratinocyte-derived chemokine), as well as apoptosis (early growth response factor and BCL2-associated X protein) in livers of Nrf2-null and wild-type mice, but these genes increased less in mice with more Nrf2. The two genotypes of over-expressed Nrf2 mice had increased expression of the Nrf2 target genes Gclm, Gclc and Nqo1 prior to furosemide administration, and the expressions of these genes were increased further after furosemide administration. Thus, our findings provide strong evidence that over-expression of Nrf2 in Keap1-KD and Keap1-HKO mice and the increases in mRNA of a number of genes involved in anti-oxidative stress, anti-inflammation, anti-ER stress and anti-apoptosis protect against furosemide-induced hepatotoxicity.

  19. Effect of honey on hepatotoxicity induced by antitubercular drugs in albino rats

    OpenAIRE

    Rakhamaji D. Chandane; Jugalkishor B. Jaju; Manik S. Ghadlinge; Rama R. Bhosale; Ajay R. Chandrakapure

    2013-01-01

    Background: Drug-induced hepatotoxicity is a potentially serious adverse effect of antituberculosis treatment (ATT) regimens containing isoniazid, rifampicin and pyrazinamide. Many in vitro and in vivo studies revealed that honey possess antioxidant property and hepotoprotective property but there is no systematic work available to test the effect of honey on antitubercular drugs induced hepatotoxicity in rats. Hence present study was carried out to explore the prophylactic and therapeutic ef...

  20. Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients.

    Science.gov (United States)

    Kondo, Kazuma; Yamada, Naohito; Suzuki, Yusuke; Toyoda, Kaoru; Hashimoto, Tatsuji; Takahashi, Akemi; Kobayashi, Akio; Shoda, Toshiyuki; Kuno, Hideyuki; Sugai, Shoichiro

    2012-01-01

    Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent. However, some patients encounter hepatotoxicity after repeated APAP dosing at therapeutic doses. In the present study, we focused on the nutritional state as one of the risk factors of APAP-induced chronic hepatotoxicity in humans and investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model mimicking undernourished patients. Rats were divided into 2 groups: the ad libitum fed (ALF) and the restricted fed (RF) rats and were assigned to 3 groups (n = 8/group) for each feeding condition. The animals were given APAP at 0, 300 and 500mg/kg for 99 days under each feeding condition. Plasma and urinary glutathione-related metabolites and liver function parameters were measured during the dosing period and hepatic glutathione levels were measured at the end of the dosing period. In the APAP-treated ALF rats hepatic glutathione levels were increased and hepatic function parameters were not changed, but in the APAP-treated RF rats hepatic glutathione levels were decreased at 500mg/kg and hepatic function parameters were increased at 300 and 500mg/kg. Moreover the urinary endogenous metabolite profile after long-term treatment with APAP in the ALF and RF rats was similar to that in human non-responders and responders to APAP-induced chronic hepatotoxicity, respectively. In conclusion, the RF rats were more sensitive to APAP-induced chronic hepatotoxicity than the ALF rats and were considered to be a useful model to estimate the contribution of the nutritional state of patients to APAP-induced chronic hepatotoxicity.

  1. Hepatotoxicity or hepatoprotection? Pattern recognition for the paradoxical effect of the Chinese herb Rheum palmatum L. in treating rat liver injury.

    Directory of Open Access Journals (Sweden)

    Jia-bo Wang

    Full Text Available The hepatotoxicity of some Chinese herbs has been a cause for concern in recent years. However, some herbs, such as rhubarb, have been documented as having both therapeutic and toxic effects on the liver, leading to the complex problem of distinguishing the benefits from the risks of using this herb. To comparatively analyze the dose-response relationship between rhubarb and hepatic health, we administrated total rhubarb extract (RE to normal and carbon tetrachloride (CCl(4-treated rats for 12 weeks at 4 dosage levels (2.00, 5.40, 14.69 and 40.00 g·kg(-1, measured as the quantity of crude material, followed by biochemical and histopathological tests of the rats' livers. A composite pattern was extracted by factor analysis, using all the biochemical indices as variables, into a visual representation of two mathematically obtained factors, which could be interpreted as the fibrosis factor and the cellular injury factor, according to the values of the variable loadings. The curative effect of administering the two lowest dosages of RE to CCl(4-treated rats was mainly expressed as a decrease in the extent of cellular injury. The hepatoprotective mechanism of RE might be related to its antioxidant effect, the antagonism of the free radical damage to hepatocytes caused by CCl(4. By contrast, the RE-induced liver damage was mainly expressed as a significant increase in the amount of fibrosis in both normal rats at all dosage levels and CCl(4-treated rats at the two highest dosage levels. Therefore, the hepatotoxic potential of RE could be attributable to the liver cell fibrosis induced by high doses of the herb. This study illustrates the bidirectional potential of rhubarb and demonstrates the feasibility of using factor analysis to study the dose-response relationships between herbal medicines and hepatotoxicity or the healing effects of these herbs by extracting the underlying interrelationships among a number of functional bio-indices in a holistic

  2. Effects of erdosteine on acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Kuvandik, Guven; Duru, Mehmet; Nacar, Ahmet; Yonden, Zafer; Helvaci, Rami; Koc, Ahmet; Kozlu, Tolunay; Kaya, Hasan; Sogüt, Sadik

    2008-07-01

    We investigated the effects of erdosteine on acetaminophen (APAP)-induced hepatotoxicity in rats. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), AST (aspartate aminotransferase), and ALT (alanine transaminase) activities, and malonyldialdehyde (MDA) and nitric oxide levels as oxidant/antioxidant biochemical parameters were investigated with light microscopic evaluation in adult female Wistar Albino rats. APAP administration produced a decrease in hepatic SOD, CAT, and GSH-Px activities, and coadministration of erdosteine (150 and 300 mg/kg) resulted in increases in the activities. MDA and NO levels increased in the APAP group, and erdosteine treatments prevented these increases. Significant elevations in serum AST and ALT levels were observed in the APAP group, and when erdosteine and APAP were coadministered, their serum levels were close to those in the control group. Light microscopic evaluation of livers showed that there were remarkable centrilobular (zone III) hepatic necrosis and mild to moderate sinusoidal congestion in the APAP group, whereas in the erdosteine group, cellular necrosis was minimal and the hepatocytes maintained a better morphology when compared to the APAP group. Erdosteine prevented APAP-induced liver injury and toxic side effects probably through the antioxidant and radical scavenging effects of erdosteine.

  3. Inhibitory effects of Schisandra chinensis on acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    Wang, Kun-Peng; Bai, Yu; Wang, Jian; Zhang, Jin-Zhen

    2014-05-01

    Schisandra chinensis is a well-known traditional medicinal herb. Acetaminophen is a commonly used over-the-counter analgesic and overdose of acetaminophen was the most frequent cause of acute liver failure. However, no studies have demonstrated the role of Schisandra chinensis in acetaminophen-induced acute liver failure to the best of our knowledge. In this study, an acute liver injury model was established in mice using acetaminophen. The protective role of Schisandra chinensis was detected by histopathological analysis, and measurement of the serum transaminase levels and hepatic Cyp activity levels in the mouse model. Subsequently, hepatocytes were isolated from the livers of the mouse model. The cell cycle, apoptosis, mitochondrial membrane potential and reactive oxygen species were determined using flow cytometry. Cell proliferation and 26S proteasome activity were determined using spectrophotometry. Schisandra chinensis was found to resist acetaminophen-induced hepatotoxicity by protecting mitochondria and lysosomes and inhibiting the phosphor-c-Jun N-terminal kinase signaling pathway. These findings provide a novel application of Schisandra chinensis against acetaminophen-induced acute liver failure.

  4. Acetaminophen hepatotoxicity: studies on the mechanism of cysteamine protection

    Energy Technology Data Exchange (ETDEWEB)

    Miller, M.G.; Jollow, D.J.

    1986-03-30

    Inhibition of the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite was investigated as a possible mechanism for cysteamine protection against acetaminophen hepatotoxicity. Studies in isolated hamster hepatocytes indicated that cysteamine competitively inhibited the cytochrome P-450 enzyme system as represented by formation of the acetaminophen-glutathione conjugate. However, cysteamine was not a potent inhibitor of glutathione conjugate formation (Ki = 1.17 mM). Cysteamine also weakly inhibited the glucuronidation of acetaminophen (Ki = 2.44 mM). In vivo studies were in agreement with the results obtained in isolated hepatocytes; cysteamine moderately inhibited both glucuronidation and the cytochrome P-450-dependent formation of acetaminophen mercapturate. The overall elimination rate constant (beta) for acetaminophen was correspondingly decreased. Since cysteamine decreased both beta and the apparent rate constant for mercapturate formation (K'MA), the proportion of the dose of acetaminophen which is converted to the toxic metabolite (K'MA/beta) was not significantly decreased in the presence of cysteamine. Apparently, cysteamine does inhibit the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite, but this effect is not sufficient to explain antidotal protection.

  5. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Andreas Buness

    Full Text Available Early and accurate pre-clinical and clinical biomarkers of hepatotoxicity facilitate the drug development process and the safety monitoring in clinical studies. We selected eight known model compounds to be administered to male Wistar rats to identify biomarkers of drug induced liver injury (DILI using transcriptomics, metabolite profiling (metabolomics and conventional endpoints. We specifically explored early biomarkers in serum and liver tissue associated with histopathologically evident acute hepatotoxicity. A tailored data analysis strategy was implemented to better differentiate animals with no treatment-related findings in the liver from animals showing evident hepatotoxicity as assessed by histopathological analysis. From the large number of assessed parameters, our data analysis strategy allowed us to identify five metabolites in serum and five in liver tissue, 58 transcripts in liver tissue and seven clinical chemistry markers in serum that were significantly associated with acute hepatotoxicity. The identified markers comprised metabolites such as taurocholic acid and putrescine (measured as sum parameter together with agmatine, classical clinical chemistry markers like AST (aspartate aminotransferase, ALT (alanine aminotransferase, and bilirubin, as well as gene transcripts like Igfbp1 (insulin-like growth factor-binding protein 1 and Egr1 (early growth response protein 1. The response pattern of the identified biomarkers was concordant across all types of parameters and sample matrices. Our results suggest that a combination of several of these biomarkers could significantly improve the robustness and accuracy of an early diagnosis of hepatotoxicity.

  6. Integrated analysis of transcriptomics and metabonomics profiles in aflatoxin B1-induced hepatotoxicity in rat.

    Science.gov (United States)

    Lu, Xiaoyan; Hu, Bin; Shao, Li; Tian, Yu; Jin, Tingting; Jin, Yachao; Ji, Shen; Fan, Xiaohui

    2013-05-01

    The aim of this work was to identify mechanisms and potential biomarkers for predicting the development and progression of aflatoxin B1 (AFB1)-induced acute hepatotoxicity. In this study, microarray analysis and metabolites profiles were used to identify shifts in gene expression and metabolite levels associated with the affected physiological processes of rats treated with AFB1. Histopathological examinations and serum biochemical analysis were simultaneously performed; the results indicated that hepatotoxicity occurred in higher dosage groups. However, gene expression analysis and metabolite profiles are more sensitive than general toxicity studies for detecting AFB1-induced acute hepatotoxicity as the patterns of low-dose AFB1-treated rats in these two technique platforms were more similar to the rats in higher dosage groups than to the control rats. Integrated analysis of the results from general toxicity studies, transcriptomics and metabonomics profiles suggested that p53 signaling pathway induced by oxidative damage was the crucial step in AFB1-induced acute hepatotoxicity, whereas gluconeogenesis and lipid metabolism disorder were found to be the major metabolic effects after acute AFB1 exposure. The genes and metabolites significantly affected in common in rat liver or serum of three doses AFB1 treatments served as potential biomarkers for detecting AFB1-induced acute hepatotoxicity.

  7. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity.

    Science.gov (United States)

    Buness, Andreas; Roth, Adrian; Herrmann, Annika; Schmitz, Oliver; Kamp, Hennicke; Busch, Kristina; Suter, Laura

    2014-01-01

    Early and accurate pre-clinical and clinical biomarkers of hepatotoxicity facilitate the drug development process and the safety monitoring in clinical studies. We selected eight known model compounds to be administered to male Wistar rats to identify biomarkers of drug induced liver injury (DILI) using transcriptomics, metabolite profiling (metabolomics) and conventional endpoints. We specifically explored early biomarkers in serum and liver tissue associated with histopathologically evident acute hepatotoxicity. A tailored data analysis strategy was implemented to better differentiate animals with no treatment-related findings in the liver from animals showing evident hepatotoxicity as assessed by histopathological analysis. From the large number of assessed parameters, our data analysis strategy allowed us to identify five metabolites in serum and five in liver tissue, 58 transcripts in liver tissue and seven clinical chemistry markers in serum that were significantly associated with acute hepatotoxicity. The identified markers comprised metabolites such as taurocholic acid and putrescine (measured as sum parameter together with agmatine), classical clinical chemistry markers like AST (aspartate aminotransferase), ALT (alanine aminotransferase), and bilirubin, as well as gene transcripts like Igfbp1 (insulin-like growth factor-binding protein 1) and Egr1 (early growth response protein 1). The response pattern of the identified biomarkers was concordant across all types of parameters and sample matrices. Our results suggest that a combination of several of these biomarkers could significantly improve the robustness and accuracy of an early diagnosis of hepatotoxicity.

  8. Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats.

    Science.gov (United States)

    Wang, Jiaying; Jiang, Zhenzhou; Ji, Jinzi; Wang, Xinzhi; Wang, Tao; Zhang, Yun; Tai, Ting; Chen, Mi; Sun, Lixin; Li, Xia; Zhang, Luyong

    2013-08-01

    Triptolide (TP), a major component of TWHF, is widely used to treat rheumatoid arthritis, systemic lupus erythematosus, nephritis and leprosy. However, its clinical use is limited by hepatotoxicity. To further elucidate the underlying mechanism of its hepatotoxic effects, hepatic gene expression profiles were analyzed. TP (1000 and 300 μg/kg) was orally administered to Wistar rats for 14 days. Current study indicated that female rats were more sensitive to TP-induced hepatotoxicity than males. Genome-wide microarray analyses identified 3329 differentially expressed genes in liver of female rats. Analyses of these genes identified over-represented functions associated with insulin signaling pathway, glucose metabolism, cell cycle, oxidative stress and apoptosis, which were consistent with the results of significant increase of Caspase-3 activity and reduction of serum glucose, GSH/GSSG ratio, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, liver glycogen. In addition, it was observed for the first time that glucocorticoids and IGF1 might get involved in TP-induced hepatotoxicity. These data suggest that TP treatment could alter the hepatic redox status, reduce serum glucose and induce hepatocyte apoptosis, consistent with the differential expression of genes involved in insulin signaling pathway, glucose metabolism pathway and cell stress pathway, all of which might contribute to the overall TP-induced hepatotoxicity.

  9. Role of metabolism in 1-bromopropane-induced hepatotoxicity in mice.

    Science.gov (United States)

    Lee, Sang Kyu; Kang, Mi Jeong; Jeon, Tae Won; Ha, Hyun Woo; Yoo, Jin Woo; Ko, Gyu Sub; Kang, Wonku; Jeong, Hye Gwang; Lyoo, Won Seok; Jeong, Tae Cheon

    2010-01-01

    A possible role of metabolism in 1-bromopropane (1-BP)-induced hepatotoxicity was investigated in male ICR mice. The depletion of glutathione (GSH) by formation of GSH conjugates was associated with increased hepatotoxicity in 1-BP-treated mice. The formation of S-propyl and 2-hydroxypropyl GSH conjugates were identified in the liver following 1-BP treatment. In addition, the formation of reactive metabolites of 1-BP by certain cytochrome P-450 (CYP) may be involved in 1-BP-induced hepatotoxicity. The decreased content of hepatic GSH produced by 1-BP was associated not only with increased activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but also with elevated levels of hepatic thiobarbituric acid-reactive substance (TBARS) in mice where metabolic enzymes were induced by pretreatment with phenobarbital. In addition, the hepatotoxicity induced by 1-BP was prevented by pretreatment with SKF-525A. Taken together, the formation of reactive metabolites by CYP and depletion of GSH may play important roles in hepatotoxicity induced by 1-BP.

  10. Treatment of Non-Small-Cell Lung Cancer with Erlotinib following Gefitinib-Induced Hepatotoxicity: Review of 8 Clinical Cases

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    Yukihiro Yano

    2012-01-01

    Full Text Available Objective. Gefitinib often induces liver damage. A few reports have described that the subsequent administration of erlotinib was associated with less hepatotoxicity, but the safety and efficacy of this treatment are still not fully investigated. Therefore, we evaluated retrospectively the patients with erlotinib following gefitinib-induced hepatotoxicity. Methods and Patients. We retrospectively reviewed the medical records between December 2007 and March 2010. The patients were evaluated including the following information: age, gender, histology of lung cancer, performance status, smoking status, epidermal growth factor receptor (EGFR mutation status, liver metastasis, viral hepatitis, alcoholic liver injury, clinical response, and hepatotoxicity due to EGFR tyrosine kinase inhibitors. Results. We identified 8 patients with erlotinib following gefitinib-induced hepatotoxicity. All achieved disease control by gefitinib. Hepatotoxicity was grades 2 and 3 in 3 and 5 patients, respectively. The median duration of treatment with gefitinib was 112.5 days and the median time to gefitinib-induced hepatotoxicity was 51.5 days. The median duration of treatment with erlotinib was 171.5 days. Grade 1 and 2 erlotinib-induced hepatotoxicity was observed in 2 and 1 patient, respectively. Conclusions. Erlotinib administration with careful monitoring is thought to be a good alternative strategy for patients who respond well to gefitinib treatment but experience hepatotoxicity.

  11. Croton zehntneri Essential oil prevents acetaminophen-induced acute hepatotoxicity in mice

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    Maria Goretti R. Queiroz

    2008-10-01

    Full Text Available Hepatoprotective activity of Croton zehntneri Pax & Hoffman (Euphorbiaceae leaf essential oil (EOCz was evaluated against single dose of acetaminophen-induced (500 mg/kg, p.o. acute hepatotoxicity in mice. EOCz significantly protected the hepatotoxicity as evident from the activities of serum glutamate pyruvate transaminase (GPT, serum glutamate oxaloacetate transaminase (GOT activities, that were significantly (p<0.01 elevated in the acetaminophen alone treated animals. Histopathological examinations of liver tissue corroborated well with the biochemical changes. Hepatic steatosis, hydropic degeneration and necrosis were observed in the acetaminophen treated group, while these were completely absent in the standard and EOCz treated groups. In conclusion, these data suggest that the Croton zehntneri essential oil can prevent hepatic injuries from acetaminophen-induced hepatotoxicity in mice.

  12. Resistance to acetaminophen-induced hepatotoxicity in glutathione S-transferase Mu 1-null mice.

    Science.gov (United States)

    Arakawa, Shingo; Maejima, Takanori; Fujimoto, Kazunori; Yamaguchi, Takashi; Yagi, Masae; Sugiura, Tomomi; Atsumi, Ryo; Yamazoe, Yasushi

    2012-01-01

    We investigated the role of glutathione S-transferases Mu 1 (GSTM1) in acetaminophen (APAP)-induced hepatotoxicity using Gstm1-null mice. A single oral administration of APAP resulted in a marked increase in plasma alanine aminotransferase accompanied by hepatocyte necrosis 24 hr after administration in wild-type mice, but its magnitude was unexpectedly attenuated in Gstm1-null mice. Therefore, it is suggested that Gstm1-null mice are resistant to APAP-induced hepatotoxicity. To examine the mechanism of this resistance in Gstm1-null mice, we measured phosphorylation of c-jun N-terminal kinase (JNK), which mediates the signal of APAP-induced hepatocyte necrosis, by Western blot analysis 2 and 6 hr after APAP administration. A marked increase in phosphorylated JNK was observed in wild-type mice, but the increase was markedly suppressed in Gstm1-null mice. Therefore, it is suggested that suppressed phosphorylation of JNK may be a main mechanism of the resistance to APAP-induced hepatotoxicity in Gstm1-null mice, although other possibilities of the mechanism cannot be eliminated. Additionally, phosphorylation of glycogen synthase kinase-3β and mitogen-activated protein kinase kinase 4, which are upstream kinases of JNK in APAP-induced hepatotoxicity, were also suppressed in Gstm1-null mice. A decrease in liver total glutathione 2 hr after APAP administration, which is an indicator for exposure to N-acetyl-p-benzoquinoneimine, the reactive metabolite of APAP, were similar in wild-type and Gstm1-null mice. In conclusion, Gstm1-null mice are considered to be resistant to APAP-induced hepatotoxicity perhaps by the suppression of JNK phosphorylation. This study indicates the novel role of GSTM1 as a factor mediating the cellular signal for APAP-induced hepatotoxicity.

  13. Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

    Science.gov (United States)

    Hassan, Hozeifa M.; Guo, Hongli; Yousef, Bashir A.; Ping-Ping, Ding; Zhang, Luyong; Jiang, Zhenzhou

    2017-01-01

    Isoniazid (INH) remains a cornerstone key constitute of the current tuberculosis management strategy, but its hepatotoxic potentiality remains a significant clinical problem. Our previous findings succeed to establish a rat model of INH hepatotoxicity employing the inflammatory stress theory in which non-injurious doses of inflammatory-mediating agent bacterial lipopolysaccharides (LPS) augmented the toxicity of INH that assist to uncover the mechanisms behind INH hepatotoxicity. Following LPS exposure, several inflammatory cells are activated and it is likely that the consequences of this activation rather than direct hepatocellular effects of LPS underlie the ability of LPS to augment toxic responses. In this study, we investigated the potential protective role of the anti-inflammatory agent dexamethasone (DEX), a potent synthetic glucocorticoid, in INH/LPS hepatotoxic rat model. DEX pre-treatment successfully eliminates the components of the inflammatory stress as shown through analysis of blood biochemistry and liver histopathology. DEX potentiated hepatic anti-oxidant mechanisms while serum and hepatic lipid profiles were reduced. However, DEX administration was not able to revoke the principal effects of cytochrome P450 2E1 (CYP2E1) in INH/LPS-induced liver damage. In conclusion, this study illustrated the DEX-preventive capabilities on INH/LPS-induced hepatotoxicity model through DEX-induced potent anti-inflammatory activity whereas the partial toxicity seen in the model could be attributed to the expression of hepatic CYP2E1. These findings potentiate the clinical applications of DEX co-administration with INH therapy in order to reduce the potential incidences of hepatotoxicity.

  14. A critical analysis of the hepatotoxicity cases described in the literature related to Herbalife (r) products

    OpenAIRE

    Flávio Ailton Duque Zambrone; Cristiana Leslie Corrêa; Ligia Mesquita Sampaio do Amaral

    2015-01-01

    Abstract The aim of this study was to assess the hepatotoxicity cases described in the literature, attributed to the consumption of Herbalife(r) products, and to determine whether a causal relationship exists between the reported cases of liver injury and the use of these products. A literature search was performed on the PubMed, LILACS and PAHO databases. Seven publications reporting a total of 53 cases of hepatotoxicity linked to the use of Herbalife(r) products were retrieved. All of the s...

  15. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats

    OpenAIRE

    Ko, Je-Won; Lee,In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-01-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological al...

  16. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

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    Miriam S. N. Hohmann

    2013-01-01

    Full Text Available 5-Lipoxygenase (5-LO converts arachidonic acid into leukotrienes (LTs and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO-/- mice and background wild type mice were challenged with APAP (0.3–6 g/kg or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO-/- mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10, superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-azinobis(3-ethylbenzothiazoline 6-sulfonate assay were prevented in 5-LO-/- mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage.

  17. Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

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    Sudin eBhattacharya

    2012-12-01

    Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

  18. Hepatoprotective Activity of Herbal Preparation (Hp-4 against Alcohol Induced Hepatotoxicity in Mice

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    P. Padmanabhan

    2014-03-01

    Full Text Available Free radicals include both Reactive Oxygen Species (ROS and Reactive Nitrogen Species (RNS.When free radicals are produced in a regulated manner in a healthy human body it is scavenged efficiently by antioxidant defense system. But excess generation of pro-oxidants by continuous chain reaction in the form of ROS and RNS cause several human diseases. The shift of the balance in the favour of pro-oxidants results in a condition called “oxidative stress”. Alcohol is primarily metabolized in the liver to generate ROS and RNS, leading to diseases such as cirrhosis, fatty liver and chronic hepatitis. Alcohol induced damage is associated with oxidative stress. The excess generation of prooxidants and reduced antioxidant levels provide an effective model of Hepatotoxicity which is noteworthy. Recent trend is to discover polyherbal formulation of medicinal plants which have hepatoprotective function. In the present study 80% alcoholic extract of leaves of Aloe vera, Bacopa monniera, Moringa oleifera and rhizome of Zingiber officinale were utilized to prepare Herbal Preparation or HP-4.Further the hepatoprotective effects of HP-4 was tested in alcohol induced Hepatotoxicity in mice. Silymarin is a well known hepatoprotective drug was used as a standard for comparison. Biochemical and histopathological studies provided ample evidence that HP-4 provided a hepatoprotective role in alcohol induced hepatotoxicity which was comparable to drug Silymarin. The presence of phytochemicals in HP-4 provided a synergistic, supra-additive and co-operative effects in the hepatoprotective function in alcohol induced hepatotoxicity mice model.

  19. Beneficial effects of Chrysin against Methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis.

    Science.gov (United States)

    Ali, Nemat; Rashid, Summya; Nafees, Sana; Hasan, Syed Kazim; Sultana, Sarwat

    2014-01-01

    Methotrexate (MTX), a folic acid antagonist, an effective chemotherapeutic agent is used in the treatment of a wide range of tumors and autoimmune diseases. Moreover, hepatotoxicity limits its clinical use. Several studies have already confirmed that the oxidative stress plays a major role in the pathogenesis of MTX-induced damage in the various organs especially in liver. The aim of this study was to determine the protective effect of Chrysin against MTX-induced hepatic oxidative stress and apoptosis in rats. In the present study, efficacy of Chrysin was investigated against hepatotoxicity caused by MTX in terms of biochemical investigations of antioxidant enzymes, apoptosis, and histopathological alteration in rat liver. In the MTX-treated group there was a significant increase in alanine transaminase, aspartate aminotransferase, lactate dehydrogenase activity and malondialdehyde content as well as decreased glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase activities and reduced glutathione content were also observed compared to the control group as a marker of oxidative stress. Histopathological alterations and apoptosis through the immunopositive staining of p53, cleaved caspases-3 and Bcl-2-associated X protein in rat liver were observed. Pretreatment of Chrysin at both doses prevents the hepatotoxicity by ameliorating oxidative stress, histopathological alterations, and apoptosis and thus our results suggest that Chrysin has a protective effect against hepatotoxicity induced by MTX and it may, therefore, improve the therapeutic index of MTX if co-administration is done.

  20. The protective effect of intraperitoneal medical ozone preconditioning and treatment on hepatotoxicity induced by methotrexate.

    Science.gov (United States)

    Aslaner, Arif; Çakır, Tuğrul; Çelik, Betül; Doğan, Uğur; Akyüz, Cebrail; Baştürk, Ahmet; Polat, Cemal; Gündüz, Umut; Mayir, Burhan; Şehirli, Ahmet Özer

    2015-01-01

    The aim of this study is to determine the effects of medical ozone preconditioning and treatment on the methotrexate acute induced hepatotoxicity in rats that has not reports elsewhere. Eighteen rats were randomly assigned into three equal groups; control, Mtx and Mtx with ozone. Hepatotoxicity was performed with a single dose of 20 mg/kg Mtx to group 2 and group 3 at the fifteenth day. The medical ozone preconditioning was administered intraperitonealy in group 3 for fifteen days and more five days after inducing Mtx. The other rats of the group 1 and 2 received saline injection. At the twentyfirst day the blood and the liver tissue samples were obtained to measure the levels of liver enzymes ALT and AST, proinflamatory cytokines TNF-α, IL-1β, malondialdehyde, glutathione and myeloperoxidase. And the histolopatological examination was evaluated for injury score. In our study Mtx administration caused a significant increase on the liver enzymes ALT and AST, the tissue MDA and MPO activity and significant decrease in the tissue GSH. Moreover the both pro-inflammatory cytokines were significantly increased in the Mtx group. Medical ozone preconditioning and treatment reversed all these biochemical parameters and histopathological changes of the hepatotoxicity induced by Mtx. We conclude that medical ozone ameliorates Mtx induced hepatotoxicity in rats.

  1. Protective effect of rutin in comparison to silymarin against induced hepatotoxicity in rats

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    M. Kasi Reddy

    2017-01-01

    Full Text Available Aim: The aim of this study is to evaluate the hepatoprotective effect of rutin (RTN in comparison to silymarin (SLM against acetaminophen (APAP-induced hepatotoxicity in rats. Materials and Methods: Male Wistar albino rats (n=24 of 3 months age were equally divided into four groups. Group 1 served as normal control. Hepatotoxicity was induced in the remaining three groups with administration of 500 mg/kg po APAP from day 1-3. Groups 2, 3, and 4 were subsequently administered orally with distilled water, 25 mg/kg of SLM, and 20 mg/kg of RTN, respectively, for 11 days. The mean body weights and biomarkers of hepatotoxicity were estimated on day 0, 4 (confirmation of toxicity, and 15 (at the end of treatment. Hematological parameters were evaluated on day 4 and 15. Antioxidant profile and adenosine triphosphatases (ATPases were assessed at the end of the experiment. Liver tissues were subjected to histopathology and transmission electron microscopy after the sacrifice on day 15. Results: Antioxidant profile, ATPases, and hematological and sero-biochemical parameters were significantly altered, and histopathological changes were noticed in the liver of toxic control group. These changes were reversed in groups 3 and 4 that were administered with SLM and RTN, respectively. Conclusion: The results of the present investigation enunciated that SLM has potent hepatoprotective activity though the RTN was found superior in restoring the pathological alterations in paracetamol-induced hepatotoxicity in Wistar albino rats.

  2. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs

    Science.gov (United States)

    Sewing, Sabine; Boess, Franziska; Moisan, Annie; Bertinetti-Lapatki, Cristina; Minz, Tanja; Hedtjaern, Maj; Tessier, Yann; Schuler, Franz; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Single stranded oligonucleotides (SSO) represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH) levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development. PMID:27442522

  3. Allopurinol and 5-aminosalicylic acid influence thiopurine-induced hepatotoxicity in vitro

    NARCIS (Netherlands)

    Broekman, M.M.T.J.; Roelofs, H.M.; Wong, D.R.; Kerstholt, M.; Leijten, A.; Hoentjen, F.; Peters, W.H.M.; Wanten, G.J.A.; Jong, D.J. de

    2015-01-01

    INTRODUCTION: The use of thiopurines is frequently accompanied by hepatotoxicity. Studies on hepatocyte cultures showed a time- and dose-dependent increase of thiopurine toxicity. 5-Aminosalicylic acid (5-ASA) and allopurinol can influence thiopurine metabolism; however, it is unknown whether this a

  4. The role of oxygen free radicals in isoniazid-induced hepatotoxicity.

    Science.gov (United States)

    Walubo, A; Smith, P; Folb, P I

    1998-10-01

    Isoniazid and its metabolites acetylisoniazid, hydrazine and monoacetylhydrazine were investigated for generation of oxygen free radicals during incubation with rat liver slices. Lipid peroxidation was assessed by the thiobarbituric acid reactive substances test using malonaldehyde as the external standard, while hepatotoxicity was assessed by histopathology studies. Malonaldehyde formed in liver slices after 10 hours of incubation with the drugs was 1.28 +/- 0.24 nmol/mg for isoniazid (control 1.12 +/- 0.17 nmol/mg); 0.88 +/- 0.45 nmol/mg for acetylisoniazid (control 0.84 +/- 0.42 nmol/mg); 1.43 +/- 0.14 nmol/mg for monoacetylhydrazine (control 1.10 +/- 0.12 nmol/mg) and 1.36 +/- 0.02 nmol/mg for hydrazine (control 1.13 +/- 0.04 nmol/mg). Histologically, all slices exhibited hepatic necrosis by 4 hours. However, hydrazine-induced hepatotoxicity was characterized by nuclear hyperchromatsia, karyolysis and karyohexis while monoacetylhydrazine exhibited hydropic karyomegaly only. Isoniazid and acetylisoniazid cytotoxicity exhibited a mixture of the above features such that it could be attributed to the two metabolites, hydrazine and monoacetylhydrazine. In conclusion, there was no evidence implicating oxygen free radicals in isoniazid-induced hepatotoxicity; however, the histopathology findings indicate a need for a review of our knowledge on pathognomonic features of isoniazid hepatotoxicity.

  5. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats

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    Issam Salouege

    2014-01-01

    Conclusion: We have evaluated the protective effect of trimetazidine on an animal model of doxorubicin-induced cardiotoxicity and hepatotoxicity. The evaluation of these effects were assessed by several means; tissular distribution of doxorubicin, histological examination, assessment of liver function, and EF LV by scintigraphy that characterizes the originality of this study.

  6. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ko, Je-Won; Lee, In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-12-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological alterations, including degeneration/necrosis of hepatocytes, vacuolation, and sinusoidal dilation. In addition, an increase in the malondialdehyde (MDA) concentration and a decrease in the reduced glutathione (GSH) content and catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) activities were observed in the cisplatin-treated rat hepatic tissues. In contrast, PYC treatment effectively prevented cisplatin-induced hepatotoxicity, including the elevation of aminotransferase and histopathological lesions, in a dosedependent manner. Moreover, PYC treatment also induced antioxidant activity by decreasing MDA level and increasing GSH content and SOD and GST activities in liver tissues. These results indicate that PYC has a protective effect against acute hepatotoxicity induced by cisplatin in rats, and that the protective effects of PYC may be due to inhibiting lipid peroxidation and increasing antioxidant activity.

  7. Caffeic acid, a phyto polyphenol mitigates fluoride induced hepatotoxicity in rats: A possible mechanism.

    Science.gov (United States)

    Kanagaraj, Vishnu Vignesh; Panneerselvam, Lakshmikanthan; Govindarajan, Vimal; Ameeramja, Jaishabanu; Perumal, Ekambaram

    2015-01-01

    Fluoride induced hepatotoxicity has been extensively studied in both humans and animals. However, the mechanism underlying in the hepatotoxicity of experimental fluorosis remains obscure. The severity of fluoride toxicity was reduced by oral administration of certain plant derived antioxidants. Caffeic acid (CA) a polyphenolic compound has diverse range of pharmacological activity in the biological system. Therefore, the present study was aimed to investigate the protective mechanism of CA, against fluoride induced hepatotoxicity in rats. The rats were treated with 300 ppm of NaF via drinking water ad libitum alone and in combination with CA at a dose of 50 mg/kg daily for 30 days by oral intubation. CA treatment significantly prevented fluoride induced hepatic damage as evident from the histopathological studies and declined levels of serum fluoride and liver marker enzymes. A significant decrease in the levels of enzymatic (SOD2, CAT, GPx, and GSTpi class) and nonenzymatic (GSH and Vitamin C) antioxidants along with increased ROS, lipid peroxidation, protein carbonyl content, and nitrate levels by fluoride were also prevented in these groups. In addition, CA inhibits fluoride induced apoptosis by altering the Bax and caspase-3p20 expressions. Further, fluoride induced upregulation of Nox4, p38α MAPK, Hsp60, and downregulation of Hsp27 are the indicators for the detection of oxidative damage, apoptosis, and mitochondrial stress was also modulated by CA. These findings reveal that CA supplementation has a protective effect against fluoride induced hepatotoxicity in rats.

  8. Screening of herbal components for attenuating amiodarone-induced hepatotoxicity on gel-entrapped rat hepatocytes.

    Science.gov (United States)

    Deng, Xudong; Shen, Chong; Meng, Qin

    2014-01-01

    Amiodarone (AMD) is a hepatotoxic drug that has been widely used as a class III antiarrhythmic drug. Because, to date, only a few kinds of protectants are able to reduce AMD hepatotoxicity, this article utilized gel-entrapped rat hepatocytes to screen effective protectants from a series of herbal compounds for their effects against AMD-induced toxicity. Herbal compounds, including matrine, silibinin, glycyrrhizic acid, schisandrin B, epigallocatechin gallate and anisodamine, were cotreated with AMD to assess their protective effect, whereas vitamin E, which has been shown to be protective in rats, was selected as a control. It was found that vitamin E, as with its function in rats, provided the best protection in gel-entrapped rat hepatocytes, whereas silibinin, a major component of silymarin, could largely reduce AMD-induced hepatotoxicity, performing a similar function as silymarin in rats. The results illustrated that gel-entrapped hepatocytes may reflect the protective effects of drugs and serve as a reliable model for screening hepatoprotectants. Moreover, matrine, a widely used monomer of the traditional Chinese medicine, Sophora flavescens, for treatment of arrhythmia, was evidenced to show some effective protections against AMD hepatotoxicity. Taken together, gel-entrapped rat hepatocytes may provide a platform for screening effective candidates from the herbal component library.

  9. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs.

    Directory of Open Access Journals (Sweden)

    Sabine Sewing

    Full Text Available Single stranded oligonucleotides (SSO represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development.

  10. Resveratrol ameliorates methotrexate-induced hepatotoxicity in rats via inhibition of lipid peroxidation.

    Science.gov (United States)

    Dalaklioglu, S; Genc, G E; Aksoy, N H; Akcit, F; Gumuslu, S

    2013-06-01

    Hepatotoxicity is one of the major complications of methotrexate (MTX) therapy. This study was carried out to evaluate the possible protective effect of resveratrol (trans-3,5,4'-trihydroxystilbene, RVT) against MTX-induced hepatotoxicity. Rats were randomly divided into four groups as control, MTX treated (7 mg/kg/day, intraperitoneally (i.p.), once daily for 3 consecutive days), MTX + RVT treated (20 mg/kg/day, i.p.), and RVT treated. First dose of RVT was administrated 3 days before the MTX injection and continued for 3 days. Histopathology of liver was evaluated by light microscopy. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. The levels of thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation) and activities of hepatic antioxidant enzymes such as catalase (CAT) and glutathione-S-transferase (GST) were used to analyze the oxidative stress-mediated lipid peroxidation in liver sections. Our results showed that MTX administration significantly increased ALT, ASP, and ALP levels. TBARS, CAT, and GST levels were also markedly increased in liver after MTX administration. RVT treatment significantly prevented MTX-induced hepatotoxicity, as indicated by AST, ALT, and ALP levels and liver histopathology. Moreover, administration of RVT significantly decreased the elevated levels of TBARS and activities of CAT and GST in the liver compared to MTX-treated group. These results revealed that RVT may have a protective effect against MTX-induced hepatotoxicity by inhibiting oxidative stress-mediated lipid peroxidation. Consequently, RVT treatment might be a promising strategy against MTX-induced hepatotoxicity.

  11. Protective effect of pioglitazone, a PPARγ agonist against acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Gupta, Gaurav; Krishna, Gopala; Chellappan, Dinesh Kumar; Gubbiyappa, Kumar Shiva; Candasamy, Mayuren; Dua, Kamal

    2014-08-01

    Acetaminophen has a reasonable safety profile when consumed in therapeutic doses. However, it could induce hepatotoxicity and even acute liver failure when taken at an overdose. Pioglitazone, PPARγ ligand, is clinically tested and used in treatment of diabetes. PPARγ is a key nuclear hormone receptor of lipid metabolisms and regulates several gene transcriptions associated with differentiation, growth arrest, and apoptosis. The aim of our study was to evaluate the hepatoprotective activity of pioglitazone on acetaminophen-induced hepatotoxicity and to understand the relationship between the PPARγ and acetaminophen-induced hepato injury. For the experiment, Sprague-Dawley rats (160-180 g) were used and divided into four groups. Groups I and II were normal and experimental controls, respectively. Groups III and IV received the pioglitazone 20 mg/kg for 10 days. Hepatotoxicity was induced in Groups II and III on the eighth day with acetaminophen (i.p. 350 mg/kg body weight). The hepatoprotective effect was evaluated by performing an assay of the total protein, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and α-fetoprotein as well as glutathione peroxidase, lipid peroxidation, catalase, superoxide dismutase, and glutathione transferase and liver histopathology. The assay results were presented as mean and standard error of mean for each group. The study group was compared with the control group by one-way ANOVA test. A p value of hepatotoxicity. Liver histopathological examination showed that pioglitazone administration antagonized acetaminophen -induced liver pathological damage. Various biochemical estimations of different hepatic markers and antioxidant enzymes and histopathological studies of liver tissues glimpse a support to its significant hepatoprotective activity on acetaminophen -induced hepatotoxicity.

  12. Altered protein S-glutathionylation identifies a potential mechanism of resistance to acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    McGarry, David J; Chakravarty, Probir; Wolf, C Roland; Henderson, Colin J

    2015-11-01

    Acetaminophen (APAP) is the most commonly used over-the-counter analgesic. However, hepatotoxicity induced by APAP is a major clinical issue, and the factors that define sensitivity to APAP remain unclear. We have previously demonstrated that mice nulled for glutathione S-transferase Pi (GSTP) are resistant to APAP-induced hepatotoxicity. This study aims to exploit this difference to delineate pathways of importance in APAP toxicity. We used mice nulled for GSTP and heme oxygenase-1 oxidative stress reporter mice, together with a novel nanoflow liquid chromatography-tandem mass spectrometry methodology to investigate the role of oxidative stress, cell signaling, and protein S-glutathionylation in APAP hepatotoxicity. We provide evidence that the sensitivity difference between wild-type and Gstp1/2(-/-) mice is unrelated to the ability of APAP to induce oxidative stress, despite observing significant increases in c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation in wild-type mice. The major difference in response to APAP was in the levels of protein S-glutathionylation: Gstp1/2(-/-) mice exhibited a significant increase in the number of S-glutathionylated proteins compared with wild-type animals. Remarkably, these S-glutathionylated proteins are involved in oxidative phosphorylation, respiratory complexes, drug metabolism, and mitochondrial apoptosis. Furthermore, we found that S-glutathionylation of the rate-limiting glutathione-synthesizing enzyme, glutamate cysteine ligase, was markedly increased in Gstp1/2(-/-) mice in response to APAP. The data demonstrate that S-glutathionylation provides an adaptive response to APAP and, as a consequence, suggest that this is an important determinant in APAP hepatotoxicity. This work identifies potential novel avenues associated with cell survival for the treatment of chemical-induced hepatotoxicity.

  13. Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats.

    Science.gov (United States)

    Hafez, Heba M; Ibrahim, Mohamed A; Ibrahim, Salwa A; Amin, Entesar F; Goma, Wafaey; Abdelrahman, Aly M

    2015-12-05

    Methotrexate (MTX), a chemotherapeutic and immunosuppressant drug, is generally well-tolerated by most patients. However, its cytotoxic nature contributes to life-threatening side effects including hepatotoxicity and nephrotoxicity. The present study investigated the possible role of tumor necrosis factor-alpha (TNF-α) inhibitor, etanercept and inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine, on MTX-induced hepatotoxicity and nephrotoxicity in rats. Rats were divided into 7 groups: control group, etanercept group, aminoguanidine group, MTX group, MTX+etanercept group, MTX+aminoguanidine group, and MTX+etanercept+aminoguanidine group. MTX caused hepatotoxicity and nephrotoxicity as evidenced biochemically by significant increase in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and creatinine, respectively as well as by histopathological changes. Such effects were associated with significant changes in oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), catalase, and glutathione (GSH)) as well as by upregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. Etanercept and aminoguanidine significantly attenuated MTX-hepatotoxicity and nephrotoxicity. The protective effect of either agent was associated with significant improvement in oxidative stress parameters as well as by downregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. The study suggested that inhibitors of either TNF-α and/or iNOS have protective effect in MTX-induced hepatotoxicity and nephrotoxicity. The protective effect of either agent relies, at least partially, on their antioxidant effects and decreased TNF-α, iNOS, and caspase-3 expressions.

  14. Efficacy of Rosmarinus officinalis leaves extract against cyclophosphamide-induced hepatotoxicity.

    Science.gov (United States)

    El-Naggar, Sabry A; Abdel-Farid, Ibrahim B; Germoush, Mousa O; Elgebaly, Hassan A; Alm-Eldeen, Abeer A

    2016-10-01

    Context Cyclophosphamide (CTX) is used to treat different cancer types, although it causes severe hepatotoxicity due to its oxidative stress effect. Rosmarinus officinalis, L. (Lamiaceae) has a therapeutic potential against hepatotoxicity due to its antioxidant activity. Objective The objective of this study is to investigate the phytochemical analysis of the methanol extract of Rosmarinus officianalis leaves (MEROL) and its efficacy against CTX-induced hepatotoxicity. Materials and methods The phytochemical analyses were assessed spectrophotometericaly. To assess the MEROL efficacy, 72 Swiss albino mice were divided into six groups. Group 1 was control, groups 2 and 3 included mice which were injected intraperitoneally (i.p.) with 100 or 200 mg/kg of MEROL at days 1, 4, 7, 10, 13 and 16; group 4 was injected (i.p.) with CTX (200 mg/kg) at day 17, groups 5 and 6 were injected (i.p.) with MEROL as groups 3 and 4 followed by 200 mg/kg CTX at day 17, respectively. At day 22, six mice from each group were sacrificed and the others were sacrificed at day 37. Results MEROL has a high content of total phenolics, saponins, total antioxidant capacity and DPPH radical scavenging activity. The median lethal dose (LD50) value of MEROL was 4.125 g/kg b.w. The inhibitory concentration 50 (IC50) value for DPPH radical scavenging was 55 μg/mL. Pretreatment with 100 mg/kg MEROL for 16 d ameliorated CTX-induced hepatotoxicity represented in lowering the levels of the aspartate aminotransferase (AST) and lipid profile and minimizing the histological damage. Conclusions Pretreatment with 100 mg/kg b.w. MEROL mitigated CTX-induced hepatotoxicity due to its antioxidant activity.

  15. Hepatotoxicity in HIV-infected children and adolescents on antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Ana Cecília Montes Gil

    Full Text Available CONTEXT AND OBJECTIVE: Adverse drug reactions are a significant problem in patients on antiretroviral therapy (ART. We determined liver enzyme elevation frequencies in HIV-infected children and adolescents receiving ART, and their association with risk factors. DESIGN AND SETTING: Cross-sectional study, at the Pediatrics Immunodeficiency Division, University Hospital, Universidade Estadual de Campinas. METHODS: Medical records of 152 children and adolescents (54.6% male; median age 7.48 years were analyzed, with a mean of 2.6 liver enzyme determinations per patient. Clinically, patients were classified in categories N (6, A (29, B (78 and C (39. Serum levels of aspartate aminotransferase and alanine aminotransferase were evaluated. Hepatotoxicity was scored as grade 1 (1.1-4.9 times upper limit of normality, ULN, grade 2 (5.0-9.9 times ULN, grade 3 (10.0-15.0 times ULN and grade 4 (> 15.0 times ULN. To assess hepatotoxicity risk factors, odds ratios (OR and adjusted odds ratios (aOR for age, gender, TCD4+ cell count, viral load and medication usage were calculated. RESULTS: We observed grade 1 hepatotoxicity in 19.7 % (30/152 patients. No cases of grade 2, 3 or 4 were detected. There was a significant association between hepatotoxicity and use of sulfonamides (OR, 3.61; 95% confidence interval (CI, 1.50-8.70; aOR, 3.58; 95% CI, 1.44-8.85 and antituberculous agents (OR, 9.23; 95% CI, 1.60-53.08; aOR, 9.05; 95% CI, 1.48-55.25. No toxicity was associated with ART. CONCLUSIONS: One fifth of patients experienced mild hepatotoxicity, attributed to antituberculous agents and sulfonamides. Our results suggest that ART was well tolerated.

  16. CYP2E1 mediated isoniazid-induced hepatotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Jiang YUE; Ren-xiu PENG; Jing YANG; Rui KONG; Juan LIU

    2004-01-01

    AIM: To investigate the role of CYP2E1 in isoniazid (INH)-induced hepatotoxicity and the influence of rifampicin (RFP) on INH-induced liver injury. METHODS: Rats were treated with INH alone (100 mg/kg, ip) or co-administered with RFP (100 mg/kg, ig) for 10 d and 21 d. Hepatotoxicity was assayed by plasma enzymes (sALT, sAST) and histopathological examinations. Hepatic CYP2E1 activity was measured by aniline hydroxylase (ANH), and CYP2E1 mRNA expression was determined by RT-PCR. Plasma hydrazine concentration was determined by RP-HPLC.RESULTS: For a 10 d INH-treatment, hepatic CYP2E1 level was increased to 3.7-fold over the control; liver impairment appeared after 21 d treatment, while CYP2E1 and plasma hydrazine were, respectively, increased to 4.6-fold and 1.7-fold. However, in INH-RFP group for 10 d, CYP2E1 and plasma hydrazine were, respectively,decreased by 13 % and 18 % over INH group; similarly, hepatic injury is equal to INH group appeared after 21 d,and CYP2E1 was further decreased by 26 %. Correlation analysis showed that sALT had a positive correlation with plasma hydrazine and with CYP2E1 activity; CYP2E1 activity was also markedly correlated with plasma hydrazine.And compared with control, there is no difference in changes of CYP2E1 mRNA expression in INH and INH-RFP treatment for 21 d. CONCLUSION: The metabolite of INH, hydrazine, plays an important role in INH-induced hepatotoxicity in rats. The induction of CYP2E1 by hydrazine is involved in the hepatotoxicity of INH. RFP does not exacerbate INH-induced hepatotoxicity in short term, which relates to down-regulation of CYP2E1.

  17. Herbal hepatotoxicity in traditional and modern medicine: Actual key issues and new encouraging steps

    Directory of Open Access Journals (Sweden)

    Rolf eTeschke

    2015-04-01

    Full Text Available Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.

  18. Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists

    Institute of Scientific and Technical Information of China (English)

    Raúl J Andrade; Mercedes Robles; Alejandra Fernández-Casta(n)er; Susana López-Ortega; M Carmen López-Vega; M Isabel Lucena

    2007-01-01

    Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and postcommercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice.To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be finetuned as further information is collected.

  19. Quantification of the joint effects of mixtures of hepatotoxic agents: evaluation of a theoretical model in mice

    Energy Technology Data Exchange (ETDEWEB)

    Shelton, D.W.; Weber, L.J.

    1981-10-01

    An approach previously developed for studying the effects of toxic mixtures on whole organism performances (i.e., growth, mortality) was evaluated to determine its applicability and limitations at the organ system level. The approach was tested by quantifying the hepatotoxic effects of carbon tetrachloride (CCl/sub 4/), monochlorobenzene (MCB), acetaminophen (ACET), and selected mixtures of these compounds in male albino CF-1 mice. Based upon parallel dose-response curves, concentration addition was predicted for the mixtures of both CCl/sub 4/ + MCB and CCl/sub 4/ + ACET. The actual dose-response relationship for each mixture was empirically determined and compared to the predicted curves. In the case of the CCl/sub 4/ + ACET mixture revealed a statistical difference between the observed and predicted curves. The joint effects for the mixture of CCl/sub 4/ + MCB is thus classified as concentration additive. The model proves to be adequate in predicting, classifying, and describing the joint effects of these hepatotoxicants.

  20. GENE EXPRESSION PROFILING IN THE LIVER OF CD-1 MICE TO CHARACTERIZE THE HEPATOTOXICITY OF TRIAZOLE FUNGICIDES

    Science.gov (United States)

    Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and ...

  1. Modulatory effects of dietary inclusion of garlic (Allium sativum on gentamycin–induced hepatotoxicity and oxidative stress in rats

    Directory of Open Access Journals (Sweden)

    Adedayo O. Ademiluyi

    2013-06-01

    Conclusions: These results suggest that dietary inclusion of garlic powder could protect against gentamycin-induced hepatotoxicity, improve antioxidant status and modulate oxidative stress; a function attributed to their phenolic constituents.

  2. Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats

    OpenAIRE

    Akbulut, Sami; Elbe, Hulya; Eris, Cengiz; Dogan, Zumrut; Toprak, Gulten; Otan, Emrah; Erdemli, Erman; Turkoz, Yusuf

    2014-01-01

    AIM: To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity.

  3. Effect of Lagenaria siceraria fruit extract (Bottle gourd on hepatotoxicity induced by antitubercular drugs in albino rats

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    Satyajeet K. Funde

    2013-12-01

    Conclusion: Ethanolic extract of Lagenaria siceraria fruit possesses significant hepatoprotective and antioxidant activity in antitubercular drugs induced hepatotoxicity. [Int J Basic Clin Pharmacol 2013; 2(6.000: 728-734

  4. Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats.

    Science.gov (United States)

    Singh, Brijesh Kumar; Tripathi, Madhulika; Chaudhari, Bhushan P; Pandey, Pramod K; Kakkar, Poonam

    2012-01-01

    Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; Pterpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity.

  5. Evaluation of Hepatoprotective Effect of Leaves of Cassia sophera Linn.

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    Arijit Mondal

    2012-01-01

    Full Text Available In the present study, the hepatoprotective activity of ethanolic extracts of Cassia sophera Linn. leaves was evaluated against carbon-tetrachloride- (CCl4- induced hepatic damage in rats. The extracts at doses of 200 and 400 mg/kg were administered orally once daily. The hepatoprotection was assessed in terms of reduction in histological damage, changes in serum enzymes, serum glutamate oxaloacetate transaminase (AST, serum glutamate pyruvate transaminase (ALT, serum alkaline phosphatase (ALP, total bilirubin, and total protein levels. The substantially elevated serum enzymatic levels of AST, ALT, ALP, and total bilirubin were restored towards the normalization significantly by the extracts. The decreased serum total protein level was significantly normalized. Silymarin was used as standard reference and exhibited significant hepatoprotective activity against carbon tetrachloride-induced hepatotoxicity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections. The results of this study strongly indicate that Cassia sophera leaves have potent hepatoprotective action against carbon tetrachloride-induced hepatic damage in rats. This study suggests that possible activity may be due to the presence of flavonoids in the extracts.

  6. Effect of Lagenaria siceraria fruit extract (Bottle gourd) on hepatotoxicity induced by antitubercular drugs in albino rats

    OpenAIRE

    Satyajeet K. Funde; Jugalkishore B. Jaju; Shrikant C. Dharmadhikari; Ganesh R. Pawar

    2013-01-01

    Background: Anti TB drug induced hepatotoxicity has higher incidence in Indian population [11.5%] than western population [4.5%]. Antitubercular drug induced hepatotoxicity is mediated through oxidative and free radical damage to hepatocytes. Lagenaria siceraria [Bottle Gourd] is reported to have antioxidant and hepatoprotective activity. Hence in the present study we tested hepatoprotective and antioxidant activity of fruit extract of L. Siceraria in anti tubercular drug induced hepatotoxici...

  7. A study of effect of Nigella sativa oil in paracetamol induced hepatotoxicity in albino rats

    OpenAIRE

    Manik S. Ghadlinge; Jugalkishor B. Jaju; Rakhamaji D. Chandane; Rakesh R. Jadhav; Rama R. Bhosle

    2014-01-01

    Background: Acetaminophen (paracetamol) toxicity is a common cause of drug induced hepatotoxicity in children and adults. Specific treatment of paracetamol induced hepatitis is available in the form of N acetylcysteine only. Nigella sativa (NS) is used for the treatment of various ailments. Many studies have shown that NS plant has hepatoprotective potential. Hence, this study study was carried out to explore the prophylactic and therapeutic effect of NS oil against hepatotoxicity induced by ...

  8. Direct Protection Against Acetaminophen Hepatotoxicity by Propylthiouracil: IN VIVO AND IN VITRO STUDIES IN RATS AND MICE

    OpenAIRE

    1981-01-01

    Hepatotoxicity caused by acetaminophen can be prevented by enzyme-catalyzed conjugation of its reactive metabolite with glutathione (GSH). Since we have shown in previous studies that 6-N-propyl-2-thiouracil (PTU) can substitute for GSH as a substrate for the GSH S-transferases, we examined the possibility that PTU might also protect against acetaminophen hepatotoxicity by direct chemical interaction with the reactive metabolite of acetaminophen. In an in vitro system consisting of [3H]acetam...

  9. Mechanisms of halocarbon-induced hepatotoxicity in the mouse. Final report, 1 April 1989-31 March 1990

    Energy Technology Data Exchange (ETDEWEB)

    Smith, M.A.; Gandy, J.

    1990-05-30

    Previous studies have shown that high-dose exposure to the halocarbon bromobenzene resulted in hepatotoxicity and lethality that was substantially diminished by co-treatment with the alpha-adrenergic antagonist, phentolamine. The purpose of this study was to compare the hepatoxicity resulting from exposure to the related halocarbons, chlorobenzene, bromobenzene and iodobenzene, and to determine whether the resulting hepatotoxicity could be antagonized by phentolamine. Halobenzene-induced changes in hepatic glutathione concentrations and serum concentrations of catecholamines were determined as possible mediators of hepatic damage. Iodobenzene administration resulted in toxicities similar to that seen with bromobenzene. Administration of either iodobenzene or bromobenzene resulted in hepatotoxicity as measured by serum alanine aminotransferase (ALT) activity about 1000 fold above normal values. Chlorobenzene was also capable of producing hepatotoxicity, but not to the same extent as iodobenzene. Chlorobenzene-induced hepatotoxicity resulted in serum ALT values approximately 100 fold above normals. Chlorobenzene, bromobenzene or iodobenzene administration significantly decreased hepatic glutathione concentrations to approximately 20% of control concentrations. Phentolamine co-treatments significantly decreased serum ALT activity for all three compounds suggesting that hepatotoxicity might be mediated through an alpha-adrenergic system.

  10. To Set Up a Logistic Regression Prediction Model for Hepatotoxicity of Chinese Herbal Medicines Based on Traditional Chinese Medicine Theory

    Science.gov (United States)

    Liu, Hongjie; Li, Tianhao; Zhan, Sha; Pan, Meilan; Ma, Zhiguo; Li, Chenghua

    2016-01-01

    Aims. To establish a logistic regression (LR) prediction model for hepatotoxicity of Chinese herbal medicines (HMs) based on traditional Chinese medicine (TCM) theory and to provide a statistical basis for predicting hepatotoxicity of HMs. Methods. The correlations of hepatotoxic and nonhepatotoxic Chinese HMs with four properties, five flavors, and channel tropism were analyzed with chi-square test for two-way unordered categorical data. LR prediction model was established and the accuracy of the prediction by this model was evaluated. Results. The hepatotoxic and nonhepatotoxic Chinese HMs were related with four properties (p flavors (p 0.05). There were totally 12 variables from four properties and five flavors for the LR. Four variables, warm and neutral of the four properties and pungent and salty of five flavors, were selected to establish the LR prediction model, with the cutoff value being 0.204. Conclusions. Warm and neutral of the four properties and pungent and salty of five flavors were the variables to affect the hepatotoxicity. Based on such results, the established LR prediction model had some predictive power for hepatotoxicity of Chinese HMs. PMID:27656240

  11. To Set Up a Logistic Regression Prediction Model for Hepatotoxicity of Chinese Herbal Medicines Based on Traditional Chinese Medicine Theory.

    Science.gov (United States)

    Liu, Hongjie; Li, Tianhao; Chen, Lingxiu; Zhan, Sha; Pan, Meilan; Ma, Zhiguo; Li, Chenghua; Zhang, Zhe

    2016-01-01

    Aims. To establish a logistic regression (LR) prediction model for hepatotoxicity of Chinese herbal medicines (HMs) based on traditional Chinese medicine (TCM) theory and to provide a statistical basis for predicting hepatotoxicity of HMs. Methods. The correlations of hepatotoxic and nonhepatotoxic Chinese HMs with four properties, five flavors, and channel tropism were analyzed with chi-square test for two-way unordered categorical data. LR prediction model was established and the accuracy of the prediction by this model was evaluated. Results. The hepatotoxic and nonhepatotoxic Chinese HMs were related with four properties (p 0.05). There were totally 12 variables from four properties and five flavors for the LR. Four variables, warm and neutral of the four properties and pungent and salty of five flavors, were selected to establish the LR prediction model, with the cutoff value being 0.204. Conclusions. Warm and neutral of the four properties and pungent and salty of five flavors were the variables to affect the hepatotoxicity. Based on such results, the established LR prediction model had some predictive power for hepatotoxicity of Chinese HMs.

  12. Protective role of food supplement Spirulina fusiformis in chemical induced hepatotoxicity: A Bromobenzene model in rats

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    Evan Prince Sabina

    2014-03-01

    Full Text Available The present study evaluated the efficacy of Spirulina fusiformis in protecting against chemical induced hepatotoxicity in rats using Bromobenzene as the candidate toxin. A single oral dose of bromobenzene (BB (10mmol/kg b.w. resulted in significant (p< 0.05 decrease in antioxidant levels (catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidese, total reduced glutathione and total protein, and significant (p< 0.05 increase in the levels of serum bilirubin, liver enzymes (alanine transaminase, aspartate transaminase and alkaline phosphatase indicating the induction of hepatotoxicity. Spirulina fusiformis (400 mg/kg b.w was orally administered for 8 days prior to the administration of BB and was seen to protect the above parameters from significant changes upon challenge with bromobenzene. This was also confirmed by the histological examination of liver tissues after sacrifice. The protective effect of Spirulina fusiformis was comparable to that of the standard hepatoprotective drug sylimarin.

  13. Protective effect of alcoholic extract of Entada pursaetha DC. against CCl4-induced hepatotoxicity in rats.

    Science.gov (United States)

    Gupta, Gaurav; More, Amar Sunil; Kumari, Rashmi Rekha; Lingaraju, Madhu Cholenahalli; Kumar, Dhirendra; Kumar, Dinesh; Mishra, Santosh Kumar; Tandan, Surender Kumar

    2014-03-01

    The alcoholic extract of stem of E. pursaetha (PSE, 30, 100, 300 mg/kg body weight, po for 7 days) showed hepatoprotective activity against CCl4 (2 mL/kg body weight, ip)-induced hepatotoxicity. The extract exhibited a significant dose-dependent hepatoprotective effect comparable to standard drug silymarin, by preventing increase in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, and total bilirubin, lactate dehydrogenase; by lowering hepatic levels of malonaldehyde, nitrate-nitrite, myeloperoxidase activity; enhancing activities of antioxidant enzymes, superoxide dismutase, catalase and increasing reduced glutathione levels in liver, which suggests the antioxidant property of PSE. Histopathological studies also supported the above biochemical parameters. The results suggested that alcoholic extract of E. pursaetha possesses significant hepatoprotective activity in CCl4-induced acute hepatotoxicity in rats and this is likely to be mediated through its antioxidant activities.

  14. Hepatoprotective effect of leaves of aqueous ethanol extract of Cestrum nocturnum against paracetamol-induced hepatotoxicity

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    M. Imran Qadir

    2014-06-01

    Full Text Available The hepatoprotective activities of Cestrum nocturnum (Queen of Night was evaluated against the paracetamol induced hepatotoxicity in the mice. Aqueous ethanol (30:70 extract of plant was obtained by maceration. Results showed that aqueous ethanol extract of C. nocturnum (250 mg/kg and 500 mg/kg produced significant (p<0.05 hepatoprotective activities against paracetamol induced liver injury in Swiss albino mice. Histopathalogical studied of liver further supported the hepatoprotective effects of C. notrunum. Phyto-chemical screening showed the presence of alkaloids, flavonoids, saponins, terpenes, phenolic compounds, carbohydrates and volatile oils. Most of the flavonoids have hepatoprotective activity. Therefore, the hepatoprotective activity of C. nocturnum may be due to the presence of flavonoids and phenolic components. It was concluded from the present study that aqueous ethanol extract of leaves of C. nocturnum has hepatoprotective activity against the paracetamol-induced hepatotoxicity in albino mice.

  15. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.

  16. Protective effect of stem bark of Ceiba pentandra linn. against paracetamol-induced hepatotoxicity in rats

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    Nirmal K Bairwa

    2010-01-01

    Full Text Available The present study reports protective activity of ethyl acetate fraction of methanol extract of stem bark of Ceiba pentandra against paracetamol-induced liver damage in rats. The ethyl acetate fraction (400 mg/kg was administered orally to the rats with hepatotoxicity induced by paracetamol (3 gm/kg. Silymarin (100 mg/kg was used as positive control. High performance thin layer chromatography (HPTLC fingerprinting of ethyl acetate fraction revealed presence of its major chemical constituents. A significant (P < 0.05 reduction in serum enzymes GOT (ALT, aspartate aminotransferase (AST, GPT alkaline phosphatase (ALP, total bilirubin content and histopathological screening in the rats treated gave indication that ethyl acetate fraction of methanolic extract of Ceiba pentandra possesses hepatoprotective potential against paracetamol-induced hepatotoxicity in rats.

  17. Enoxaparin-induced hepatotoxicity: an under-recognised complication of enoxaparin therapy.

    Science.gov (United States)

    Pivarnik, Katie Ann; Schiffman, Fred; Sullivan, James; Finn, Arkadiy

    2016-09-23

    Low-molecular-weight heparins including enoxaparin are commonly used for anticoagulation as prophylaxis and treatment for deep vein thrombosis (DVT). Prescribers of enoxaparin monitor for common side effects, such as bleeding and thrombocytopenia, but hepatotoxicity, a less common and under-reported adverse effect, may be overlooked. This report describes a case of enoxaparin-induced hepatotoxicity in a 57-year-old man who was started on the drug for a DVT. Within 3 days of taking enoxaparin, elevated transaminases were noted, and the drug was discontinued after 6 days. Similar to other published reports, the patient's transaminases peaked 1 day after discontinuation of the drug and then trended down to normal over 32 days.

  18. Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States

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    Mark I. Avigan

    2016-03-01

    Full Text Available In the United States (US, the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized.

  19. Hepatotoxic effect of 1-bromopropane and its conjugation with glutathione in male ICR mice.

    Science.gov (United States)

    Lee, Sang Kyu; Jo, Sang Wook; Jeon, Tae Won; Jun, In Hye; Jin, Chun Hua; Kim, Ghee Hwan; Lee, Dong Ju; Kim, Tae-Oh; Lee, Eung-Seok; Jeong, Tae Cheon

    2005-10-01

    The hepatotoxic effects of 1-bromopropane (1-BP) and its conjugation with glutathione were investigated in male ICR mice. A single dose (1000 mg/kg, po) of 1-BP in corn oil to mice significantly increased serum activities of alanine aminotransferase and aspartate aminotransferase. Glutathione (GSH) content was dose-dependently reduced in liver homogenates 12 h after 1-BP treatment. In addition, 1-BP treatment dose-dependently increased levels of S-propyl GSH conjugate at 12 h after treatment, as measured by liquid chromatography-electrospray ionization tandem mass spectrometry. The GSH conjugate was maximally increased in liver at 6 h after 1-BP treatment (1000 mg/kg), with a parallel depletion of hepatic GSH content. Finally, 1-BP induced the production of malondialdehyde in liver. The present results suggest that 1-BP might cause hepatotoxicity, including lipid peroxidation via the depletion of GSH, due to the formation of GSH conjugates in male ICR mice.

  20. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats

    OpenAIRE

    Attalla Farag El-Kott, PhD; Mashael Mohammed Bin-Meferij, PhD

    2015-01-01

    Background: Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. Objective: To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Methods: Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. Results: The treatment with Arctium lappa extract reduc...

  1. The thermostable direct hemolysin from Grimontia hollisae causes acute hepatotoxicity in vitro and in vivo.

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    Yan-Ren Lin

    Full Text Available BACKGROUND: G. hollisae thermostable direct hemolysin (Gh-TDH is produced by most strains of G. hollisae. This toxin has been reported to be absorbed in the intestines in humans. Secondary liver injury might be caused by venous return of the toxin through the portal system. We aimed to firstly analyze the in vitro and in vivo hepatotoxicity of Gh-TDH. METHODS: Liver cells (primary human non-cancer cell and FL83B mouse cells were treated and mice (BALB/c were fed with this toxin to investigate its hepatotoxicity. Morphological examination and cytotoxicity assays using liver cells were also performed. Fluorescein isothiocyanate-conjugated toxin was used to analyze the localization of this protein in liver cells. Mice were subjected to liver function measurements and liver biopsies following toxin treatment and wild-type bacterial infection. PET (positron emission tomography/CT (computed tomography images were taken to assess liver metabolism during acute injury and recovery. RESULTS: The effect of hepatotoxicity was dose and time dependent. Cellular localization showed that the toxin was initially located around the cellular margins and subsequently entered the nucleus. Liver function measurements and liver biopsies of the mice following treatment with toxin or infection with wild-type Grimontia hollisae showed elevated levels of transaminases and damage to the periportal area, respectively. The PET/CT images revealed that the reconstruction of the liver continued for at least one week after exposure to a single dose of the toxin or bacterial infection. CONCLUSIONS: The hepatotoxicity of Gh-TDH was firstly demonstrated. The damage was located in the periportal area of the liver, and the liver became functionally insufficient.

  2. Preventive effect of zinc toward the hepatotoxicity of nickel in rats

    OpenAIRE

    Kechrid, Zine

    2013-01-01

    We studied the effect of zinc treatment on nickel sulphate-induced hepatotoxicity in male albino rats. Liver dysfunction parameters represented by aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), blood glucose, serum total protein and serum albumin were estimated. Liver glutathione level, catalase and GPx activities were also determined in liver as indicators of oxidative damage. Exposure of rats to nickel caused a significant a decrease in body weight and...

  3. Hepatoprotective potential of ethanolic extract of Pandanus odoratissimus root against paracetamol-induced hepatotoxicity in rats

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    Garima Mishra

    2015-01-01

    Full Text Available Background: Pandanus odoratissimus (Pandanaceae is popular in the indigenous system of medicines like Ayurveda, Siddha, Unani and Homoeopathy. In the traditional system of medicine various plant parts such as leaves, root, flowers, and oils are used as anthelmintic, tonic, stomachic, digestive and in the treatment of jaundice and various liver disorders. Objective: The aim was to investigate the hepatoprotective activity of ethanolic extract of the root of P. odoratissimus against paracetamol (PCM induced hepatotoxicity in rats. Materials and Methods: Hepatotoxicity was induced in male Wistar rat by PCM (2 g/kg b.w. p.o. for 7 days. The ethanolic extract of P. odoratissimus root was administered at the dose level of 200 mg/kg and 400 mg/kg b.w. orally for 7 days and silymarin (100 mg/kg b.w. p.o. as standard drug was administered once daily for a week. The hepatoprotective effect of ethanolic extract was evaluated by assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic-pyruvic transaminase, serum alkaline phosphatase, total and direct bilirubin and triglycerides. Histopathological study of rat liver was also done. Results: Experimental findings revealed that the extract at dose level of 200 mg/kg and 400 mg/kg of b.w. showed dose dependant hepatoprotective effect against PCM induced hepatotoxicity by significantly restoring the levels of serum enzymes to normal that was comparable to that of silymarin, but the extract at dose level of 400 mg/kg was found to be more potent when compared to that of 200 mg/kg. Besides, the results obtained from histopathological study also support the study. Conclusion: From the results, it can be concluded that ethanolic extract of the root of P. odoratissimus afforded significant protection against PCM induced hepatotoxicity in rats.

  4. A multiple endpoint approach to predict the hepatotoxicity of pharmaceuticals in vitro

    OpenAIRE

    Truisi, Germaine Loredana

    2014-01-01

    A new approach was evaluated to predict the hepatotoxic potential of pharmaceuticals. For this purpose, primary rat and human hepatocytes cultured in an optimised sandwich configuration were used; thus, allowing the long-term, repeat-dosing of drugs. The strategy based on the evaluation of multiple endpoints, including cytotoxicity, biokinetic profiling, transcriptomics and proteomics. Pharmaceuticals with known toxicities and pharmacokinetic properties were used as model compounds.

  5. Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways.

    Science.gov (United States)

    Zou, Hui; Liu, Xuezhong; Han, Tao; Hu, Di; Wang, Yi; Yuan, Yan; Gu, Jianhong; Bian, Jianchun; Zhu, Jiaqiao; Liu, Zong-ping

    2015-01-01

    It is known that cadmium (Cd) induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A) and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI) of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC) and activation of mitogen-activated protein kinase (MAPK) pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA), administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK) inhibitor (U0126) and a p38 inhibitor (SB202190) but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways.

  6. Aggravation of clozapine-induced hepatotoxicity by glycyrrhetinic acid in rats.

    Science.gov (United States)

    Jia, Ling-ling; Zhong, Ze-yu; Li, Feng; Ling, Zhao-li; Chen, Yang; Zhao, Wei-man; Li, Ying; Jiang, Shu-wen; Xu, Ping; Yang, Yang; Hu, Meng-yue; Liu, Li; Liu, Xiao-dong

    2014-01-01

    Clozapine (CLZ) was reported to be associated with hepatotoxicity. Glycyrrhetinic acid (GA) has a liver protective effect. Our preliminary experiments showed that GA aggravated rather than attenuated CLZ-induced hepatotoxicity in primary cultured rat hepatocytes. The study aimed to describe the enhancing effect of GA on CLZ-induced hepatotoxicity in vivo and in vitro. Data from primary cultured rat hepatocytes showed the decreased formation of metabolites demethylclozapine (nor-CLZ) and clozapine N-oxide (CLZ N-oxide). The results in vivo showed that 7-day CLZ treatment led to marked accumulation of triglyceride (TG) and increase in γ-glutamyl transpeptidase (γ-GT) activity, liver weight, and serum AST in rats. Co-administration of GA enhanced the increases in hepatic TG, γ-GT, liver weight, and serum total cholesterol induced by CLZ. GA decreased plasma concentrations of nor-CLZ and CLZ N-oxide. Compared with control rats, hepatic microsomes of GA rats exhibited the decreased formations of nor-CLZ and CLZ N-oxide, accompanied by decreases in activities of CYP2C11 and CYP2C19 and increased activity of CYP1A2. QT-PCR analysis demonstrated that GA enhanced expression of CYP1A2, but suppressed expression of CYP2C11 and CYP2C13. All these results support the conclusion that GA aggravated CLZ-induced hepatotoxicity, which was partly via inhibiting CYP2C11 and CYP2C13 or inducing CYP1A2.

  7. Protective effect of stem bark of Ceiba pentandra linn. against paracetamol-induced hepatotoxicity in rats

    OpenAIRE

    Bairwa, Nirmal K.; Sethiya, Neeraj K.; Mishra, S. H.

    2010-01-01

    The present study reports protective activity of ethyl acetate fraction of methanol extract of stem bark of Ceiba pentandra against paracetamol-induced liver damage in rats. The ethyl acetate fraction (400 mg/kg) was administered orally to the rats with hepatotoxicity induced by paracetamol (3 gm/kg). Silymarin (100 mg/kg) was used as positive control. High performance thin layer chromatography (HPTLC) fingerprinting of ethyl acetate fraction revealed presence of its major chemical constituen...

  8. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats

    OpenAIRE

    Daniela Rodrigues; Themis Reverbel Da Silveira; Ursula Matte

    2012-01-01

    CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7) ...

  9. Clinical and Laboratory Findings of Lead Hepatotoxicity in the Workers of a Car Battery Manufacturing Factory

    OpenAIRE

    Bita Dadpour; Reza Afshari; Seyed Reza Mousavi; Sina Kianoush; Mohamad Reza Keramati; Vali Allah Moradi; Mahmood Sadeghi; Faezeh Madani Sani; Mahdi Balali Mood

    2016-01-01

    Background: Occupational lead poisoning is common in workers of some industries, but lead hepatotoxicity has rarely been reported. Several animal studies have revealed lead induced liver damage but clinical studies concerning the manifestations of lead induced liver toxicity in humans are scares. This study was designed to investigate the clinical manifestations and pathological parameters of hepatic dysfunction and its relationship with blood and urine lead concentrations in a car battery-ma...

  10. Clinical and Laboratory Findings of Lead Hepatotoxicity in the Workers of a Car Battery Manufacturing Factory

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    Bita Dadpour

    2016-02-01

    Full Text Available Background: Occupational lead poisoning is common in workers of some industries, but lead hepatotoxicity has rarely been reported. Several animal studies have revealed lead induced liver damage but clinical studies concerning the manifestations of lead induced liver toxicity in humans are scares. This study was designed to investigate the clinical manifestations and pathological parameters of hepatic dysfunction and its relationship with blood and urine lead concentrations in a car battery-manufacturing workers. Methods: This cross sectional study was carried out in Mashhad, Iran, during April-June 2011. One hundred and twelve workers underwent blood and urine sampling for determination of lead concentrations and liver function tests. Clinical signs and symptoms of possible lead hepatotoxicity were investigated. Results: Mean (±SD age of the workers was 28.78 (±5.17 yr with a daytime work of 8.67 (±1.41 h and mean work duration of 3.89 (±2.40 yr. Mean blood lead concentration (BLC and urine lead concentration (ULC were 398.95 (±177.41 µg/l and 83.67(±50 μg/l, respectively. We found no correlation between the clinical findings and BLC or ULC. A weak correlation (R: 0.27, P=0.087 between serum alkaline phosphatase concentration and BLC was obtained. No significant relationship was found between other liver function tests and BLC or ULC. Conclusion: We found no specific clinical and laboratory abnormalities of liver in the workers of car battery manufacturer who had chronic lead toxicity. Further investigations with more specific laboratory tests such as LDH5 and gamma glutamyl transferase (GGT as well as novel biomarkers of metal induced hepatotoxicity might be helpful in evaluating lead hepatotoxicity.

  11. Increased susceptibility of Nrf2-null mice to 1-bromopropane-induced hepatotoxicity.

    Science.gov (United States)

    Liu, Fang; Ichihara, Sahoko; Valentine, William M; Itoh, Ken; Yamamoto, Masayuki; Sheik Mohideen, Sahabudeen; Kitoh, Junzoh; Ichihara, Gaku

    2010-06-01

    1-Bromopropane (1-BP) was introduced as an alternative to ozone-depleting solvents. However, it was found to exhibit neurotoxicity, reproductive toxicity, and hepatotoxicity in rodents and neurotoxicity in human. However, the mechanisms underlying the toxicities of 1-BP remain elusive. The present study investigated the role of oxidative stress in 1-BP-induced hepatotoxicity using nuclear factor erythroid 2-related factor 2 (Nrf2)-null mice. Groups of 24 male Nrf2-null mice and 24 male wild-type (WT) C57BL/6J mice were each divided into three groups of eight and exposed to 1-BP at 0, 100, or 300 ppm for 8 h/day for 28 days by inhalation. Liver histopathology showed significantly larger area of necrosis in Nrf2-null mice relative to WT mice at the same exposure level. Nrf2-null mice also had greater malondialdehyde (MDA) levels, higher ratio of oxidized glutathione/reduced form of glutathione, and lower total glutathione content. The constitutive level and the increase in ratio per exposure level of glutathione S-transferase (GST) activity were lower in the liver of Nrf2-null mice than WT mice. Exposure to 1-BP at 300 ppm increased the messenger RNA levels of heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GcLm), glutamate-cysteine synthetase (GcLc), glutathione reductase, and NAD(P)H: quinone oxidoreductase 1 (NQO1) in WT mice but not in Nrf2-null mice except for GST Yc2. Nrf2-null mice were more susceptible to 1-BP-induced hepatotoxicity. That oxidative stress plays a role in 1-BP hepatotoxicity is deduced from the low expression levels and activities of antioxidant enzymes and high MDA levels in Nrf2-null mice.

  12. Ipomoea aquatica Extract Shows Protective Action Against Thioacetamide-Induced Hepatotoxicity

    OpenAIRE

    Hadi, A. Hamid A.; Siddig Ibrahim Abdelwahab; Suzy Munir Salama; Salim Said Alkiyumi; Mahmood Ameen Abdullah; Ahmed Salim Alrashdi

    2012-01-01

    In the Indian system of traditional medicine (Ayurveda) it is recommended to consume Ipomoea aquatica to mitigate disorders like jaundice. In this study, the protective effects of ethanol extract of I. aquatica against liver damage were evaluated in thioacetamide (TAA)-induced chronic hepatotoxicity in rats. There was no sign of toxicity in the acute toxicity study, in which Sprague-Dawley (SD) rats were orally fed with ...

  13. Hepatotoxicity associated with microcystin/ Hepatotoxicidade associada à microcistina

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    Ana Paula Frederico Rodrigues Loureiro Bracarense

    2008-08-01

    Full Text Available Urban and industrial discharges, intense agricultural exploitation and fisheries have been causing the eutrophication in both drinking and recreational waters. A frequent consequence of eutrophication in waters is the massive development of cyanobacteria. The occurrence of these blooms induces a severe problem, as Microcystis aeruginosa, the most widespread distributed cyanobacteria, can produce microcystins (MC. Toxic effects of MC have been described in liver, lungs, stomach, and intestine. Deaths in wildlife, livestock and human beings were also associated with MC exposition. MC exposition can occurs directly by ingestion, inhalation, contact, intravenous inoculation of contaminated water (hemodialysis or indirectly, by the consumption of animals, as fish and mollusks, the majors ingestors of cyanobacteria and its toxins. The most toxic MC, an also the most common is microcystin-LR (MC-LR, that has the liver as the main target organ. Microcystin is taken up specifically into the liver by bile acid transporters and, after entering the cytoplasm, inhibit protein phosphatases 1 and 2A, which leads to the increase in protein phosphorylation. This effect has two main consequences: the destruction of cytoskeleton directly causing cytotoxic effects, and deregulation of cell division, leading to tumor-promoting activity. Acute exposition to MC induces severe intrahepatic hemorrhage, necrosis and apoptosis, while chronic exposure can cause hepatic or intestinal neoplasia. It has been documented that MC hepatotoxicity is closely associated with intracellular reactive oxygen species formation. Natural degradation of microcystins depends on the solar radiation and bacteria. If degradation is insufficient, MC will persist in the freshwater food chain. Microcystin contamination of waters is therefore a hazard to human and animal health, so efforts to avoid eutrophication of waters sources are essential, in order to minimize the risks to public health

  14. Sirtuin 1 modulation in rat model of acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    Wojnarová, L; Kutinová Canová, N; Farghali, H; Kučera, T

    2015-01-01

    Sirtuin 1 (SIRT1) is involved in important biological processes such as energy metabolism and regulatory functions of the cell cycle, apoptosis, and inflammation. Our previous studies have shown hepatoprotective effect of polyphenolic compound resveratrol, which is also an activator of SIRT1. Therefore, the aim of our present study was to clarify the role of SIRT1 in process of hepatoprotection in animal model of drug-induced liver damage. Male Wistar rats were used for both in vivo and in vitro studies. Hepatotoxicity was induced by single dose of acetaminophen (APAP). Some rats and hepatocytes were treated by resveratrol or synthetic selective activator of sirtuin 1 (CAY10591). The degree of hepatotoxicity, the activity and expression of the SIRT1 were determined by biochemical, histological and molecular-biological assessments of gained samples (plasma, liver tissue, culture media and hepatocytes). Resveratrol and CAY attenuated APAP-induced hepatotoxicity in vivo and in vitro. Moreover, both drugs enhanced APAP-reduced SIRT1 activity. Our results show that modulation of the SIRT1 activity plays a role in hepatoprotection. Synthetic activators of SIRT1 would help in understanding the role of SIRT1 and are therefore a major boost towards the search for specific treatment of liver disease.

  15. Hepatoprotective activity of quercetin against acrylonitrile-induced hepatotoxicity in rats.

    Science.gov (United States)

    Abo-Salem, Osama M; Abd-Ellah, Mohamed F; Ghonaim, Mabrouk M

    2011-01-01

    Acrylonitrile is a potent hepatotoxic, mutagen, and carcinogen. A role for free radical-mediated lipid peroxidation in the toxicity of acrylonitrile has been suggested. The present study was designed to assess the hepatoprotective effect of quercetin against acrylonitrile-induced hepatotoxicity in rats. Liver damage was induced by oral administration of acrylonitrile (50 mg/kg/day/5 weeks). Acrylonitrile produced a significant elevation of malondialdehyde (138.9%) with a marked decrease in reduced glutathione (72.4%), and enzymatic antioxidants; superoxide dismutase (81%), and glutathione peroxidase (53.2%) in the liver. Serum aspartate aminotransferase, alanine aminotransferases, direct bilirubin, and total bilirubin showed a significant increase in acrylonitrile alone treated rats (115.5%, 110.8%, 1006.8%, and 1000.8%, respectively). Pretreatment with quercetin (70 mg/kg/day/6 weeks) and its coadministration with acrylonitrile prevented acrylonitrile-induced alterations in hepatic lipid peroxides and enzymatic antioxidants as well as serum aminotransferases and bilirubin. Histopathological findings supported the biochemical results. We suggest that querectin possess hepatoprotective effect against acrylonitrile-induced hepatotoxicity through its antioxidant activity.

  16. Evaluation of the Antidepressant Activity, Hepatotoxicity and Blood Brain Barrier Permeability of Methyl Genipin

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    Xin Che

    2016-07-01

    Full Text Available Geniposide (GE is the main bioactive component of Gardeniae Fructus. The hepatotoxicity of geniposide limited clinical application. In order to get a new geniposide derivative that has less hepatotoxicity and still possesses the antidepressant activity, a new C-1 hydroxyl methylation derivative named methyl genipin (MG was synthesized from geniposide. In the present study, we demonstrated that MG did not increase the liver index, alanine aminotransferase (ALT and aspirate aminotransferase (AST. Histopathological examination suggested that no toxic damages were observed in rats treated orally with MG (0.72 mmol/kg. More importantly, a 7-day treatment with MG at 0.13, 0.26, and 0.52 mmol/kg/day could reduce the duration of immobility. It showed that the antidepressant-like effects of MG were similar to GE in the tail suspension test and the forced swim test. Furthermore, we found MG could be detected in the brain homogenate of mice treated orally with MG 0.52 mmol/kg/day for 1 day by HPLC. The area under the curve (AUC of MG in the brain homogenate was enhanced to 21.7 times that of GE. The brain amount and distribution speed of MG were improved significantly after oral administration. This study demonstrated that MG possessed the antidepressant effects and could cross the blood–brain barrier, but had less hepatotoxicity.

  17. Mitigation of hepatotoxic effects of arsenic trioxide through omega-3 fatty acid in rats.

    Science.gov (United States)

    Mathews, Varghese V; Paul, Mv Sauganth; Abhilash, M; Manju, Alex; Abhilash, S; Nair, R Harikumaran

    2014-10-01

    Arsenic trioxide (As(2)O(3)) is an effective drug in the treatment of leukaemia and many solid tumours. In clinical trials, arsenic therapy is closely associated with hepatic toxicity. The present study was designed to investigate the efficacy of omega-3 fatty acid against As(2)O(3)-induced hepatotoxicity. A 4 mg/kg body weight (bw) of As(2)O(3) was orally administered to Wistar male rats for 45 days. Hepatotoxicity was evaluated by biochemical tests, antioxidant assays and histopathological examinations. Arsenic accumulation was found in the liver tissue of rats treated with As(2)O(3). Hepatoprotective efficacy of omega-3 fatty acid was analysed by the combination therapy with As(2)O(3). In vivo studies revealed a significant rise in lipid peroxidation with concomitant decline in reduced glutathione, glutathione-dependant antioxidant enzymes and antiperoxidative enzymes in the liver tissue of rats treated with arsenic. The supplementation of omega-3 fatty acid at a dose of 50 mg/kg bw with As(2)O(3) offers ameliorative effect against hepatocellular toxicity. Omega-3 fatty acid maintained hepatic marker enzymes, antioxidant enzymes and decreased lipid peroxidation. The combination treatment clearly reduced the hepatic structural abnormalities such as haemorrhage, necrosis and cholangiofibrosis in the rats treated with arsenic. This study concludes that the omega-3 fatty acid might be useful for the protection against As(2)O(3)-induced hepatotoxicity.

  18. The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

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    Jun Ho Shin

    2013-03-01

    Full Text Available The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC on acetaminophen (APAP-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH production and glutathione peroxidase (GSH-px activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

  19. A critical analysis of the hepatotoxicity cases described in the literature related to Herbalife (r products

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    Flávio Ailton Duque Zambrone

    2015-12-01

    Full Text Available Abstract The aim of this study was to assess the hepatotoxicity cases described in the literature, attributed to the consumption of Herbalife(r products, and to determine whether a causal relationship exists between the reported cases of liver injury and the use of these products. A literature search was performed on the PubMed, LILACS and PAHO databases. Seven publications reporting a total of 53 cases of hepatotoxicity linked to the use of Herbalife(r products were retrieved. All of the studies lacked sufficient information to some degree, whether related to patients' history, concomitant use of medication and/or other compounds (including alcohol, observations on interrupted use (dechallenge, results found with markers, viral serology and autoantibodies or observations concerning re-exposure to the products. In addition to these items, the lack of clear information on the type of products evaluated and their respective composition is an important factor to be considered. Furthermore, data quality was also questionable due to the presence of confounding factors, absence of proper exclusion of alternative explanations, and the use of questionable methods for attributing causality. Hence, an association between hepatotoxicity and consumption of these products cannot be proven based on the data collected and rigorous scientific analysis.

  20. In silico models for the prediction of dose-dependent human hepatotoxicity

    Science.gov (United States)

    Cheng, Ailan; Dixon, Steven L.

    2003-12-01

    The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-limiting considerations in the drug development cycle, yet there remains a serious shortage of methods to predict hepatotoxicity from chemical structure. We discuss our latest findings in this area and present a new, fully general in silico model which is able to predict the occurrence of dose-dependent human hepatotoxicity with greater than 80% accuracy. Utilizing an ensemble recursive partitioning approach, the model classifies compounds as toxic or non-toxic and provides a confidence level to indicate which predictions are most likely to be correct. Only 2D structural information is required and predictions can be made quite rapidly, so this approach is entirely appropriate for data mining applications and for profiling large synthetic and/or virtual libraries.

  1. A fatal case of bupropion (Zyban hepatotoxicity with autoimmune features: Case report

    Directory of Open Access Journals (Sweden)

    Humayun Fawwaz

    2007-09-01

    Full Text Available Abstract Background Bupropion is approved for the treatment of mood disorders and as an adjuvant medication for smoking cessation. Bupropion is generally well tolerated and considered safe. Two randomized controlled trials of bupropion therapy for smoking cessation did not report any hepatic adverse events. However, there are three reports of severe but non-fatal bupropion hepatotoxicity published in the literature. Case Presentation We present the case of a 55-year old man who presented with jaundice and severe hepatic injury approximately 6 months after starting bupropion for smoking cessation. Laboratory evaluation demonstrated a mixed picture of hepatocellular injury and cholestasis. Liver biopsy demonstrated findings consistent with severe hepatotoxic injury due to drug induced liver injury. Laboratory testing was also notable for positive autoimmune markers. The patient initially had clinical improvement with steroid therapy but eventually died of infectious complications. Conclusion This report represents the first fatal report of bupropion related hepatotoxicity and the second case of bupropion related liver injury demonstrating autoimmune features. The common use of this medication for multiple indications makes it important for physicians to consider this medication as an etiologic agent in patients with otherwise unexplained hepatocellular jaundice.

  2. Effects of ebselen on radiocontrast media-induced hepatotoxicity in rats.

    Science.gov (United States)

    Basarslan, Fatmagul; Yilmaz, Nigar; Davarci, Isil; Akin, Mustafa; Ozgur, Mustafa; Yilmaz, Cahide; Ulutas, Kemal Turker

    2013-09-01

    Oxidative stress is accepted as a potential responsible mechanism in the pathogenesis of radiocontrast media (RCM)-induced hepatotoxicity. Therefore, we aimed to investigate the protective effects of ebselen against RCM-induced hepatotoxicity by measuring tissue oxidant/antioxidant parameters and histological changes in rats. Wistar albino rats were randomly separated into four groups consisting of eight rats per group. Normal saline was given to the rats in control group (group 1). RCM was given to the rats in group 2, and both RCM and ebselen were given to the rats in group 3. Only ebselen was given to the rats in group 4. Liver sections of the killed animals were analyzed to measure the levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as histopathological changes. In RCM group, SOD and CAT levels were found increased. In RCM-ebselen group, MDA, SOD and CAT levels were found decreased. In RCM-ebselen group, however, GSH-Px activities of liver tissue increased. All these results indicated that ebselen produced a protective mechanism against RCM-induced hepatotoxicity and took part in oxidative stress.

  3. Carvacrol suppresses the expression of inflammatory marker genes in D-galactosamine-hepatotoxic rats

    Institute of Scientific and Technical Information of China (English)

    Balakrishnan Aristatile; Abdullah H Al-Assaf; Kodukkur Viswanathan Pugalendi

    2013-01-01

    Objective:To unravel the mechanism of anti-inflammatory activity of carvacrol in D-galactosamine(D-GalN)-induced hepatotoxic rats.Methods:The mRNA and protein expression levels of tumor necrosis factor-alpha(TNF-α), interleukin-6(IL-6), inducible nitric oxide synthase(iNOS), cyclooxygenase-2(COX-2) and nuclear factor kappa-B(NF-κB) were assayed by semi-quantitative reverse transcriptase polymerase chain reaction(RTPCR) and western blot analysis.Results:We found that the mRNA and protein expressions ofTNF-α, IL-6, iNOS,COX-2 andNF-κB were significantly up-regulated inD-galactosamine induced hepatotoxic rats and treatment with carvacrol significantly down-regulated the expressions of these genes showing the mechanism behind the anti-inflammatory activity of carvacrol. Conclusions:All above results reveal that the carvacrol well known anti-inflammatory activities inD-galactosamine induced hepatotoxic rats.

  4. FDA proposals to limit the hepatotoxicity of paracetamol (acetaminophen): are they reasonable?

    Science.gov (United States)

    Graham, Garry G; Day, Richard O; Graudins, Andis; Mohamudally, Anthoulla

    2010-04-01

    Hepatotoxicity from paracetamol is of great concern because of the considerable number of patients who develop severe toxicity from this drug. A group of senior medical practitioners, academics and scientists were brought together on June 29 and 30, 2009 by the Food and Drug Administration of USA (FDA) with the aim of providing advice on how to limit the number of cases of hepatotoxicity due to paracetamol in USA. The most contentious recommendations were the reduction in the dose of paracetamol to 650 mg and the elimination of prescription combination products of paracetamol and opiates. The first recommendation indicates that many members of the committee consider, despite much evidence to the contrary, that therapeutic doses of paracetamol (up to 4 g daily) are associated with a significant incidence of hepatotoxicity. The second recommendation, if accepted by FDA, will require major changes in the therapeutic use of paracetamol and opiates. Adoption of these two recommendations may lead to the increased use of NSAIDs with the potential of increasing incidence of NSAIDs-related adverse reactions.

  5. Protective effects of 2,4-dihydroxybenzophenone against acetaminophen-induced hepatotoxicity in mice

    Institute of Scientific and Technical Information of China (English)

    Yue-Ying He; Bao-Xu Zhang; Feng-Lan Jia

    2011-01-01

    AIM: To examine the effects of 2,4-dihydroxybenzophenone (BP-1), a benzophenone derivative used as an ultraviolet light absorbent, on acetaminophen (APAP)- induced hepatotoxicity in C57BL/6J mice. METHODS: Mice were administered orally with BP-1 at doses of 200, 400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP (350 mg/kg body weight) was given subcutaneously. Twenty four hours after APAP intoxication, the serum enzyme including serum alaine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) were measured and liver histopathologic changes were examined. RESULTS: BP-1 administration dramatically reduced serum ALT, AST and LDH levels. Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner. Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment, and glutathione depletion was ameliorated obviously. CONCLUSION: BP-1 can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity, and reduction of oxidative stress might be part of the protection mechanism.

  6. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats

    Science.gov (United States)

    Ncube, Denver

    2017-01-01

    Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels (p = 0.0017) and AST levels (p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment (p fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

  7. Hepatoprotective activity of the methanolic extract of Tylophora indica (Burm. f. Merill. leaves

    Directory of Open Access Journals (Sweden)

    Mujeeb M

    2009-01-01

    Full Text Available The methanolic extract of Tylophora indica leaves was screened for hepatoprotective activity in carbon tetrachloride induced hepatotoxicity in albino rats. The degree of protection was measured by estimating biochemical parameters like Serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, total protein and level of serum bilirubin (both total and direct. Hepatoprotective activity of methanolic extract at a dose of 200 mg/kg and 300 mg/kg body weight, i.p., was compared with Silymarin (25 mg/kg, i.p. treated animals. Tylophora indica leaves (200 and 300 mg/kg exhibited significant reduction in serum hepatic enzymes when compared to rats treated with carbon tetrachloride alone. Furthermore, histopathological studies were also done to support the study.

  8. A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose

    Directory of Open Access Journals (Sweden)

    Kalsi SS

    2011-12-01

    Full Text Available Sarbjeet S Kalsi1,2, Paul I Dargan2–4, W Stephen Waring5, David M Wood2–41Emergency Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3King’s Health Partners, London, UK; 4King’s College London, London, UK; 5York Teaching Hospital NHS Foundation Trust, York, UKAbstract: Paracetamol (acetaminophen poisoning is common throughout the world. The management of nonstaggered (acute paracetamol overdose is based on the plasma paracetamol concentration plotted on a treatment nomogram. In the UK there are two treatment lines on this nomogram, with the lower treatment line used for individuals felt to be at ‘high risk’ of paracetamol-related hepatotoxicity either as a result of induction of cytochrome P450 isoenzymes or reduction of intrahepatic glutathione. In this article we review the risk factors that, in current guidelines, are felt to increase risk due to a reduction in intrahepatic glutathione concentrations. Based on our review of the published literature, we feel that cystic fibrosis, acute viral illness, malnutrition, and eating disorders such as anorexia nervosa are likely to be associated with reduction in intrahepatic glutathione concentrations, and that this risk is likely to be related to malnutrition secondary to the disease. Chronic hepatitis C infection is also associated with reduced glutathione concentrations, although this appears to be independent of any associated malnutrition. Ageing and acute fasting are not associated with an increased risk of paracetamol-related hepatotoxicity due to reductions in glutathione concentrations. Finally, the evidence for HIV infection is inconclusive, particularly as the majority of studies were conducted in the pre-anti-viral treatment (HAART era; however it is likely that patients with symptomatic HIV/AIDS have reduced glutathione concentrations due to associated malnutrition. Although

  9. The Relation between Hepatotoxicity and the Total Coumarin Intake from Traditional Japanese Medicines Containing Cinnamon Bark

    Science.gov (United States)

    Iwata, Naohiro; Kainuma, Mosaburo; Kobayashi, Daisuke; Kubota, Toshio; Sugawara, Naoko; Uchida, Aiko; Ozono, Sahoko; Yamamuro, Yuki; Furusyo, Norihiro; Ueda, Koso; Tahara, Eiichi; Shimazoe, Takao

    2016-01-01

    Cinnamon bark is commonly used in traditional Japanese herbal medicines (Kampo medicines). The coumarin contained in cinnamon is known to be hepatotoxic, and a tolerable daily intake (TDI) of 0.1 mg/kg/day, has been quantified and used in Europe to insure safety. Risk assessments for hepatotoxicity by the cinnamon contained in foods have been reported. However, no such assessment of cinnamon bark has been reported and the coumarin content of Kampo medicines derived from cinnamon bark is not yet known. To assess the risk for hepatotoxicity by Kampo medicines, we evaluated the daily coumarin intake of patients who were prescribed Kampo medicines and investigated the relation between hepatotoxicity and the coumarin intake. The clinical data of 129 outpatients (18 male and 111 female, median age 58 years) who had been prescribed keishibukuryogankayokuinin (TJ-125) between April 2008 and March 2013 was retrospectively investigated. Concurrent Kampo medicines and liver function were also surveyed. In addition to TJ-125, the patients took some of the other 32 Kampo preparations and 22 decoctions that include cinnamon bark. The coumarin content of these Kampo medicines was determined by high performance liquid chromatography (HPLC). TJ-125 had the highest daily content of coumarin (5.63 mg/day), calculated from the daily cinnamon bark dosage reported in the information leaflet inserted in each package of Kampo medicine. The coumarin content in 1g cinnamon bark decoction was 3.0 mg. The daily coumarin intake of the patients was 0.113 (0.049–0.541) mg/kg/day, with 98 patients (76.0%) exceeding the TDI. Twenty-three patients had an abnormal change in liver function test value, but no significant difference was found in the incidence of abnormal change between the group consuming less than the TDI value (6/31, 19.4%) and the group consuming equal to or greater than the TDI value (17/98, 17.3%). In addition, no abnormal change related to cinnamon bark was found for individual

  10. The Relation between Hepatotoxicity and the Total Coumarin Intake from Traditional Japanese Medicines Containing Cinnamon Bark.

    Science.gov (United States)

    Iwata, Naohiro; Kainuma, Mosaburo; Kobayashi, Daisuke; Kubota, Toshio; Sugawara, Naoko; Uchida, Aiko; Ozono, Sahoko; Yamamuro, Yuki; Furusyo, Norihiro; Ueda, Koso; Tahara, Eiichi; Shimazoe, Takao

    2016-01-01

    Cinnamon bark is commonly used in traditional Japanese herbal medicines (Kampo medicines). The coumarin contained in cinnamon is known to be hepatotoxic, and a tolerable daily intake (TDI) of 0.1 mg/kg/day, has been quantified and used in Europe to insure safety. Risk assessments for hepatotoxicity by the cinnamon contained in foods have been reported. However, no such assessment of cinnamon bark has been reported and the coumarin content of Kampo medicines derived from cinnamon bark is not yet known. To assess the risk for hepatotoxicity by Kampo medicines, we evaluated the daily coumarin intake of patients who were prescribed Kampo medicines and investigated the relation between hepatotoxicity and the coumarin intake. The clinical data of 129 outpatients (18 male and 111 female, median age 58 years) who had been prescribed keishibukuryogankayokuinin (TJ-125) between April 2008 and March 2013 was retrospectively investigated. Concurrent Kampo medicines and liver function were also surveyed. In addition to TJ-125, the patients took some of the other 32 Kampo preparations and 22 decoctions that include cinnamon bark. The coumarin content of these Kampo medicines was determined by high performance liquid chromatography (HPLC). TJ-125 had the highest daily content of coumarin (5.63 mg/day), calculated from the daily cinnamon bark dosage reported in the information leaflet inserted in each package of Kampo medicine. The coumarin content in 1g cinnamon bark decoction was 3.0 mg. The daily coumarin intake of the patients was 0.113 (0.049-0.541) mg/kg/day, with 98 patients (76.0%) exceeding the TDI. Twenty-three patients had an abnormal change in liver function test value, but no significant difference was found in the incidence of abnormal change between the group consuming less than the TDI value (6/31, 19.4%) and the group consuming equal to or greater than the TDI value (17/98, 17.3%). In addition, no abnormal change related to cinnamon bark was found for individual

  11. Studies on the mechanism of enhancement of carbon tetrachloride hepatotoxicity by Triton WR 1339.

    OpenAIRE

    de Ferreyra, E. C.; de Toranzo, E. G.; de Fenos, O. M.; Castro, J A

    1981-01-01

    Pretreatment of rats with Triton WR 1339 significantly enhanced the intensity of CC14-induced liver necrosis. Previous workers suggested that this effect might be due to enhancement by Triton WR 1339 of cellular degradative processes. This pretreatment, however, also enhanced the intensity of covalent binding of [14C]CC14 metabolites to microsomal protein at 3 or 6 h, but not 1 h after its administration. This effect is not due to changes of microsomal P-450 content or increased activity of m...

  12. The in vivo toxicity of carbon tetrachloride and carrageenan on heart microsomes: analysis by Fourier transform infrared spectroscopy.

    Science.gov (United States)

    Melin, A M; Perromat, A; Deleris, G

    2001-09-01

    We investigated the sensitivity of rat heart microsomes to free radical attack using Fourier transform infrared (FT-IR) spectroscopy. This physico-chemical method seemed a valuable technique: quite sensitive to changes in the vibrational spectra. The spectral variations observed between normal and treated rats were in great part due to reactive oxygen species that led to changes in protein conformation involving beta-sheets, aggregation of proteins, and modification of protein synthesis. Carrageenan-induced inflammation slightly enhanced the total lipid content; rearrangement of acyl chains and accumulation of cholesterol esters and phospholipids also occurred in the treated rats. Carbon tetrachloride induced a decrease in both lipid and protein contents. The level of glucidic substrates was diminished with carbon tetrachloride and enhanced with carrageenan; these changes were due to metabolic interactions between cell components and drugs. FT-IR spectroscopy provided an accurate means to monitor, in rat heart, the in vivo effects of inflammatory and peroxidative damages, to discriminate and classify the affected cells, and to correlate the findings with known physiological and biochemical data in close relationship with metabolic disruptions induced by the two xenobiotics.

  13. Evaluation of protective effect of Sapindus mukorossi saponin fraction on CCl4-induced acute hepatotoxicity in rats

    Science.gov (United States)

    Rao, M Srinivasa; Asad, B Syed; Fazil, MA; Sudharshan, RD; Rasheed, SA; Pradeep, HA; Aboobacker, S; Thayyil, AH; Riyaz, AK; Mansoor, M; Aleem, MA; Zeeyauddin, K; Narasu, M Lakshmi; Anjum, A; Ibrahim, M

    2012-01-01

    Aim This investigation aimed to assess the hepatoprotective effect of saponin fraction isolated from the fruit pericarp of Sapindus mukorossi on carbon tetrachloride (CCl4)-induced hepatotoxicity. Methods Fruit of S. mukorossi was collected and authenticated, and dried pericarp powder subjected to extraction with cold ethanol (70%) by maceration followed by isolation of total saponin fraction. Hepatoprotective activity was demonstrated in the CCl4-damaged primary monolayer culture. In in vivo studies, pretreatment with total saponin fraction (50,100 and 150 mg/kg per os once a day for 4 days before CCl4 introduction and continued afterward for 3 days) attenuated the CCl4-induced acute increase in serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, and alkaline phosphatase activities and considerably reduced histopathological alterations. Further, saponin fraction reduced thiopentone-induced (4 mg/kg, intraperitoneal) sleeping time in rats. Results Saponin fraction pretreatment improves bromsulphalein clearance and also increases cellular viability. Saponin administration replenished depleted hepatic glutathione and superoxide dismutase by improving the antioxidant status of the liver and liver function enzymes. These effects substantiate protection of cellular phospholipids from peroxidative damage induced by highly reactive toxic intermediate radicals formed during biotransformation of CCl4. Conclusion The above findings lead to the conclusion that the saponin fraction of S. mukorossi has a protective capability both in vitro on primary hepatocyte cultures and in vivo in a rat model of CCl4-mediated liver injury. Hence, we suggest that the inclusion of this S. mukorossi fruit pericarp in the management of liver disorders is justified. PMID:22888266

  14. Effect of methanol extract of Cuscuta reflexa aerial parts on hepatotoxicity induced by antitubercular drugs in rats

    Directory of Open Access Journals (Sweden)

    B R Balakrishnan

    2010-03-01

    Full Text Available Abstract: Evaluation of hepatoprotective activity of extracts of Cuscuta reflexa (Convolvulaceae on Isoniazid (INH and Rifambicin (RIF induced hepatotoxicity rats. Hepatotoxicity was observed by biochemical measurments: Serum alanine aminotransferase (ALT, aspartate aminotransferase (AST and alkaline phosphatase (ALP activities, ﻻ- GT the levels of total bilirubin were evaluated. There was a significant decrease in serum parameters in extract and standard drug treated groups. Histopathological changes were also observed in livers of animals that received extract and standard drug. Industrial relevance: The data generated in this study suggest that Cuscuta reflexa, could be very useful in the management of hepatoprotection on INH and RIF induced hepatotoxicity. Further studies will still be required at identifying the active hypoglycaemic phytoconstituents and their possible mechanism.

  15. Detecting mRNA Predictors of Acetaminophen-Induced Hepatotoxicity in Mouse Blood Using Quantitative Real-Time PCR.

    Science.gov (United States)

    Kanno, Syu-ichi; Tomizawa, Ayako; Yomogida, Shin

    2016-01-01

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Drug-induced liver injury from agents such as APAP is known to vary between individuals within a species. To avoid liver injury and ensure the proper use of pharmaceutical products, it is important to be able to predict such risks using genetic information. This study evaluated the use of quantitative real-time polymerase chain reaction (RT-qPCR) to identify mRNAs (carried in the blood of male ddY mice) capable of predicting susceptibility to APAP-induced hepatotoxicity. Screening was performed on samples obtained at 18 h after treatment from mice that had been orally treated with 500 mg/kg APAP. APAP-induced hepatotoxicity was seen in 60% of the mice, and the mortality rate was 12%. Blood APAP concentration did not differ significantly between mice with and without APAP-induced hepatotoxicity. We compared blood mRNA expression levels between mice with (positive, serious or lethal injury) and without hepatotoxicity in the APAP-treated group. The transcript levels of interleukin-encoding loci Il1β, Il10, and tumor necrosis factor (Tnf) were increased in the lethal injury group. Transcripts of the loci encoding transthyretin (Ttr) and metallothionein 1 (Mt1) showed increases in the liver injury group, while those of the glutathione peroxidase 3-encoding locus (Gpx3) were decreased. APAP hepatotoxicity was potentiated in fasted animals, although fasting did not appear to affect the level of expression of these genes. These results indicate that mRNA expression of Il1β, Il10, Tnf, Ttr, Mt1, and Gpx3 in mouse blood may provide useful surrogate markers of APAP-induced hepatotoxicity.

  16. The Role of RAAS Inhibition by Aliskiren on Paracetamol-Induced Hepatotoxicity Model in Rats.

    Science.gov (United States)

    Karcioglu, Saliha Sena; Palabiyik, Saziye Sezin; Bayir, Yasin; Karakus, Emre; Mercantepe, Tolga; Halici, Zekai; Albayrak, Abdulmecit

    2016-03-01

    Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS.

  17. Ameliorative effect of vitamin C against hepatotoxicity induced by emamectin benzoate in rats.

    Science.gov (United States)

    Khaldoun Oularbi, H; Richeval, C; Lebaili, N; Zerrouki-Daoudi, N; Baha, M; Djennas, N; Allorge, D

    2016-07-26

    In the present study, we aimed to assess the potential protective effect of ascorbic acid (AA) against emamectin benzoate (EMB)-induced hepatotoxicity. For this purpose, biochemical, histopathological and analytical investigations were performed. Male Wistar rats were distributed into three groups, that is, a control group, an EMB group given 10 mg EMB/kg body weight (BW) by gavage and an EMB + AA group given 10 mg EMB/kg BW and vitamin C intraperitoneally (200 mg/kg). The duration of the treatment was 28 days and the duration of the study was 42 days. There was a statistically significant increase of all hepatic biomarkers, that is, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase activities, and glycemia, in EMB-treated group when compared with the control group. Light microscopic observations revealed variable signs of hepatotoxicity in the EMB group, which were represented by alteration of normal hepatic architecture, inflammatory cell infiltration, hepatocellular steatosis and foci of necrosis at 28 and 42 days post-treatment. However, co-treatment with vitamin C reduced EMB-related liver toxicity and diminished the abnormal biochemical and architectural damage. Emamectin B1a and B1b residues were detectable in all plasma samples of treated rats at 14, 21 and 28 days of treatment. The drug liver tissue concentration was significantly lower in EMB + AA group compared with EMB group at 28 and 42 days. In conclusion, the findings of the present study clearly indicate a significant protective action of vitamin C against EMB hepatotoxicity.

  18. Effects of platelet-rich plasma on liver regeneration in CCl4-induced hepatotoxicity model.

    Science.gov (United States)

    Mafi, Afsaneh; Dehghani, Farzaneh; Moghadam, Abbas; Noorafshan, Ali; Vojdani, Zahra; Talaei-Khozani, Tahereh

    2016-12-01

    Numerous bioactive growth factors and cytokines in platelet-rich plasma (PRP) have recently made it an attractive biomaterial for therapeutic purposes. These growth factors have the potential to regenerate the injured tissues. The aim of this study was to investigate the therapeutic effects of PRP in hepatotoxic animal model. Hepatotoxicity was induced in rats by oral administration of 4 mL/kg/week of CCl4 diluted 1:1 in corn oil for 10 weeks. To confirm the hepatotoxicity, 24 h after the last CCl4 administration, blood samples were collected via cardiac puncture to assess the serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total protein, and total bilirubin. Twenty-four hours after blood collection, the experimental animals received a single injection of PRP (1 mL) via the anterior mesenteric vein. One week later, all biochemical tests were performed again, and the rats were scarified and their livers were removed, prepared histologically, and stained. The stereological analyses were performed to evaluate the effects of PRP on histopathological features of CCl4-treated livers. The results were compared statistically with the corresponding control and CCl4+normal saline (NS)-treated animals. A significant decrease in the number and volume of hepatocytes (p = 0.01), and also a reduction in the volume of sinusoids (p = 0.001) and connective tissue (p = 0.04), were observed in the PRP-treated animals compared with the CCl4+NS-treated ones. Our findings demonstrated that application of PRP had beneficial effects on CCl4-induced fibrosis; however, it had detrimental effects on the total number of hepatocytes and the volume of hepatocytes and sinusoidal spaces.

  19. Prevention of hepatotoxicity due to anti tuberculosis treatment: A novel integrative approach

    Institute of Scientific and Technical Information of China (English)

    Meghna R Adhvaryu; Narsimha M Reddy; Bhasker C Vakharia

    2008-01-01

    AIM: To evaluate the ability of Curcuma longa (CL) and Tinospora cordifolia (TC) formulation to prevent anti-tuberculosis (TB) treatment (ATT) induced hepatotoxicity.METHODS: Patients with active TB diagnosis were randomized to a drug control group and a trial group on drugs plus an herbal formulation.Isoniazid,rifampicin,pyrazinamide and ethambutol for first 2 mo followed by continuation phase therapy excluding Pyrazinamide for 4 mo comprised the anti-tuberculous treatment.Curcumin enriched (25%) CL and a hydro-ethanolic extract enriched (50%) TC 1 g each divided in two doses comprised the herbal adjuvant.Hemogram,bilirubin and liver enzymes were tested initially and monthly till the end of study to evaluate the result.RESULTS: Incidence and severity of hepatotoxicity was significantly lower in trial group (incidence: 27/192 vs 2/316,P < 0.0001).Mean aspartate transaminase (AST) (195.93 ± 108.74 vs 85 ± 4.24,P < 0.0001),alanine transaminase (ALT) (75.74 ± 26.54 vs 41 ±1.41,P < 0.0001) and serum bilirubin (5.4 ± 3.38 vs 1.5± 0.42,P < 0.0001).A lesser sputum positivity ratio at the end of 4 wk (10/67 vs 4/137,P = 0.0068) and decreased incidence of poorly resolved parenchymal lesion at the end of the treatment (9/152 vs 2/278,P = 0.0037) was observed.Improved patient compliance was indicated by nil drop-out in trial vs 10/192 in control group (P < 0.0001).CONCLUSION: The herbal formulation prevented hepatotoxicity significantly and improved the disease outcome as well as patient compliance without any toxicity or side effects.

  20. Effect of imidacloprid on hepatotoxicity and nephrotoxicity in male albino mice

    Directory of Open Access Journals (Sweden)

    Yasir Arfat

    2014-01-01

    Full Text Available Imidacloprid (IC is a systemic insecticide related to the tobacco toxin nicotine. IC is a toxic substance frequently used into combat insects, rodents and plants pests and other creatures that can pose problems for agriculture. We, therefore, planned this study to assess risk factors, biochemical and histological alterations associated with hepatotoxicity and nephrotoxicity. Forty-eight adult male albino mice were divided into four groups of 12 animals each. All the animals were given standard synthetic pellet diet. One group served as control, and the other three were served as experimental groups. Decrease in the body weight of the high dose group was observed at 15 mg/kg/day, and no mortality occurred during the treatment period. High dose of imidacloprid caused a significant elevation of serum clinical chemistry parameters, serum glutamic oxaloacetic transaminase (SGOT, serum glutamic pyruvate kinase (SGPT, alkaline phosphatase (ALP and total bilirubin (TBIL. Histology of liver and kidney indicates hepatotoxicity and nephrotoxicity at a high dose of imidacloprid. Based on the morphological, biochemical and histopathological analysis, it is evident that imidacloprid induced toxicological effects at 15 mg/kg/day to mice. The results of the present study demonstrate that IC had significant effects on body weight, liver functions and kidney (p < 0.05 at a dose of 15 mg/kg body weight. IC treatment 5 and 10 mg/kg/day may be considered as no observed adverse effect level (NOAEL for mice. It was concluded that IC can cause hepatotoxicity and nephrotoxicity at a dose much lower than the LD50 (131 mg/kg body weight in mice.

  1. Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity.

    Science.gov (United States)

    Chiu, Chun-Hung; Chang, Chun-Chao; Lin, Shiang-Ting; Chyau, Charng-Cherng; Peng, Robert Y

    2016-07-14

    Lipopolysaccharide (LPS)-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST), a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA) apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group) were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10) for seven days and then were LPS-challenged (i.p., 5 mg/kg). The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), creatinine (CRE), hepatic malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS), suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day). Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.

  2. Antioxidant and anti-inflammatory role of zingerone in ethanol-induced hepatotoxicity.

    Science.gov (United States)

    Mani, Vijay; Arivalagan, Sivaranjani; Siddique, Aktarul Islam; Namasivayam, Nalini

    2016-10-01

    Alcoholic liver disease is a direct result of alcohol-induced hepatotoxicity coupled with impaired hepatic regenerative activity. Our aim of the study was to investigate the beneficial effect of zingerone on hepatic oxidative stress and inflammation induced by ethanol in experimental rats. Male albino Wistar rats were divided into four groups. Rats of groups 1 and 2 received isocaloric glucose and dimethyl sulfoxide (2 % DMSO). Hepatotoxicity was induced in groups 3 and 4 by supplementing 30 % ethanol post orally for 60 days. Rats of groups 2 and 4 received zingerone (20 mg/kg body weight in 2 % DMSO p.o) daily during the final 30 days of the experimental period. Ethanol alone administered rats showed significant increase in the plasma and tissue lipid peroxidation markers such as thiobarbituric acid reactive substances, lipid hydroperoxides, conjugated dienes, and a significant decrease in the activities of plasma and tissue enzymic and non-enzymic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, vitamin C, and vitamin E. Moreover, the presence of mast cells and increase in the expressions of inflammatory markers such as NF-κB, COX-2, TNF-α, and IL-6 and decrease in the expression of Nrf2 in the liver was observed in ethanol-fed rats. Supplementation with zingerone to ethanol-fed rats reversed the changes induced by ethanol in the experimental rats. Thus, zingerone, through its antioxidant and anti-inflammatory effects, may represent a therapeutic option to protect against ethanol-induced hepatotoxicity.

  3. The role of infliximab on paracetamol-induced hepatotoxicity in rats.

    Science.gov (United States)

    Ferah, Irmak; Halici, Zekai; Bayir, Yasin; Demirci, Elif; Unal, Bunyami; Cadirci, Elif

    2013-06-01

    Paracetamol has a reasonable safety profile when consumed in therapeutic doses. However, it could induce hepatotoxicity and even acute liver failure when taken at an overdose. Infliximab is tumor necrosis factor alpha (TNF-α) inhibitor agent, which has been developed as a therapeutic agent for TNF-α-mediated disease. It acts by binding and neutralizing TNF. The aim of our study was to evaluate the hepatoprotective activity of infliximab on paracetamol-induced hepatotoxicity and to understand the relationship between the TNF-α and paracetamol-induced liver injury. Fifty-six rats were divided into eight groups as each composed of seven rats: (1) intact, (2) 7 mg/kg infliximab, (3) 140 mg/kg NAC, (4) 2 g/kg paracetamol, (5) 2 g/kg paracetamol + 140 mg/kg NAC, (6) 2 g/kg paracetamol + 3 mg/kg infliximab, (7) 2 g/kg paracetamol + 5 mg/kg infliximab and (8) 2 g/kg paracetamol + 7 mg/kg infliximab groups. Liver function tests including lipid peroxidation levels were analyzed and histopathological changes of liver were also observed. There were statistically significant increases in the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), levels of TNF-α and malondialdehyde (MDA) and decreases in the activity of superoxide dismutase (SOD) and level of glutathione (GSH) in the group treated with paracetamol. Infliximab administration dramatically reduced serum ALT, AST and TNF-α level. Also, it restored GSH, SOD and decreased MDA levels in liver. Liver histopathological examination showed that infliximab administration antagonized paracetamol-induced liver pathological damage. The results of present study suggest that infliximab has significant hepatoprotective activity on paracetamol-induced hepatotoxicity.

  4. Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Chun-Hung Chiu

    2016-07-01

    Full Text Available Lipopolysaccharide (LPS-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST, a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10 for seven days and then were LPS-challenged (i.p., 5 mg/kg. The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT, glutamic oxaloacetic transaminase (GOT, blood urea nitrogen (BUN, creatinine (CRE, hepatic malondialdehyde (MDA and glutathione peroxidase (GSH-Px, IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS, suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day. Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.

  5. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Henninger, Christian [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany); Huelsenbeck, Johannes; Huelsenbeck, Stefanie [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Grösch, Sabine [Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main (Germany); Schad, Arno [Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Lackner, Karl J. [Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Kaina, Bernd [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Fritz, Gerhard, E-mail: fritz@uni-duesseldorf.de [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany)

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  6. Interaction between nitric oxide synthase and cyclooxygenase in the development of acetaminophen-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Meltem Kolgazi

    2015-03-01

    Results: AG and KET prevented the increase in liver malondialdehyde levels due to APAP toxicity. Decreased liver glutathione in APAP group was prevented by all treatments except NIM. Stimulated liver myeloperoxidase activity in APAP group was attenuated by all treatments except INDO and NIM. Elevation of liver chemiluminescence, nuclear factor (NF- and #61547;B expression and serum alanine transferase level due to APAP overdose were also suppressed by all treatments. Conclusions: NOS and COX pathways interact in the development of hepatotoxicity due to APAP overdose. [J Exp Integr Med 2015; 5(1.000: 16-22

  7. Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements

    Institute of Scientific and Technical Information of China (English)

    Lily Dare; Jennifer Hewett; Joseph Kartaik Lim

    2008-01-01

    Dietary supplements represent an increasingly common source of drug-induced liver injury. Hydroxycut is a popular weight loss supplement which has previously been linked to hepatotoxiciLy, although the individual chemical components underlying liver injury remain poorly understood. We report two cases of acute hepatitis in the seLLing of Hydroxycut exposure and describe possible mechanisms of liver injury. We also comprehensively review and summarize the existing literature on commonly used weight loss supplements,and their individual components which have demonstrated potential for liver toxicity. An increased effort to screen for and educate patients and physicians about supplement-associated hepatotoxicity is warranted.

  8. Hepatotoxicity of anti-inflammatory and analgesic drugs:ultrastructural aspects

    Institute of Scientific and Technical Information of China (English)

    Irena MANOV; Helen MOTANIS; Idan FRUMIN; Theodore C IANCU

    2006-01-01

    With the increasing incidence of drug-induced liver disease,attempts are being made to better understand the mechanisms behind these frequently life-endangering reactions.Analgesics and anti-inflammatory drugs are a major group exhibiting hepatotoxicity.We review research relating to these reactions,focusing on ultrastructural findings,which may contribute to the comprehension and possible avoidance of drug-induced liver disease.We also present some original observations on clinical material and cultured cells exposed to acetaminophen alone or in combination with the antioxidant N-acetylcysteine or the P-glycoprotein inhibitor verapamil.

  9. Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis

    Energy Technology Data Exchange (ETDEWEB)

    Brusko, C.S.; Marten, J.T. (Purdue University School of Pharmacy and Pharmacal Sciences, Lafayette, IN (United States))

    1991-12-01

    Environmental illness, a hypothesized disease caused by exposure to substances such as combustion products, pesticides, food additives, and Candida albicans, is discussed. The case of a patient with environmental illness and systemic candidiasis for six weeks with ketoconazole, liver enzyme concentrations increased. One month after discontinuation of ketoconazole, the liver enzyme concentrations decreased; however, over the next five months, liver enzymes and bilirubin increased. The patient developed encephalopathy and eventually was transferred to a medical center for possible liver transplant. A review of the literature pertaining to ketoconazole hepatotoxicity is also presented.16 references.

  10. Evaluation of hepatotoxicity and clastogenicity of carbofuran in male Wistar rats.

    Science.gov (United States)

    Gbadegesin, Michael A; Owumi, Solomon E; Akinseye, Victor; Odunola, Oyeronke A

    2014-03-01

    Carbofuran based pesticides have gained wide usage in Nigeria recently. Consequently, animals and human populations are exposed to them in the environment. Information on in vivo toxicity of carbofuran in experimental models is scanty. The present study therefore examined the hepatotoxicity and clastogenic effects of carbofuran in rats. Male Wistar rats were exposed to carbofuran (p.o) at 0-5mg/kg bw for 5weeks. Carbofuran induced significant (prats. It therefore may constitute an environmental health risks in individuals so exposed.

  11. The pericarp extract of Prunus persica attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity in mice.

    Science.gov (United States)

    Lee, Chang Ki; Park, Kwang-Kyun; Hwang, Jae-Kwan; Lee, Sang Kook; Chung, Won-Yoon

    2008-06-01

    The fruit of Prunus persica L. (peach) is one of the common fruits. Its seed is well known as a traditional medicine (Persicae Semen) in Japan, China, and other Asian countries. However, the biological activities of P. persica fruit except its seed are poorly understood. This study was aimed at evaluating the protective effect of the pericarp extract of P. persica (PPE) against cisplatin-induced acute toxicity in mice. PPE (500 mg/kg, p.o.) showed a significant protection against the acute nephrotoxicity and hepatotoxicity induced by a single administration of cisplatin (45 mg/kg, i.p.) over a 16-hour period in mice. Its protective effect was evaluated by serum and tissue biochemical parameters. The pretreatment with PPE for 7 days prevented the cisplatin-induced decrease in the kidney and liver weights as a percentage of the total body weight. PPE significantly inhibited both the cisplatin-induced elevation in serum blood urea nitrogen and creatinine levels caused by kidney damage and the cisplatin-induced increase in serum alanine aminotransferase and aspartate aminotransferase levels by the liver damage. In addition, the administration of PPE caused recovery of the cisplatin-mediated changes in levels of serum nitric oxide and tissue lipid peroxidation, and reduced glutathione content returned to control levels. These results suggest that PPE protects against cisplatin-induced nephrotoxicity and hepatotoxicity by reducing cisplatin-induced oxidative stress in mice.

  12. Effect of fenugreek seed extract on adriamycin-induced hepatotoxicity and oxidative stress in albino rats.

    Science.gov (United States)

    Sakr, Saber A; Abo-El-Yazid, Samah M

    2012-11-01

    The purpose of this work was to evaluate the effect of aqueous extract of fenugreek seeds against hepatotoxicity induced in albino rats by the anticancer drug adriamycin (ADR). Animals were given single dose of ADR (10 mg/kg body weight) and were killed after 2 and 4 weeks. Liver of ADR-treated animals showed histopathological and biochemical alterations. The histopathological changes include hepatic tissue impairment, cytoplasmic vacuolization of the hepatocytes, congestion of blood vessels, leucocytic infiltrations and fatty infiltration. Moreover, the expression of proliferating cell nuclear antigen was increased in ADR-treated rats. The liver enzymes, aspartate aminotransferase (ALT) and alanine aminotransferase (AST) were increased in the sera of treated rats. Moreover, ADR significantly increased the concentration of malondialdehyde (MDA) and decreased the activities of superoxide dismutase (SOD) and catalase (CAT) in hepatic tissue. Treating animals with ADR and aqueous extract of fenugreek (0.4 g/kg body weight) seeds led to an improvement in histological and biochemical alterations induced by ADR. The biochemical results showed that AST and ALT appeared normal together with reduction in the level of MDA (lipid peroxidation marker) and increase in SOD and CAT activities. It was concluded from this study that the aqueous extract fenugreek seeds has a beneficial impact on ADR-induced hepatotoxicity due to its antioxidant effect in albino rats.

  13. An antibody of TNF-alpha did not prevent thioacetamide-induced hepatotoxicity in rats.

    Science.gov (United States)

    Demirel, Ulvi; Harputluoglu, Murat M M; Seckin, Yuksel; Ciralik, Harun; Temel, Ismail; Ozyalin, Fatma; Otlu, Baris; Yilmaz, Bilgic; Dincturk, Mehmet Sarp; Aladag, Hulya

    2011-07-01

    Tumor necrosis factor (TNF)-α antibodies have been shown to reduce liver damage in different models. We investigated the effects of infliximab (a TNF-α antibody) on liver damage in thioacetamide (TAA)-induced hepatotoxicity in rats. Group 1 (n = 8) was the control group. In group 2 (n = 8), the TAA group, the rats received 300 mg/kg intraperitoneal (ip) TAA daily for 2 days. In group 3 (n = 8), the TAA + Infliximab (INF) group, infliximab (5 mg/kg ip daily) was administered 48 hours before the first dose of TAA daily for 2 days and was maintained for 4 consecutive days. In group 4 (n = 8), the INF group, the rats received only ip infliximab (5 mg/kg) daily. Livers were excised for histopathological and biochemical tests (thiobarbituric-acid-reactive substances [TBARS], and myeloperoxidase [MPO]). Serum ammonia, aspartate transaminase (AST), alanine transaminase (ALT), TNF-α, liver TBARS and MPO levels, and liver necrosis and inflammation scores in the TAA group were significantly higher than in the control and INF groups (all p induced hepatotoxicity, and infliximab does not improve oxidative liver damage.

  14. Hepatoprotective potential of ethanolic extract of Aquilaria agallocha leaves against paracetamol induced hepatotoxicity in SD rats.

    Science.gov (United States)

    Alam, Janey; Mujahid, Md; Badruddeen; Jahan, Yasmeen; Bagga, Paramdeep; Rahman, Md Azizur

    2017-01-01

    Many traditional systems of medicines employ herbal drugs for the hepatoprotection. Aim of the study was designed to evaluate the hepatoprotective potential of 'ethanolic extract of Aquilaria agallocha ( Chen Xiang) leaves' (AAE) against paracetamol (PCM) induced hepatotoxicity in SD rats. Group I animals were treated with 1% CMC for 8 days. Group II, III, IV and V animals were first treated with '1% CMC' 1 ml/kg/day, AAE 200 mg/kg/day, AAE 400 mg/kg/day and silymarin 100 mg/kg/day respectively for 7 days and then, orally administered with PCM 3 g/kg b. wt. on 8th day in a single dose. 24 h after the last dosing by PCM, the blood was obtained through the retro-orbital plexus under light anesthesia and the animals were sacrificed. Hepatoprotective potential was assessed by various biochemical parameters such as ALT, AST, ALP, LDH, bilirubin, cholesterol, TP and ALB. Group IV rats showed significant (p rats. Hepatoprotective potential of AAE 400 mg/kg/day was comparable to that of standard drug silymarin 100 mg/kg/day. Results of the study were well supported by the histopathological observations. This study confirms that AAE possesses hepatoprotective potential comparable to that of standard drug silymarin as it exhibited comparable protective potential against PCM induced hepatotoxicity in SD rats.

  15. Syzygium Cumini (L. Seeds Extract Ameliorates Cisplatin Induced Hepatotoxicity in Male Wistar Rats

    Directory of Open Access Journals (Sweden)

    R.Maheswari

    2015-02-01

    Full Text Available The discovery of cisplatin, cis-[Pt(II(NH(3(2Cl(2] ([PtCl2(NH32] or CDDP, was a corner stone which triggered the interest in platinum(II-and other metal-containing compounds as potential anticancer drugs. Cisplatin, is one of the most potent chemotherapy drugs widely used for cancer treatment. In our present study, an attempt has been made to study the effect of Cisplatin on biochemical and histopathological parameters and ameliorating effects of the Syzygium cumini (L. aqueous seeds extract or Eugena Jambolana in male wistar rats. Adult male wistar rats were divided into four different groups. Group I Served as vehicle treated normal saline (Control, Group II Rats received single intra-peritoneal (Ip injection of cisplatin (7mg/kg bw, Group III received Syzygium cumini (L. aqueous seeds extract 400mg/kg/bw orally for 7 days beginning one day prior to cisplatin (CP injection. Group IV Rats received alone Syzygium cumini (L. aqueous seeds extract (400mg/kg bw treated. Cisplatin exposure leads to adverse effects on hematological, hepatotoxic parameters including Erythrocytes (RBCs. Cisplatin induction leads to reduction in the levels of Enzymic and Non-Enzymic antioxidants levels. However, on treatment with Syzygium cumini (L. aqueous seeds extract normalized the levels of all the biochemical and hematological parameters. These findings highlight the efficacy of Syzygium cumini (L. aqueous seeds extract as protective effects Cisplatin induced hepatotoxicity.

  16. Protective effect of Etlingera elatior (torch ginger) extract on lead acetate--induced hepatotoxicity in rats.

    Science.gov (United States)

    Haleagrahara, Nagaraja; Jackie, Tan; Chakravarthi, Srikumar; Rao, Mallikarjuna; Kulur, Anupama

    2010-10-01

    Lead is known to disrupt the biological systems by altering the molecular interactions, cell signaling, and cellular function. Exposure to even low levels of lead may have potential hazardous effects on brain, liver, kidneys and testes. The efficacy of Etlingera elatior (torch ginger) to protect hepatotoxicity induced by lead acetate was evaluated experimentally in male Sprague - Dawley rats. Rats were exposed to lead acetate in drinking water (500 ppm) for 21 days and the effects of concurrent treatment with extract of E. elatior on hepatic lipid hydroperoxides (LPO), protein carbonyl content (PCC), total antioxidants (TA), superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione S- Transferase (GST) levels and histopathological changes in liver were evaluated. There was a significant decrease in TA and other antioxidant enzymes (p induced changes in hepatic architecture. E. elatior has also reduced the blood lead levels (BLL). Thus, there has been extensive biochemical and structural alterations indicative of liver toxicity with exposure to lead and E. elatior treatment significantly reduced these oxidative damage. Our results suggest that E. elatior has a powerful antioxidant effect against lead-induced hepatotoxicity.

  17. Protective effect of Pisonia aculeata on thioacetamide induced hepatotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Anbarasu C; Rajkapoor B; Bhat KS; John Giridharan; A Arul Amuthan; Satish K

    2012-01-01

    Objective:To evaluate the protective effect of Pisonia aculeata (P. aculeata) on thioacetamide induced hepatotoxicity in rats. Methods:Male Wistar rats were administered 250 or 500 mg/kg p.o. of P. aculeata extract for 21 days and simultaneously administered thioacetamide (TAA) 50 mg/kg bw s.c. 1 h after the respective assigned treatments every 72 h. At the end of all experimental methods, all the animals were sacrificed by cervical decapitation. Blood samples were collected. Serum was separated and analyzed for various biochemical parameters. Results: TAA induced a significant rise in aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total bilirubin, gamma glutamate transpeptidase (GGTP), lipid peroxidase (LPO) with a reduction of total protein, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione S-transferase (GST). Treatment of rats with different doses of plant extract (250 and 500 mg/kg) significantly (P<0.001) altered serum marker enzymes and antioxidant levels to near normal against TAA treated rats. The activity of the extract at a dose of 300 mg/kg was comparable to the standard drug, silymarin (50 mg/kg, p.o.). Conclusions:It can be concluded that P. aculeata extract possesses a remarkable hepatoprotective and antioxidant activity against TAA induced hepatotoxicity. More research is required to derive an optimal therapeutic dose.

  18. Effects of selenium on chromium (VI)-induced hepatotoxicity in adult rats.

    Science.gov (United States)

    Soudani, Nejla; Ben Amara, Ibtissem; Sefi, Mediha; Boudawara, Tahia; Zeghal, Najiba

    2011-09-01

    Chromium, a major environmental pollutant, is known for its wide toxic manifestations. The present experiment pertains to the protective role of selenium (Se) against K(2)Cr(2)O(7)-induced hepatotoxicity. Female Wistar rats were divided into four groups of six each: group I served as controls which received standard diet; group II received in drinking water K(2)Cr(2)O(7) alone (700 ppm); group III received both K(2)Cr(2)O(7) and Se (0.5 Na(2)SeO(3) mg/kg of diet); group IV received Se (0.5 mg/kg of diet) for 3 weeks. Exposure of rats to chromium promoted oxidative stress with an increase in malondialdehyde (MDA) and a decrease in glutathione (GSH) levels. A decrease in glutathione peroxidase (GPx) and an increase in superoxide dismutase (SOD) and catalase (CAT) activities were observed. Se supplementation to the diet of group III improved all the parameters cited above. Yet, plasma transaminases (AST and ALT), lactate dehydrogenase (LDH) activities, cholesterol, triglycerides (TG) and low density lipoprotein-cholesterol (LDL-C) levels increased, while high density lipoprotein-cholesterol (HDL-C) decreased. Co-administration of Se to the diet of group III restored hepatic markers to near-normal values. The biochemical results confirmed the histopathological findings. Therefore, our investigation revealed that Se was effective in preventing K(2)Cr(2)O(7)-induced hepatotoxicity.

  19. Therapeutic effects of Cassia angustifolia in a cadmium induced hepatotoxicity assay conducted in male albino rats

    Directory of Open Access Journals (Sweden)

    Muhammad Tahir Haidry

    2016-06-01

    Full Text Available The present study aims to investigate the therapeutic effects of Senna plant (Cassia angustifolia L. in a cadmium induced hepatotoxicity assay by evaluating the activity of alanine transaminase (ALT, aspartate transaminase (AST, alkaline phosphatase (ALP and total protein (TP in the albino rats’ serum. A total of 30 white albino rats were taken and divided into three groups; each group comprising ten rats. The group A was taken as a control group; group B was given cadmium chloride concentration of 5 mg/kg (body weight for 42 days; and group C was given cadmium chloride 5 mg/kg body weight for first 21 days and then extract of C. angustifolia 100 mg/kg (body weight was given for remaining 21 days. The analysis were performed twice i.e., on 21st day and 42nd day. Results illustrated that the concentration of cadmium was significantly elevated (P<0.05 at the levels of serum biochemical markers namely ALT, AST, ALP which lowered the protein levels in albino rats. Moreover, treatment with the standard extracts of C. angustifolia observed to reverse the effects of the cadmium significantly (P<0.05. It is concluded that the C. angustifolia had hepatoprotective effects and therapeutic potential against the cadmium induced hepatotoxicity in albino rats.

  20. Hepatoprotective potential of ethanolic extract of Caesalpenia crista leaves against paracetamol induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Garima Mishra

    2015-01-01

    Full Text Available Objective: To investigate the hepatoprotective activity of ethanolic extract of leaves of Caesalpenia crista (C. crista against paracetamol induced hepatotoxicity in rats. Methods: Paracetamol (2 g/kg body weight was used to induce hepatotoxicity in albino rats. Ethanolic extract of leaves of C. crista was administered at the dose levels of 200 and 400 mg/kg body weight orally for 7 d. Silymarin (100 mg/kg was used as standard drug. The hepatoprotective effect of ethanolic extract was evaluated by assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, serum alkaline phosphatase, bilirubin (total and direct, and triglycerides content. Histopathological study of rat liver was also done. Results: Administration of ethanolic extract at doses 200 mg/kg and 400 mg/kg body weight exhibited significant reduction in elevated level of serum marker enzymes, bilirubin (total and direct and triglycerides when compared to positive control group. Conclusions: It is concluded that the ethanolic extract of C. crista leaves seems to justify the promising hepatoprotective effect on paracetamol induced liver damage in rats.

  1. Retro-orbital blood acquisition facilitates circulating microRNA measurement in zebrafish with paracetamol hepatotoxicity.

    Science.gov (United States)

    Vliegenthart, Adriaan D B; Starkey Lewis, Philip; Tucker, Carl S; Del Pozo, Jorge; Rider, Sebastein; Antoine, Daniel J; Dubost, Valérie; Westphal, Magdalena; Moulin, Pierre; Bailey, Matthew A; Moggs, Jonathan G; Goldring, Chris E; Park, B Kevin; Dear, James W

    2014-06-01

    Paracetamol is the commonest cause of acute liver failure in the Western world and biomarkers are needed that report early hepatotoxicity. The liver-enriched microRNA (miRNA), miR-122, is a promising biomarker currently being qualified in humans. For biomarker development and drug toxicity screening, the zebrafish has advantages over rodents; however, blood acquisition in this model remains technically challenging. We developed a method for collecting blood from the adult zebrafish by retro-orbital (RO) bleeding and compared it to the commonly used lateral incision method. The RO technique was more reliable in terms of the blood yield and minimum amount per fish. This new RO technique was used in a zebrafish model of paracetamol toxicity. Paracetamol induced dose-dependent increases in liver cell necrosis, serum alanine transaminase activity, and mortality. In situ hybridization localized expression of miR-122 to the cytoplasm of zebrafish hepatocytes. After collection by RO bleeding, serum miR-122 could be measured and this miRNA was substantially increased by paracetamol 24 h after exposure, an increase that was prevented by delayed (3 h poststart of paracetamol exposure) treatment with acetylcysteine. In summary, collection of blood by RO bleeding facilitated measurement of miR-122 in a zebrafish model of paracetamol hepatotoxicity. The zebrafish represents a new species for measurement of circulating miRNA biomarkers that are translational and can bridge between fish and humans.

  2. Hypericum perforatum-induced hepatotoxicity with possible association with copaiba (Copaifera langsdorffii Desf):case report.

    Science.gov (United States)

    Agollo, Marjorie Costa; Miszputen, Sender Jankiel; Diament, Jayme

    2014-09-01

    We report a case of liver damage in an elderly patient after the use of herbal products of Hypericum perforatum and copaiba (Copaifera langsdorffii Desf). Hepatotoxicity related to Hypericum perforatum is anecdotally known, but for copaiba, widely used as anti-inflammatory, there is just experimental data in the national literature. This report aimed to draw attention to the possible toxic effects of this association as well as to the clinical recovery of the patient after discontinuing their use. There is a tendency to suspect of the action of drugs to justify a non-viral acute liver injury, because of the large number of drugs responsible for hepatotoxicity. There are experiments and clinical reports in the literature describing some herbal products, including Hypericum perforatum, as the causative agents of this aggression, and are considered innocuous and used with no restrictions. We must remember that adverse reactions also occur with these substances; hence, they should be investigated when collecting the patient´s history, for leading to severe liver failure.

  3. Prophylactic and therapeutic effects of taurine against aluminum-induced acute hepatotoxicity in mice.

    Science.gov (United States)

    El-Sayed, Wael M; Al-Kahtani, Mohamed A; Abdel-Moneim, Ashraf M

    2011-08-30

    Aluminum is a well known neurotoxin and a possible candidate of hepatotoxins to humans. Using natural antioxidants against metal-induced hepatotoxicity is a modern approach. In the present study, Aluminum (AlCl(3)) intoxication (a single injection of 25mg Al(3+)/kg, i.p.) for 24h in mice resulted in elevations in serum alanine aminotransferase activity and serum tumor necrosis factor and hepatic malondialdehyde levels. Aluminum reduced the activities of glutathione peroxidase, glutathione S-transferase, quinone oxidoreductase, and catalase in liver. In addition, Al caused hepatic hemorrhage, cellular degeneration as well as necrosis of hepatocytes. Ultrastructure examination showed swelling of mitochondria, derangement of rough endoplasmic reticulum cisternae and pleomorphic nuclei with abnormal chromatin distribution. Taurine, a sulfur-containing amino acid was administered to mice daily for 5 days before (at 100mg/kg, i.p.) or 2h after (a single dose of 1g/kg, i.p.) aluminum administration. Treating mice with taurine at either dosing regimens, pre- or post-aluminum administration alleviated aluminum oxidative damaging effects. The rate of recovery was better when taurine was administered prior to Al. Taurine had anaphylactic and therapeutic activity against hepatotoxicity induced by aluminum in mice.

  4. Hepatoprotective potential of ethanolic extract of Caesalpenia crista leaves against paracetamol induced hepatotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Garima Mishra; Ratan Lal Khosa; Pradeep Singh; Keshri Kishor Jha

    2015-01-01

    Objective:To investigate the hepatoprotective activity of ethanolic extract of leaves of Caesalpenia crista (C. crista) against paracetamol induced hepatotoxicity in rats. Methods:Paracetamol (2 g/kg body weight) was used to induce hepatotoxicity in albino rats. Ethanolic extract of leaves of C. crista was administered at the dose levels of 200 and 400 mg/kg body weight orally for 7 d. Silymarin (100 mg/kg) was used as standard drug. The hepatoprotective effect of ethanolic extract was evaluated by assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, serum alkaline phosphatase, bilirubin (total and direct), and triglycerides content. Histopathological study of rat liver was also done. Results:Administration of ethanolic extract at doses 200 mg/kg and 400 mg/kg body weight exhibited significant reduction in elevated level of serum marker enzymes, bilirubin (total and direct) and triglycerides when compared to positive control group. Conclusions:It is concluded that the ethanolic extract of C. crista leaves seems to justify the promising hepatoprotective effect on paracetamol induced liver damage in rats.

  5. Evaluation of diazinon-induced hepatotoxicity and protective effects of crocin.

    Science.gov (United States)

    Lari, Parisa; Abnous, Khalil; Imenshahidi, Mohsen; Rashedinia, Marzieh; Razavi, Marjan; Hosseinzadeh, Hossein

    2015-04-01

    Diazinon (DZN) is one of the most widely used insecticides in agricultural pest control. Previous studies have shown that DZN may induce hepatotoxicity. Reactive oxygen species and apoptosis pathways are involved in the toxicity of DZN. Crocin, a constituent of saffron, has hepatoprotective effects due to its antioxidant activity. In this study, we examined the effects of subacute DZN exposure and ameliorating effect of crocin on lipid peroxidation and pathological changes in rat liver. Moreover, protein levels of activated and total caspases-3 and -9 and Bax/Bcl-2 ratio were measured. Five groups of rats were used in the experiment. Corn oil (control), DZN (15 mg/kg per day, orally) and crocin (12.5, 25 and 50 mg/kg per day, intraperitoneally in combination with DZN) were given to male Wistar rats (n = 6) for 4 weeks. The level of malondialdehyde (MDA) increased significantly in DZN group compared with the control group (p liver after oral exposure to DZN was observed. DZN also induced apoptosis through activation of caspases-9 and -3 and increasing Bax/Bcl-2 ratio. Crocin attenuated the activation of caspases and reduced the Bax/Bcl-2 ratio. It is concluded that subacute exposure to DZN induces oxidative stress-mediated apoptosis and crocin may reduce DZN-induced hepatotoxicity.

  6. Spontaneous reports of primarily suspected herbal hepatotoxicity by Pelargonium sidoides: was causality adequately ascertained?

    Science.gov (United States)

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2012-06-01

    Spontaneous reports of primarily assumed hepatotoxicity in connection with the use of Pelargonium sidoides (PS) have been interpreted by the Drug Commission of the German Medical Association (DCGMA) as showing some hepatotoxic potential of PS used to treat common cold and other respiratory tract infections. Causality for PS was assessed using the liver specific, structured, quantitative, and updated scale of the Council for International Organizations of Medical Sciences (CIOMS). In none of the 15 cases was there a highly probable or probable causality for PS. Analysis revealed confounding factors such as numerous final diagnoses unrelated to PS and poor data quality in virtually all cases. In only a minority of the cases were data provided to consider even common other diseases of the liver. For instance, biliary tract imaging data were available in only 3 patients; data to exclude virus infections by hepatitis A-C were provided in 4 cases and by CMV and EBV in 1 case, whereas HSV and VZV virus infections remained unconsidered. Thus, convincing evidence is lacking that PS was a potential hepatotoxin in the analyzed cases.

  7. Hepatotoxic effects of polidocanol in a model of autologously perfused porcine livers.

    Science.gov (United States)

    Grosse-Siestrup, Christian; Unger, Volker; Pfeffer, Jeanette; Dinh, Q Thai; Nagel, Stefan; Springer, Jochen; Witt, Christian; Wussow, Anke; Groneberg, David A

    2004-12-01

    Polidocanol is an effective sclerosing agent that consists of 95% hydroxypolyethoxydodecane and 5% ethyl alcohol and is known to have a low risk of complications. However, since the compound has been proposed for the local treatment of liver diseases, the potential for topical hepatic side effects should be examined. Therefore, the new model of normothermic-hemoperfused isolated porcine slaughterhouse livers was used to examine polidocanol-hepatotoxicity encompassing the advantages of slaughterhouse organs to reduce animal experiments and autologous blood as an optimal perfusate. Polidocanol was administered via the hepatic artery and portal vein and the effects of the sclerosant on organ function parameters were compared with those in an untreated control group. In contrast to the untreated control organs, significant differences were found in the polidocanol group for parameters such as alanine aminotransferase or organ weight after perfusion. The most striking differences were found for hepatic bile flow, which dropped in the polidocanol group to 0.24+/-0.02 ml/min per 1000 g after administration of the compound compared with 3.80+/-1.08 ml/min per 1000 g in the control group. In summary, the present observations indicate a risk of hepatotoxic effects of polidocanol. Clinicians should be aware of this problem and the use of polidocanol for intrahepatic sclerosing should be restricted to specialized centers.

  8. Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice.

    Science.gov (United States)

    Ishii, Isao; Kamata, Shotaro; Hagiya, Yoshifumi; Abiko, Yumi; Kasahara, Tadashi; Kumagai, Yoshito

    2015-12-01

    The key mechanism for hepatotoxicity resulting from acetaminophen (APAP) overdose is cytochrome P450-dependent formation of N-acetyl-p-benzoquinone imine (NAPQI), a potent electrophilic metabolite that forms protein adducts. The fundamental roles of glutathione in the effective conjugation/clearance of NAPQI have been established, giving a molecular basis for the clinical use of N-acetylcysteine as a sole antidote. Recent evidence from in vitro experiments suggested that sulfide anions (S(2-)) to yield hydrogen sulfide anions (HS(-)) under physiological pH could effectively react with NAPQI. This study evaluated the protective roles of HS(-) against APAP-induced hepatotoxicity in mice. We utilized cystathionine γ-lyase-deficient (Cth(-/-)) mice that are highly sensitive to acetaminophen toxicity. Intraperitoneal injection of acetaminophen (150 mg/kg) into Cth(-/-) mice resulted in highly elevated levels of serum alanine/aspartate aminotransferases and lactate dehydrogenase associated with marked increases in oncotic hepatocytes; all of which were significantly inhibited by intraperitoneal preadministration of sodium hydrosulfide (NaHS). NaHS preadministration significantly suppressed APAP-induced serum malondialdehyde level increases without abrogating APAP-induced rapid depletion of hepatic glutathione. These results suggest that exogenous HS(-) protects hepatocytes by directly scavenging reactive NAPQI rather than by increasing cystine uptake and thereby elevating intracellular glutathione levels, which provides a novel therapeutic approach against acute APAP poisoning.

  9. Amelioration of ferric nitrilotriacetate-induced hepatotoxicity in Wistar rats by diallylsulfide.

    Science.gov (United States)

    Ansar, S; Iqbal, M

    2016-03-01

    Garlic contains diallylsulfide (DAS) and other structurally related compounds that are widely believed to be active agents in preventing cancer. This study shows the effect of DAS (a phenolic antioxidant used in foods, cosmetics, and pharmaceutical products) on ferric nitrilotriacetate (Fe-NTA)-induced hepatotoxicity in rats. Male albino rats of Wistar strain weighing 125-150 g were given a single dose of Fe-NTA (9 mg kg(-1) body weight, intraperitoneally) after 1 week of treatment with 100 and 200 mg kg(-1) DAS in corn oil respectively administered through the gavage. Fe-NTA administration led to 2.5-fold increase in the values of both alanine transaminase and aspartate aminotransferase, respectively, and 3.2-fold increase in the activity of lactate dehydrogenase, microsomal lipid peroxidation to approximately 2.0-fold compared to saline-treated control. The activities of glutathione (GSH) and other antioxidant enzymes decreased to a range of 2.2-2.5-fold. These changes were reversed significantly (p induced tissue injury and hepatotoxicity in rats.

  10. The role of glutathione detoxification pathway in MCLR-induced hepatotoxicity in SD rats.

    Science.gov (United States)

    Li, Shangchun; Chen, Jun; Xie, Ping; Guo, Xiaochun; Fan, Huihui; Yu, Dezhao; Zeng, Cheng; Chen, Liang

    2015-12-01

    In the present study, we investigated the role of glutathione (GSH) and its related enzymes in Sprague Dawley (SD) rats subjected to microcystin-leucine-arginine (MCLR)-induced hepatotoxicity. SD rats were intraperitoneally (i.p.) injected with MCLR after pretreating with or without buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GSH synthesis. The depletion of GSH with BSO enhanced MCLR-induced oxidative stress, resulting in more severe liver damage and higher MCLR accumulation. Similarly, the contents of malondialdehyde (MDA), total GSH (T-GSH), oxidized GSH (GSSG) and GSH were significantly enhanced in BSO pretreated rats following MCLR treatment. The study showed that the transcription of GSH-related enzymes such as glutathione-S-transferase (GST), γ-glutamylcysteine synthetase (γ-GCS), glutathione reductase (GR) varied in different ways (expect for glutathione peroxidase (GPx), whose gene expression was induced in all treated groups) with or without BSO pretreatment before MCLR exposure, suggesting an adaptative response of GSH-related enzymes at transcription level to combat enhancement of oxidative stress induced by MCLR when pretreated with BSO. These data suggested the tissues with low GSH concentration are highly vulnerable to MCLR toxicity and GSH was critical for the detoxification in MCLR-induced hepatotoxicity in vivo.

  11. Ameliorative Influence of Green Tea Extract on Copper Nanoparticle-Induced Hepatotoxicity in Rats

    Science.gov (United States)

    Ibrahim, Marwa A.; Khalaf, A. A.; Galal, Mona K.; Ogaly, Hanan A.; H. M. Hassan, Azza

    2015-09-01

    The potential toxicity of copper nanoparticles (CNPs) to the human health and environment remains a critical issue. In the present study, we investigated the protective influence of an aqueous extract of green tea leaves (GTE) against CNPs-induced (20-30 nm) hepatotoxicity. Four different groups of rats were used: group I was the control, group II received CNPs (40 mg/kg BW), group III received CNPs plus GTE, and group IV received GTE alone. We highlighted the hepatoprotective effect of GTE against CNPs toxicity through monitoring the alteration of liver enzyme activity, antioxidant defense mechanism, histopathological alterations, and DNA damage evaluation. The rats that were given CNPs only had a highly significant elevation in liver enzymes, alteration in oxidant-antioxidant balance, and severe pathological changes. In addition, we detected a significant elevation of DNA fragmentation percentage, marked DNA laddering, and significance over expression of both caspase-3 and Bax proteins. The findings for group III clarify the efficacy of GTE as a hepatoprotectant on CNPs through improving the liver enzyme activity, antioxidant status, as well as suppressing DNA fragmentation and the expression of the caspase-3 and Bax proteins. In conclusion, GTE was proved to be a potential hepatoprotective additive as it significantly ameliorates the hepatotoxicity and apoptosis induced by CNPs.

  12. Dietary protocatechuic acid ameliorates dextran sulphate sodium-induced ulcerative colitis and hepatotoxicity in rats.

    Science.gov (United States)

    Farombi, Ebenezer O; Adedara, Isaac A; Awoyemi, Omolola V; Njoku, Chinonye R; Micah, Gabriel O; Esogwa, Cynthia U; Owumi, Solomon E; Olopade, James O

    2016-02-01

    The present study investigated the antioxidant and anti-inflammatory effects of dietary protocatechuic acid (PCA), a simple hydrophilic phenolic compound commonly found in many edible vegetables, on dextran sulphate sodium (DSS)-induced ulcerative colitis and its associated hepatotoxicity in rats. PCA was administered orally at 10 mg kg(-1) to dextran sulphate sodium exposed rats for five days. The result revealed that administration of PCA significantly (p rats. Furthermore, PCA prevented the increase in the plasma levels of pro-inflammatory cytokines, markers of liver toxicity and markedly suppressed the DSS-mediated elevation in colonic nitric oxide concentration and myeloperoxidase activity in the treated rats. Administration of PCA significantly protected against colonic and hepatic oxidative damage by increasing the antioxidant status and concomitantly decreased hydrogen peroxide and lipid peroxidation levels in the DSS-treated rats. Moreover, histological examinations confirmed PCA chemoprotection against colon and liver damage. Immunohistochemical analysis showed that PCA significantly inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression in the colon of DSS-treated rats. In conclusion, the effective chemoprotective role of PCA in colitis and the associated hepatotoxicity is related to its intrinsic anti-inflammatory and anti-oxidative properties.

  13. The protective effects of vitamin C on hepatotoxicity induced by radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Ki Jung; Park, Sung Kwang; Cho, Heung Lae [Pusan Paik Hospital, Inje University, Busan (Korea, Republic of); Kang, Ki Mun; Chai, Gyu Young; Chung, Duck Wha [Gyungsang National University, Jinju (Korea, Republic of); Kang, Jin Soon [Jinju International University, Jinju (Korea, Republic of)

    2004-12-15

    This study was carried out to determine the protective effects of vitamin C on the hepatotoxicity induced by radiation. The Spraque Dawley rats were randomly divided into 3 groups; the control group, the radiation exposed group, and the radiation and vitamin C-treated group. SOD activity catalase, malondialdehyde and liver enzymes were analyzed to assess the antioxidant effects of vitamin C. The increased level of malondialdehyde and the decreased catalase activity that were induced by radiation were improved after vitamin C but were was no statistical significance among three groups. The superoxide dismutase activity of the liver was increased by vitamin C, but there were no statistically significant differences between the vitamin C-treated group and the non vitamin C-treated group. The level of liver enzymes in sera such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactate dehyrogenase and alkaline phosphatase were remarkably elevated by radiation. The levels of those enzymes were decreased in the vitamin C-treated group and statistical significance was noted for the GPT level ({rho} < 0.01). On the electromicrographic findings, the hepatic cell destruction was considerably decreased in the vitamin C-treated group. Vitamin C is thought to be an effective antioxidant against the hepatotoxicity induced by radiation.

  14. Influence of Moxifloxacin on Hepatic Redox Status and Plasma Biomarkers of Hepatotoxicity and Nephrotoxicity in Rat

    Directory of Open Access Journals (Sweden)

    Ayokanmi Ore

    2015-01-01

    Full Text Available Moxifloxacin is a broad spectrum fluoroquinolone antibacterial agent. We examined the hepatic redox status and plasma biomarkers of nephrotoxicity and hepatotoxicity in rat following administration of moxifloxacin (MXF. Twenty-four Wistar rats, 180–200 g, were randomized into four groups (I–IV. Animals in group I (control received 1 mL of distilled water, while animals in groups II, III, and IV received 1 mL each of MXF equivalent to 4 mg/kg b.w., 8 mg/kg b.w., and 16 mg/kg b.w., respectively. After seven days, plasma urea, bilirubin, and creatinine were significantly (P<0.05 elevated in the MXF-treated animals. Activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase were significantly increased in the plasma of MXF-treated animals compared to control. Also plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides increased significantly in the MXF-treated groups relative to control. Moreover, MXF triggered a significant decrease in hepatic catalase, superoxide dismutase, and glutathione-S transferase activities. Likewise, MXF caused a decrease in the hepatic levels of glutathione and vitamin C. A significant increase in hepatic MDA content was also observed in the MXF-treated animals relative to control. Overall, our data suggest that the half-therapeutic, therapeutic, and twice the therapeutic dose of MXF induced nephrotoxicity, hepatotoxicity, and altered hepatic redox balance in rats.

  15. Vitamin E and selenium treatment of monocrotaline induced hepatotoxicity in rats.

    Science.gov (United States)

    Cuce, G; Canbaz, H T; Sozen, M E; Yerlikaya, F H; Kalkan, S

    2017-01-01

    Monocrotaline (MCT) is a hepatotoxic pyrrolizidine alkaloid that is derived from plants; exposure may occur by consumption of contaminated grains, herbal teas and medicines. MCT can cause liver damage. We investigated the antioxidant effects of selenium (Se) and vitamin E against the toxic effects of MCT. Female Wistar albino rats were divided into four groups: a control group, an MCT group, an MCT + Se group, and an MCT + vitamin E group. Liver tissues were harvested, fixed, processed to paraffin and sections were cut. Anti-von Willebrand factor (vWF) immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL), and hematoxylin and eosin staining were performed. Serum and liver tissue glutathione (GSH), catalase (CAT), and glutathione peroxidase (GPx) levels were measured. Histopathological and TUNEL data showed significantly increased liver damage in the MCT group compared to controls. Histopathological and TUNEL staining indicated significant improvements in the MCT + vitamin E and MCT + Se groups compared to the MCT group. MCT significantly reduced the serum GSH level and GPx activity, and liver GPx activity. Biochemical data indicated a significant improvement in serum GSH level in the MCT + vitamin E group compared to the MCT group. We suggest that vitamin E and Se afford limited protection against MCT hepatotoxicity.

  16. Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.

    Science.gov (United States)

    Yu, Hong; Barrass, Nigel; Gales, Sonya; Lenz, Eva; Parry, Tony; Powell, Helen; Thurman, Dale; Hutchison, Michael; Wilson, Ian D; Bi, Luke; Qiao, Junwen; Qin, Qiuping; Ren, Jin

    2015-03-01

    1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.

  17. Metabolomics evaluation of the effects of green tea extract on acetaminophen-induced hepatotoxicity in mice.

    Science.gov (United States)

    Lu, Yihong; Sun, Jinchun; Petrova, Katya; Yang, Xi; Greenhaw, James; Salminen, William F; Beger, Richard D; Schnackenberg, Laura K

    2013-12-01

    Green tea has been purported to have beneficial health effects including protective effects against oxidative stress. Acetaminophen (APAP) is a widely used analgesic drug that can cause acute liver injury in overdose situations. These studies explored the effects of green tea extract (GTE) on APAP-induced hepatotoxicity in liver tissue extracts using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance spectroscopy. Mice were orally administered GTE, APAP or GTE and APAP under three scenarios. APAP alone caused a high degree of hepatocyte necrosis associated with increases in serum transaminases and alterations in multiple metabolic pathways. The time of GTE oral administration relative to APAP either protected against or potentiated the APAP-induced hepatotoxicity. Dose dependent decreases in histopathology scores and serum transaminases were noted when GTE was administered prior to APAP; whereas, the opposite occurred when GTE was administered after APAP. Similarly, metabolites altered by APAP alone were less changed when GTE was given prior to APAP. Significantly altered pathways included fatty acid metabolism, glycerophospholipid metabolism, glutathione metabolism, and energy pathways. These studies demonstrate the complex interaction between GTE and APAP and the need to employ novel analytical strategies to understand the effects of dietary supplements on pharmaceutical compounds.

  18. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity.

    Science.gov (United States)

    Beger, Richard D; Sun, Jinchun; Schnackenberg, Laura K

    2010-03-01

    Hepatotoxicity and nephrotoxicity are two major reasons that drugs are withdrawn post-market, and hence it is of major concern to both the FDA and pharmaceutical companies. The number of cases of serious adverse effects (SAEs) in marketed drugs has climbed faster than the number of total drug prescriptions issued. In some cases, preclinical animal studies fail to identify the potential toxicity of a new chemical entity (NCE) under development. The current clinical chemistry biomarkers of liver and kidney injury are inadequate in terms of sensitivity and/or specificity, prompting the need to discover new translational specific biomarkers of organ injury. Metabolomics along with genomics and proteomics technologies have the capability of providing translational diagnostic and prognostic biomarkers specific for early stages of liver and kidney injury. Metabolomics has several advantages over the other omics platforms such as ease of sample preparation, data acquisition and use of biofluids collected through minimally invasive procedures in preclinical and clinical studies. The metabolomics platform is reviewed with particular emphasis on applications involving drug-induced hepatotoxicity and nephrotoxicity. Analytical platforms for metabolomics, chemometrics for mining metabolomics data and the applications of the metabolomics technologies are covered in detail with emphasis on recent work in the field.

  19. Piperine, an active ingredient of black pepper attenuates acetaminophen-induced hepatotoxicity in mice

    Institute of Scientific and Technical Information of China (English)

    Evan Prince Sabina; Annie Deborah Harris Souriyan; Deborah Jackline; Mahaboob Khan Rasool

    2010-01-01

    Objective: To explore the hepatoprotective and antioxidant effects of piperine against acetaminophen-induced hepatotoxicity in mice. Methods: In mice, hepatotoxicity was induced by a single dose of acetaminophen (900 mg/kg b.w. i.p.). Piperine (25 mg/kg b.w. i.p.) and standard drug silymarin (25 mg/kg b.w. i.p.) were given to mice, 30 min after the single injection of acetaminophen. After 4 h, the mice were decapitated. Activities of liver marker enzymes [(aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP)] and inflammatory mediator tumour necrosis factor-alpha (TNF-α) were estimated in serum, while lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-s-transferase and glutathione) were determined in liver homogenate of control and experimental mice. Results: Acetaminophen induction (900 mg/kg b.w. i.p.) significantly increased the levels of liver marker enzymes, TNF-α, and lipid peroxidation, and caused the depletion of antioxidant status. Piperine and silymarin treatment to acetaminophen challenged mice resulted in decreased liver marker enzymes activity, TNF-α and lipid peroxidation levels with increase in antioxidant status. Conclusions: The results clearly demonstrate that piperine shows promising hepatoprotective effect as comparable to standard drug silymarin.

  20. In vitro and in vivo antioxidant activity of alfalfa (Medicago sativa L.) on carbon tetrachloride intoxicated rats.

    Science.gov (United States)

    Al-Dosari, Mohammed S

    2012-01-01

    The present study was conducted to determine whether lyophilized aqueous extract of alfalfa, or Medicago sativa L. could exert antioxidant activity against carbon tetrachloride-induced oxidative stress and liver injury in rats. The hepatoprotective activity of alfalfa extract was determined by assessing the levels of serum transaminases, ALP, bilirubin and lipid profile. Further, the effect of the test substance on malondialdehyde (MDA), an end product of lipid peroxidation; antioxidant liver enzyme non-protein sulfhydryl (NP-SH); and total protein (TP) were also studied. Serum transaminase, ALP, bilirubin level, lipid profile and liver MDA were significantly elevated and the antioxidant status in liver NP-SH and TP contents were declined in animals treated with CCl (4) alone. Pretreatment with alfalfa and silymarin for three weeks prior to the administration of CCl (4) significantly prevented the increase in the serum levels of hepatic marker, LDL, VLDL levels enzymes and reduced oxidative stress indicated by elevated NP-SH and TP concentration. The histopathological examination of the livers also showed that the alfalfa extract reduced the incidence of liver lesions induced by CCl (4). The in vitro antioxidant assessment of alfalfa extract on DPPH and carotene-linoleic assays demonstrated a moderate antioxidant potential. Results suggest that the alfalfa extract possesses hepatoprotective and antioxidative stress properties possibly through its antioxidant phytochemical constituents and substantiates its use in various liver disorders as a hepatoprotector.

  1. Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats.

    Science.gov (United States)

    Okwa, Iniviefien B; Akindele, Abidemi J; Agbaje, Esther O; Oshinuga, Oladoyin T; Anunobi, Chidozie C; Adeyemi, Olufunmilayo O

    2013-01-01

    Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca(2+) has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid-rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses.

  2. D-galactosamine/lipopolysaccharide-induced hepatotoxicity downregulates sirtuin 1 in rat liver: role of sirtuin 1 modulation in hepatoprotection.

    Science.gov (United States)

    Kemelo, M K; Wojnarová, L; Kutinová Canová, N; Farghali, H

    2014-01-01

    D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.

  3. Enniatin B and beauvericin are common in Danish cereals and show high hepatotoxicity on a high-content imaging platform

    DEFF Research Database (Denmark)

    Svingen, Terje; Hansen, Niels Lund; Taxvig, Camilla;

    2016-01-01

    , beauvericin, altenariol, deoxynivalenol, aflatoxin B1, andrastin A, citrinin, and penicillic acid), enniatin B and beauvericin showed significant cytotoxicity at a concentration lower than that for aflatoxin B1, which is the archetypal acute hepatotoxic and liver-carcinogenic mycotoxin. Hence, the quadroprobe...

  4. Comparative Proteomic Analysis Shows an Elevation of Mdh1 Associated with Hepatotoxicity Induced by Copper Nanoparticle in Rats

    Institute of Scientific and Technical Information of China (English)

    DONG Shu-wei; GAO Zhao-hui; SHEN Xiao-yun; XUE Hui-wen; LI Xia

    2014-01-01

    Copper nanoparticle is a new material widely used in biological medicine, animal husbandry and industrial areas, but its potential toxicity to human health and environment remains unclear. In order to study the hepatotoxic mechanisms of nanoparticles copper, two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time of lfight mass spectrometry (MALDI/TOF MS) of proteomics technology were used to isolate and identify the differentially expressed proteins from liver, which associated with hepatotoxicity induced by copper nanoparticle in rats. In this study, we have screened 15 kinds of proteins related with hepatotoxicity, of which spot8212 was identiifed as Malate dehydrogenase (Mdh1). The mRNA expression trend of Mdh1 was consistent with the result of 2-DE by RT-PCR validation. Bioinformatics analysis showed that Mdh1 was stable and no signal peptides, subcellular location was in endoplasmic reticulum;it contained many functional sites such as malate dehydrogenase activity signal sites 155LTRLDHNRAKSQI167; α helixes and random coils were the two main elements. Homologous analysis demonstrated high homologous of Mdh1 in rats with mouse and human, and the phylogenetic tree of Mdh1 was constructed. The result indicated that copper nanoparticle could regulate up the Mdh1 protein expression so as to compensate the energy deifcit. Energy metabolic disturbance may be a pathway for copper nanoparticle particles to exert the hepatotoxic effects in rats.

  5. Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity.

    Science.gov (United States)

    El-Mansy, A A; Mazroa, S A; Hamed, W S; Yaseen, A H; El-Mohandes, E A

    2016-01-01

    The liver is a target for toxic chemicals such as cadmium (Cd). When the liver is damaged, hepatic stellate cells (HSC) are activated and transformed into myofibroblast-like cells, which are responsible for liver fibrosis. Curcuma longa has been reported to exert a hepato-protective effect under various pathological conditions. We investigated the effects of C. longa administration on HSC activation in response to Cd induced hepatotoxicity. Forty adult male albino rats were divided into: group 1 (control), group 2 (Cd treated), group 3 (C. longa treated) and group 4 (Cd and C. longa treated). After 6 weeks, liver specimens were prepared for light and electron microscopy examination of histological changes and immunohistochemical localization of alpha smooth muscle actin (αSMA) as a specific marker for activated HSC. Activated HSC with a positive αSMA immune reaction were not detected in groups 1 and 3. Large numbers of activated HSC with αSMA immune reactions were observed in group 2 in addition to Cd induced hepatotoxic changes including excess collagen deposition in thickened portal triads, interlobular septa with hepatic lobulation, inflammatory cell infiltration, a significant increase in Kupffer cells and degenerated hepatocytes. In group 4, we observed a significant decrease in HSC that expressed αSMA with amelioration of the hepatotoxic changes. C. longa administration decreased HSC activation and ameliorated hepatotoxic changes caused by Cd in adult rats.

  6. Sorghum [Sorghum bicolor (L.) Moench] leaf sheath dye protects against cisplatin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Agbebi, Oluwaseun J; Boligon, Aline A; Athayde, Margareth L

    2014-12-01

    This study sought to determine the protective effect of dietary inclusion of sorghum leaf sheath dye on cisplatin-induced hepatotoxicity and oxidative stress in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups I and II were fed a basal diet, while groups III and IV were fed diets containing 0.5% and 1% sorghum leaf sheath dye, respectively, for 20 days before cisplatin administration. Hepatotoxicity was induced by a single dose of cisplatin (7 mg/kg body weight, i.p.), and the experiment was terminated at 3 days after cisplatin injection. The liver and plasma were studied for hepatotoxicity and antioxidant capacity. Cisplatin caused a significant (Pinduced alteration of both plasma and liver antioxidant indices suggests an antioxidant mechanism of action. Hence, this protective effect of Sorghum bicolor leaf sheath dye against cisplatin-induced hepatotoxicity in rats reflects its potential and beneficial role in the prevention of liver damage associated with cisplatin administration.

  7. Modulatory effects of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity and oxidative stress in rats

    Institute of Scientific and Technical Information of China (English)

    Adedayo O Ademiluyi; Ganiyu Oboh; Tosin R Owoloye; Oluwaseun J Agbebi

    2013-01-01

    To investigate the ameliorative effect of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity in rats. Methods: Adult male rats were randomly divided into four groups with six animals in each group. Groups 1 and 2 were fed basal diet while Groups 3 and 4 were fed diets containing 2% and 4% garlic respectively for 27 d prior to gentamycin administration. Hepatotoxicity was induced by the intraperitoneal administration of gentamycin (100 mg/kg body weight) for 3 d. The liver and plasma were studied for hepatotoxicity and antioxidant indices. Results: Gentamycin induces hepatic damage as revealed by significant (P<0.05) elevation of liver damage marker enzymes (aspartate transaminase and alanine aminotransferase) and reduction in plasma albumin level. Gentamycin also caused a significant (P<0.05) alteration in plasma and liver enzymatic (catalase, glutathione and super oxygen dehydrogenises) and non-enzymatic (glutathione and vitamin C) antioxidant indices with concomitant increase in the malondialdehyde content; however, there was a significant (P<0.05) restoration of the antioxidant status coupled with significant (P<0.05) decrease in the tissues’ malondialdehyde content, following consumption of diets containing garlic. Conclusions: These results suggest that dietary inclusion of garlic powder could protect against gentamycin-induced hepatotoxicity, improve antioxidant status and modulate oxidative stress; a function attributed to their phenolic constituents.

  8. Relationship Between Structural Alerts in NSAIDs and Idiosyncratic Hepatotoxicity : An Analysis of Spontaneous Report Data from the WHO Database

    NARCIS (Netherlands)

    Jessurun, Naomi; van Puijenbroek, Eugene

    2015-01-01

    BACKGROUND: Idiosyncratic drug reactions such as hepatotoxicity and blood dyscrasias represent one of the major causes of drug withdrawal from the market. According to the reactive metabolite (RM) concept, this may be due to the metabolic activation of structural alerts (SAs), functionalities in the

  9. Use of the HepaRG Cell Line to Assess Potential Human Hepatotoxicity of ToxCast™ Chemicals

    Science.gov (United States)

    The HepaRG cell line is a promising model system for predicting human hepatotoxicity in part because of the greater capacity to metabolize chemicals than other cell models. We hypothesized that this cell line would be a relevant model for toxicity testing of industrial chemicals....

  10. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events

    Directory of Open Access Journals (Sweden)

    Rankin Elizabeth

    2008-04-01

    Full Text Available Abstract Background Spontaneous reporting systems for adverse drug reactions (ADRs are handicapped by under-reporting and limited detail on individual cases. We report an investigation from a local surveillance for serious adverse drug reactions associated with disease modifying anti-rheumatic drugs that was triggered by the occurrence of liver failure in two of our patients. Methods Serious ADR reports have been solicited from local clinicians by regular postcards over the past seven years. Patients', who had hepatotoxicity on sulfasalazine and met a definition of a serious ADR, were identified. Two clinicians reviewed structured case reports and assessed causality by consensus and by using a causality assessment instrument. The likely frequency of hepatotoxicity with sulfasalazine was estimated by making a series of conservative assumptions. Results Ten cases were identified: eight occurred during surveillance. Eight patients were hospitalised, two in hepatic failure – one died after a liver transplant. All but one event occurred within 6 weeks of treatment. Seven patients had a skin rash, three eosinophilia and one interstitial nephritis. Five patients were of Black British of African or Caribbean descent. Liver enzymes showed a hepatocellular pattern in four cases and a mixed pattern in six. Drug-related hepatotoxicity was judged probable or highly probable in 8 patients. The likely frequency of serious hepatotoxicity with sulfasalazine was estimated at 0.4% of treated patients. Conclusion Serious hepatotoxicity associated with sulfasalazine appears to be under-appreciated and intensive monitoring and vigilance in the first 6 weeks of treatment is especially important.

  11. Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats.

    Directory of Open Access Journals (Sweden)

    Brijesh Kumar Singh

    Full Text Available Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(PH and GSH (56% and 74% respectively; P<0.001, increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c. It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05. A combination of camphene and geraniol (CG; 1:1, when pre-administered in rats (10 mg/kg BW, accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(PH and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore

  12. Short-term treatment with alcohols causes hepatic steatosis and enhances acetaminophen hepatotoxicity in Cyp2e1(-/-) mice.

    Science.gov (United States)

    Sinclair, J F; Szakacs, J G; Wood, S G; Walton, H S; Bement, J L; Gonzalez, F J; Jeffery, E H; Wrighton, S A; Bement, W J; Sinclair, P R

    2000-10-15

    CYP2E1 has been reported to have an essential role in alcohol-mediated increases in hepatic steatosis and acetaminophen hepatotoxicity. We found that pretreatment of Cyp2e1(-/-) mice with ethanol plus isopentanol, the predominant alcohols in alcoholic beverages, for 7 days resulted in micro- and macrovesicular steatosis in the livers of all mice, as well as a dramatic increase in acetaminophen hepatotoxicity. In Cyp2e1(-/-) mice administered up to 600 mg acetaminophen/kg alone and euthanized 7 h later, there was no increase in serum levels of ALT. In Cyp2e1(-/-) mice pretreated with ethanol and isopentanol, subsequent exposure to 400 or 600 mg acetaminophen/kg resulted in centrilobular necrosis in all mice with maximal elevation in serum levels of ALT. Acetaminophen-mediated liver damage was similar in males and females. Hepatic microsomal levels of APAP activation in untreated females were similar to those in males treated with the alcohols. However, the females, like the males, required pretreatment with the alcohols in order to increase APAP hepatotoxicity. These findings suggest that, in the Cyp2e1(-/-) mice, the alcohol-mediated increase in acetaminophen hepatotoxicity involves the contribution of other factors, in addition to induction of CYP(s) that activate acetaminophen. Alternatively, CYP-mediated activation of acetaminophen measured in vitro may not reflect the actual activity in vivo. Our findings that a 7-day treatment with ethanol and isopentanol causes extensive hepatic steatosis and increases acetaminophen hepatotoxicity in Cyp2e(-/-) mice indicate that CYP2E1 is not essential for either response.

  13. Crucial role of cytochrome P450 in hepatotoxicity induced by 2,3-dimethoxy-1,4-naphthoquinone in rats.

    Science.gov (United States)

    Ishihara, Yasuhiro; Ishii, Satomi; Sakai, Yufu; Yamamura, Nobue; Onishi, Yukiko; Shimamoto, Norio

    2011-03-01

    Quinone toxicity is induced by two principal mechanisms: arylation/alkylation and a redox cycle. We have previously shown that increases in intracellular levels of superoxide anion and cell death induced by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), a redox cycling quinone, are enhanced by pretreatment of rat primary hepatocytes with cytochrome P450 inhibitors. This indicates a novel interaction of quinones with cytochrome P450, and is thus worthy of further investigation using an in vivo model. The aim of this study was to examine the effects of cytochrome P450 inhibitors on DMNQ-induced hepatotoxicity in rats. When DMNQ was administered intraperitoneally, the activities of serum alanine aminotransferase and aspartate aminotransferase were found to increase in a dose-dependent manner, indicating that hepatotoxicity was induced by treatment with DMNQ. Pretreatment with the cytochrome P450 inhibitors SKF-525A (SKF), cimetidine and ketoconazole potentiated the DMNQ-induced hepatotoxicity. The blood concentration of DMNQ was not affected by administration of SKF. Pretreatment with the antioxidant α-tocopherol almost completely attenuated the hepatotoxicity induced by DMNQ and by the combination of DMNQ with SKF. Levels of reduced glutathione in the liver were decreased and levels of oxidized glutathione were increased by treatment with DMNQ. These effects were potentiated by pretreatment with SKF. DMNQ-induced lipid peroxidation in the liver was also enhanced by pretreatment with SKF. Taken together, these results indicate that DMNQ-induced hepatotoxicity is augmented by inhibition of cytochrome P450 and that this augmentation is due to the enhancement of oxidative stress.

  14. Comparison of the phenolic component profiles of skullcap (Scutellaria lateriflora) and germander (Teucrium canadense and T. chamaedrys), a potentially hepatotoxic adulterant

    Science.gov (United States)

    Scutellaria laterifora, commonly known as skullcap, is used as an ingredient in numerous herbal products. However, it has been occasionally adulterated with Teucrium canadense and T. chamaedrys, commonly known as germander, which contain potentially hepatotoxic diterpenes. Analytical methodologie...

  15. Hepatoprotective activity of methanolic extract of Mussaenda philippica (stems against anti-tubercular drugs induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Swarnalatha Reddy Dugasani

    2014-12-01

    Full Text Available The present study was designed to evaluate the hepatoprotective effect of methanolic extract of Mussaenda philippica against isoniazid and rifampicin induced hepatotoxicity in experimental rats. Six groups of six rat were selected for the study. Methanolic extract of Mussaendaphilippicaat a dose of 100, 200 and 400 mg/kg as well as silymarin (50 mg/kg were administered orally once daily for 14 d in isoniazid and rifampicin group. The serum levels of glutamic oxaloacetic transaminase (SGOT, glutamate pyruvate transaminase (SGPT, alkaline phosphatase, and bilirubin were estimated along with total protein. Histopathological analysis was carried out to assess injury to the liver. The altered biochemical parameters were significantly reverting back by the methanolic extract treatment. Histopathology also supported the biochemical variation. From this study it has been concluded that the methanolic extract of Mussaendaphilippicashows significant hepatoprotective activity.

  16. Metabolism of the hepatotoxic compound sophoraflavanone G in rat liver microsomes.

    Science.gov (United States)

    Chen, Ping; Zhang, Xiuwen; Huang, Taomin; Yu, Qianqian; Cheng, Nengneng

    2014-07-01

    Our study aimed at investigating the metabolic characteristics of sophoraflavanone G (SFG), one of the hepatotoxic constituents of Sophora flavescens, in rat liver microsomes (RLMs). SFG was metabolized to 3 phase I metabolites, di-hydroxylated SFG (M1), mono-hydroxylated SFG (M2), dehydrogenated product of mono-hydroxylated SFG (M3) and 3 SFG glucuronides (M4, M5, and M6) by RLMs. The formation kinetics of M2 conformed to biphasic kinetics in RLMs. The formation kinetics of M4 and M5 best-fitted the Hill equation kinetics. Chemical inhibition studies found that CYP1A2 and CYP2E1 were the major enzymes responsible for the formation of M2, and the formation of M4 and M5 may be catalyzed by multiple UGT1A isoforms.

  17. Hepatotoxicity after liver irradiation in children and adolescents. Results from the RiSK

    Energy Technology Data Exchange (ETDEWEB)

    Roesler, Pascal; Christiansen, Hans [Medical School Hannover, Department of Radiotherapy and Special Oncology, Hannover (Germany); Kortmann, Rolf-Dieter [University of Leipzig, Department of Radiotherapy, Leipzig (Germany); Martini, Carmen [University Hospital of Freiburg, Department of Radiotherapy, Freiburg im Breisgau (Germany); Matuschek, Christiane [Heinrich-Heine University of Duesseldorf, Department of Radiotherapy, Medical Faculty, Duesseldorf (Germany); Meyer, Frank [Hospital Augsburg, Department of Radiotherapy, Augsburg (Germany); Ruebe, Christian [University Hospital of Homburg/Saar, Department of Radiotherapy, Homburg/Saar (Germany); Langer, Thorsten [University Hospital of Schleswig-Holstein, Department of Pediatrics, Pediatric Oncology, Campus Luebeck (Germany); Koch, Raphael [University of Muenster, Institute of Biostatistics and Clinical Research, Muenster (Germany); Eich, Hans Theodor; Willich, Normann [University Hospital of Muenster, Department of Radiotherapy, Muenster (Germany); Steinmann, Diana [Medical School Hannover, Department of Radiotherapy and Special Oncology, Hannover (Germany); University Hospital of Muenster, Department of Radiotherapy, Muenster (Germany)

    2015-05-01

    The aim of this study was to evaluate acute and late radiotherapy-associated hepatotoxicity in consideration of dose-volume effects and liver function in childhood and adolescence. Since 2001, irradiated children and adolescents in Germany have been prospectively documented in the ''Register of Treatment-Associated Late Effects After Radiotherapy of Malignant Diseases in Childhood and Adolescence (RiSK)'' using standardized forms. Toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) criteria. Until April 2012, 1,392 children and adolescents from 62 radiotherapy centers were recruited. In all, 216 patients underwent irradiation of the liver (median age 9 years, range 1-18 years, 70 patients with total-body irradiation, TBI). For 75 % of patients without TBI, information on acute toxicity of the liver was available: 24 patients had acute toxicity of grade 1-4 (grade 1, 2, and 4, in 20, 3, and 1 patient, respectively), including five patients receiving simultaneous hepatotoxic chemotherapy. Information on late toxicity was documented in 465 forms from 216 patients, with a median follow-up of 2 years. A maximum grade of toxicity of ≥ 0 occurred in 18 patients over time (with grade 1, 2, and 3 toxicity occurring in 15, 2, and 1 patient, respectively), including three patients (17 %) with TBI. One of them received simultaneous hepatotoxic chemotherapy. In multivariable analysis, volume-dose correlations showed no statistically noticeable effect on acute or chronic toxicity. Only low hepatotoxicity developed in children after irradiation of various abdominal and thoracic tumors. Due to the low radiation doses to the liver (median liver dose = 5 Gy) and the low toxicities that were consecutively observed, dose-volume curves for liver toxicity could not be established. These findings reflect the cautious attitude of radiation oncologists in terms of attributable liver doses in the treatment of the investigated tumor entities. It

  18. Development of a Capillary Zone Electrophoretic Method for the Rapid Separation and Detection of Hepatotoxic Microcystins

    Energy Technology Data Exchange (ETDEWEB)

    Li, Paul C.H.; Hu, Shen; Lam, Paul K.S

    1999-01-01

    Analysis of trace amounts of various hepatotoxic microcystins in marine and freshwater samples is very important since these toxins, especially microcystin-LR, have been demonstrated to have tumour-promoting activity. In this study, instead of measuring the total amount of microcystins, we developed a capillary zone electrophoretic method for the separation and detection of individual toxin standards. No additives were used for enhancement of resolution. This technique is characterized by a high separation efficiency, short analysis time and small sample volume. In order to improve the detection sensitivity, a laser-induced fluorescence detector was used, and the labelling of microcystins was accomplished through a two-step procedure. First, the microcystin standards were converted into cysteine conjugates, followed by derivatization with Fluorescein 5-Isothiocyanate (FITC). After derivatization, the FITC-labelled microcystins were directly injected, separated and detected in 8 min. This method was shown to be a promising technique for sensitive and rapid analysis of individual microcystin toxins.

  19. Hepatoprotective and Antioxidant potential of Tephrosia Purprea in Paracetamol Induced Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Shivshankar M. Gunjegaonkar

    2016-03-01

    Full Text Available The present study was designed to evaluate Hepatoprotective and antioxidant potential of Tephrosia Purprea whole plant aqueous extract in paracetamol intoxicated rats. 75mg/kg and 150mg/kg of aqueous extract were administered orally once a daily for seven days. Animals were challenged with paracetamol on 5th day of treatment protocol. Elevated serum levels of transaminases, alkaline phosphatase and bilirubin (direct and total were restored significantly by the extract. Silymarine (reference standard exhibited significant hepatoprotective activity against paracetamol induced hepatotoxicity. The biochemical parameters were supplemented with histopathological studies. In-vitro free radical scavenging activity was screened and results concluded that possible mechanism of hepatoprotective activity may be due to its free radical scavenging activity.

  20. Ameliorative effect of vitamin E on potassium dichromate-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Ali A. Shati

    2014-07-01

    There was a significant accumulation of Cr in the livers of the Cr group compared with the control group. In addition, exposure to K2Cr2O7 induced significant increases in the level of thiobarbituric-reactive substances (TBARS and significant decreases in glutathione (GSH content and superoxide dismutase (SOD activity in the Cr group compared with the control group. Moreover, livers of the Cr group showed major histological alterations, such as severe necrosis, increased lymphocytic infiltration, and a significant decrease in the DNA content. Oral vitamin E administration concomitant with K2Cr2O7 ameliorated all these changes and resulted in normal hepatic histological and cellular contents. In conclusion, oral vitamin E administration has a hepatoprotective role against K2Cr2O7-induced hepatotoxicity in rats.

  1. N-deacetyl ketoconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes.

    Science.gov (United States)

    Rodriguez, R J; Acosta, D

    1997-02-28

    Ketoconazole (KT) is an azole antifungal agent that has been associated with hepatotoxicity. The mechanism of its hepatotoxicity has not yet been resolved. It has been suggested that a reactive metabolite may be the cause of toxicity because the hepatic injury does not appear to be mediated through an immunoallergic mechanism. Several metabolites of KT have been reported in the literature of which the deacetylated metabolite, N-deacetyl ketoconazole (DAK), is the major metabolite which undergoes further metabolism by the flavin-containing monooxygenases (FMO) to form a potentially toxic dialdehyde. The objective of this study was to evaluate DAK's cytotoxicity and the role of FMO in a primary culture system of rat hepatocytes. Cytotoxicity was evaluated by measuring the leakage of the cytosolic enzyme, lactate dehydrogenase (LDH), into the medium and by assessing mitochondrial reduction of 3-(4,5-dimethythiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT). The cultures were exposed to various concentrations of DAK (20-160 microM) for 0.5-4 h. There was a significant increase (P DAK at 0.5, 1.0, 2.0 and 4.0 h, respectively). The concentrations to observe 50% LDH leakage from the hepatocytes were 155, 133, 100, 70 microM DAK at 0.5, 1.0, 2.0 and 4.0 h, respectively. Moreover, co-treatment with methimazole, a competitive substrate for FMO, produced a significant decrease (P DAK. Also, the toxicity was significantly (P DAK is a more potent cytotoxicant than its parent compound, KT, as reported previously by our laboratory (Rodriguez and Acosta, Toxicology, 96: 83-92, 1995) and its toxicity was expressed in a dose- and time-dependent manner. Furthermore, DAK's cytotoxicity was enhanced with n-octylamine and suppressed with methimazole, suggesting a role for FMO in the toxicity of the metabolite.

  2. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Ruibing [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Lihui [Shandong Normal University, Jinan, Shandong Province 250012 (China); Luo, Zheng; Guo, Xiaolan [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Ming, E-mail: ymylh@163.com [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  3. Protective effects of combined β-caryophyllene and silymarin against ketoprofen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Kelany, Mohamed Elsayed; Abdallah, Mohamed Abdelmohsen

    2016-07-01

    Ketoprofen (Ket), widely utilized in treatment of many inflammatory disorders, is found to induce liver toxicity especially with overdose. This study aimed to evaluate the possible protective effects of concomitant β-caryophyllene (Cary) and silymarin (Sily) against Ket-induced hepatotoxicity in rats. Forty adult male albino rats were divided into 5 groups (each n = 8): the control group received distilled water for 6 weeks; the Ket-treated group received distilled water for 5 weeks and Ket in a dose of 8 mg·kg(-1)·day(-1) p.o. for the 6th week; the Cary + Ket treated group received Cary in a dose of 200 mg·kg(-1)·day(-1) orally for 6 weeks and Ket for the 6th week; the Sily + Ket treated group received Sily in the dose of 150 mg·kg(-1)·day(-1) for 6 weeks and Ket for the 6th week; and the Cary + Sily + Ket treated group received Sily and Cary for 6 weeks and Ket for the 6th week. At end of the experiment, serum ALT, AST, and albumin and liver total antioxidant capacity (t.TAC) and malondialdehyde (t.MDA) were measured in all rats. Ket increased serum ALT and AST and t.MDA and decreased t.TAC. Cary and Sily improved these changes. Combined Cary and Sily restored these liver changes to nearly normal. Combined Cary and Sily is hepatoprotective, with the ability to scavenge oxidants against Ket-induced hepatotoxicity in rats.

  4. Pomegranate seed extract attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity in rats.

    Science.gov (United States)

    Cayır, Kerim; Karadeniz, Ali; Simşek, Nejdet; Yıldırım, Serap; Karakuş, Emre; Kara, Adem; Akkoyun, Hürrem Turan; Sengül, Emin

    2011-10-01

    Cisplatin (CDDP), one of the most active cytotoxic agents against cancer, has adverse side effects, such as nephrotoxicity and hepatotoxicity. The present study was designed to investigate the potential protective effect of pomegranate seed extract (PSE) against oxidative stress caused by CDDP injury of the kidneys and liver by measuring tissue biochemical and antioxidant variables and immunohistochemically testing caspase-3-positive cells. Twenty-four Sprague-Dawley rats were divided into 4 groups: control; CDDP: injected intraperitoneally with CDDP (7 mg/kg body weight, single dose); PSE: treated for 15 consecutive days by gavage with PSE (300 mg/kg per day); and PSE+CDDP: treated by gavage with PSE 15 days after a single injection of CDDP. The degree of protection against CDDP injury afforded by PSE was evaluated by determining the levels of malondialdehyde as a measure of lipid peroxidation. The levels of glutathione and activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase were estimated from liver and kidney homogenates; the liver and kidney were also histologically examined. PSE elicited a significant protective effect toward liver and kidney by decreasing the level of lipid peroxidation; elevating the levels of glutathione S-transferase; and increasing the activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase. These biochemical observations were supported by immunohistochemical findings and suggested that PSE significantly attenuated nephrotoxicity and hepatotoxicity by the way of its antioxidant, radical-scavenging, and antiapoptotic effects. This PSE extract could be used as a dietary supplement in patients receiving chemotherapy medications.

  5. Mitochondrial dysfunction induced by Bisphenol A is a factor of its hepatotoxicity in rats.

    Science.gov (United States)

    Khan, Somaira; Beigh, Saba; Chaudhari, Bhushan P; Sharma, Shikha; Aliul Hasan Abdi, Sayed; Ahmad, Shahzad; Ahmad, Firoz; Parvez, Suhel; Raisuddin, Sheikh

    2015-10-09

    Bisphenol A (BPA), an estrogenic and endocrine disrupting agent, is widely used in manufacturing of polycarbonate plastics and epoxy resins. BPA and other endocrine disrupting chemicals (EDCs) act via multiple mechanisms including interference with mitochondrial functions. Mitochondria are the hub of cellular energy pool and hence are the target of many EDCs. We studied perturbation of activities of mitochondrial enzymes by BPA and its possible role in hepatotoxicity in Wistar rats. Rats were exposed to BPA (150 mg/kg, 250 mg/kg, 500 mg/kg per os, for 14 days) and activities of enzymes of mitochondrial electron transport chain (ETC) were measured. Besides, other biochemical parameters such as superoxide generation, protein oxidation, and lipid peroxidation (LPO) were also measured. Our results indicated a significant decrease in the activities of enzymes of mitochondrial ETC complexes, i.e., complex I, II, III, IV, and V along with significant increase in LPO and protein oxidation. Additionally, a significant increase in mitochondrial superoxide generation was also observed. All these findings could be attributed to enhanced oxidative stress, decrease in reduced glutathione level, and decrease in the activity of superoxide dismutase in rat liver mitochondria isolated from BPA-treated rats. BPA treatment also caused a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase indicating its potential hepatotoxicity. Furthermore, histopathological findings revealed marked edema formation, hepatocellular degeneration, and necrosis of liver tissue in BPA-exposed rats. In conclusion, this study provides an evidence of impaired mitochondrial bioenergetics and liver toxicity after high-dose BPA exposure in rats. © 2015 Wiley Periodicals, Inc. Environ Toxicol, 2015.

  6. Fumonisin B(1) is hepatotoxic and nephrotoxic in milk-fed calves.

    Science.gov (United States)

    Mathur, S; Constable, P D; Eppley, R M; Waggoner, A L; Tumbleson, M E; Haschek, W M

    2001-04-01

    Fumonisins are a group of mycotoxins that alter sphingolipid biosynthesis and induce leukoencephalomalacia in horses and pulmonary edema in pigs. Experimental administration of fumonisin induces hepatotoxicity in all species, including cattle, as well as nephrotoxicity in rats, rabbits, and sheep. We investigated the hepatotoxicity and nephrotoxicity of fumonisin B(1) to calves. Ten milk-fed male Holstein calves aged 7 to 14 days were instrumented to obtain blood and urine. Treated calves (n = 5) were administered fumonisin B(1) at 1 mg/kg, iv, daily and controls (n = 5) 10 ml 0.9% NaCl, iv, daily until euthanized on day 7. Fumonisin B(1)-treated calves were lethargic and had decreased appetite from day 4 onward, serum biochemical evidence of severe liver and bile duct injury, and impaired hepatic function. Treated calves also had biochemical evidence of renal injury that functionally involved the proximal convoluted tubules. Sphinganine and sphingosine concentrations in liver, kidney, lung, heart, and skeletal muscle were increased in treated calves. Sphinganine, but not sphingosine, concentration was increased in brains of treated calves. In fumonisin B(1)-treated calves, hepatic lesions were characterized by disorganized hepatic cords, varying severity of hepatocyte apoptosis, hepatocyte proliferation, and proliferation of bile ductular cells. Renal lesions in treated calves consisted of vacuolar change, apoptosis, karyomegaly, and proliferation of proximal renal tubular cells, as well as dilation of proximal renal tubules, which contained cellular debris and protein. This is the first report of fumonisin B(1)-induced renal injury and organ sphingolipid alterations in cattle.

  7. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease.

    Science.gov (United States)

    Cerda, Cristian; Bruguera, Miguel; Parés, Albert

    2013-08-28

    Glucosamine and chondroitin sulfate are molecules involved in the formation of articular cartilage and are frequently used for symptom relief in patients with arthrosis. These molecules are well tolerated with scarce secondary effects. Very few cases of possible hepatotoxicity due to these substances have been described. The aim of this paper is to report the frequency of presumed glucosamine hepatotoxicity in patients with liver disease. A questionnaire was given to 151 consecutive patients with chronic liver disease of different etiology (mean age 59 years, 56.9% women) attended in an outpatient clinic with the aim of evaluating the frequency of consumption of these drugs and determine whether their use coincided with a worsening in liver function test results. Twenty-three patients (15.2%) recognized having taken products containing glucosamine or chondroitin sulfate previously or at the time of the questionnaire. Review of the clinical records and liver function tests identified 2 patients presenting an elevation in aminotransferase values temporarily associated with glucosamine treatment; one of the cases simultaneously presented a skin rash attributed to the drug. Review of these two patients and the cases described in the literature suggest toxicity of glucosamine and chondroitin sulfate. The clinical spectrum is variable, and the mechanism of toxicity is not clear but may involve reactions of hypersensitivity. The consumption of products containing glucosamine and/or chondroitin sulfate is frequent among patients with chronic liver diseases and should be taken into account on the appearance of alterations in liver function tests not explained by the underlying disease.

  8. Protective role of licochalcone B against ethanol-induced hepatotoxicity through regulation of Erk signaling

    Science.gov (United States)

    Gao, Xiao-peng; Qian, Dong-wei; Xie, Zhen; Hui, Hao

    2017-01-01

    Objective(s): Oxidative stress has been established as a key cause of alcohol-induced hepatotoxicity. Licochalcone B, an extract of licorice root, has shown antioxidative properties. This study was to investigate the effects and mechanisms of licochalcone B in ethanol-induced hepatic injury in an in vitro study. Materials and Methods: An in vitro model of Ethanol-induced cytotoxicity in BRL cells was used in this study. Cell injury was assessed using WST-1 assay and lactate dehydrogenase, alanine transaminase, and aspartate aminotransferase release assay. Cell apoptosis were quantified by flow cytometric analysis. The intracellular oxidative level was evaluated by reactive oxidative species, malondialdehyde and glutathione detection. Furthermore, the expression level of Erk, p-Erk, Nrf-2 were assessed using Western blot. Results: Treatment with ethanol induced marked cell injury and cell apoptosis in BRL cells. Licochalcone B significantly attenuated ethanol-induced cell injury, and inhibited cell apoptosis. Furthermore, licochalcone B significantly inhibited ethanol-induced intracellular oxidative level, upregulated the expression of p-Erk, and promoted nuclear localization of Nrf2. Additionally, this hepatoprotective role was significantly abolished by inhibition of Erk signaling. However, no apparent effects of Erk inhibition were observed on ethanol-induced hepatotoxicity. Conclusion: This study demonstrates that licochalcone B protects hepatocyte from alcohol-induced cell injury, and this hepatoprotective role might be attributable to apoptosis reduction, inhibition of oxidative stress, and upregulation of Erk–Nrf2. Therefore, licochalcone B might possess potential as a novel therapeutic drug candidate for alcohol-related liver disorders.

  9. The effect of fluorine substitution on the hepatotoxicity and metabolism of paracetamol in the mouse.

    Science.gov (United States)

    Barnard, S; Kelly, D F; Storr, R C; Park, B K

    1993-09-01

    The widely used analgesic paracetamol (P) produces fulminant hepatocellular necrosis in humans when taken in overdose. The toxicity is mediated by drug oxidation and depletion of hepatic glutathione. We have, therefore, explored the effects of fluorine substitution on the hepatotoxicity of P in female CD1 mice. 3-Fluoro-4-hydroxyacetanilide (1FPO), 3,5-difluoro-4-hydroxyacetanilide (2FPO), 2,6-difluoro-4-hydroxyacetanilide (2FPN) and 2,3,5,6-tetrafluoro-4-hydroxyacetanilide (4FP) were synthesized, characterized and investigated for their potential to cause hepatotoxicity in the mouse. Introduction of fluorine into P increases the oxidation potential of the drug. The oxidation potentials of paracetamol and its fluorinated analogues were measured by cyclic voltametry and found to increase in the order P < 1FPO < 2FPO < 2FPN < 4FP. Serum transaminase (ALT) and hepatic glutathione were measured 24 and 6 hr, respectively, after administration of a single dose (2.65 mmol/kg) of each compound to female CD1 mice. There was significant elevation of ALT in mice given P, 1FPO and 2FPO, but not in those which received either 2FPN or 4FP. Hepatic glutathione was reduced significantly by administration of P and IFP, but not after administration of 2FPO, 2FPN or 4FP. Accordingly, glucuronide and sulphate conjugates, but not thioether metabolites, were detected in urine after administration of 14C-labelled 2FPO, 2FPN and 4FP. These data indicate that introduction of fluorine into the 2 and 6 positions increases the oxidation potential of paracetamol which in turn reduces the propensity of the molecule to undergo oxidative bioactivation, and thereby reduces the in vivo toxicity of the molecule.

  10. Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats

    Science.gov (United States)

    El-Hosseiny, L. S.; Alqurashy, N. N.; Sheweita, S. A.

    2016-01-01

    Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats’ liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes’ activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition. PMID:27493593

  11. Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats.

    Science.gov (United States)

    El-Hosseiny, L S; Alqurashy, N N; Sheweita, S A

    2016-06-01

    Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats' liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes' activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition.

  12. Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Dan; Wu, Chun-qi [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Li, Ze-jun [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Guang Dong Pharmaceutical University, Guangzhou 510006 (China); Liu, Yue; Fan, Xing [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Wang, Quan-jun, E-mail: wangquanjunbeijing@163.com [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Ding, Ri-gao, E-mail: dingrigao@nic.bmi.ac.cn [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China)

    2015-04-15

    Objective: To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. Methods: Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50 μM) for 48 h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrial respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p < 0.05. Results: Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. Conclusion: All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles. - Highlights: • We compared three TZD mitochondrial toxicity characteristics in HepaRG cells. • TZD induced respiratory disorders and mitochondrial structural damage. • Mitochondrial toxicity evaluation presents guidance value for hepatotoxicity.

  13. An Amino Acids Mixture Improves the Hepatotoxicity Induced by Acetaminophen in Mice

    Directory of Open Access Journals (Sweden)

    Francesco Di Pierro

    2013-01-01

    Full Text Available Acetaminophen (APAP is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The aim of this study was to evaluate the protective role of DDM-GSH, a mixture of L-cysteine, L-methionine, and L-serine in a weight ratio of 2 : 1 : 1, in comparison to N-acetylcysteine (NAC, against acetaminophen- (APAP- induced hepatotoxicity in mice. Toxicity was induced in mice by the intraperitoneal (ip administration of low dose (2 mmol/kg or high dose (8 mmol/kg of APAP. DDM-GSH (0.4 to 1.6 mmol/kg was given ip to mice 1 h before the APAP administration. The same was done with NAC (0.9 to 3.6 mmol/kg, the standard antidote of APAP toxicity. Mice were sacrificed 8 h after the APAP injection to determine liver weight, serum alanine aminotransferase (ALT, and total glutathione (GSH depletion and malondialdehyde (MDA accumulation in liver tissues. DDM-GSH improved mouse survival rates better than NAC against a high dose of APAP. Moreover, DDM-GSH significantly reduced in a dose-dependent manner not only APAP-induced increases of ALT but also APAP-induced hepatic GSH depletion and MDA accumulation. Our results suggest that DDM-GSH may be more potent than NAC in protecting the liver from APAP-induced liver injury.

  14. Overexpression of Nrf2 protects against microcystin-induced hepatotoxicity in mice.

    Science.gov (United States)

    Lu, Yuan-Fu; Liu, Jie; Wu, Kai Connie; Qu, Qiang; Fan, Fang; Klaassen, Curtis D

    2014-01-01

    Oxidative stress and glutathione (GSH) depletion are implicated in mycocystin hepatotoxicity. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in microcystin-induced liver injury, Nrf2-null, wild-type, and Keap1-hepatocyte knockout (Keap1-HKO) mice were treated with microcystin (50 μg/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Microcystin increased serum alanine aminotransferase and aspartate aminotransferase activities, and caused extensive inflammation and necrosis in Nrf2-null and wild-type mice, but not in Keap1-HKO mice. Oxidative stress and inflammation are implicated in microcystin-induced hepatotoxicity, as evidenced by increased lipid peroxidation and increased expression of pro-inflammatory genes, such as neutrophil-specific chemokines mKC and MIP-2, and pro-inflammatory cytokines IL-1β and IL-6. The increased expression of these pro-inflammatory genes was attenuated in Keap1-HKO mice. Nrf2 and Nqo1 mRNA and protein were higher in Keap1-HKO mice at constitutive levels and after microcystin. To further investigate the mechanism of the protection, hepatic GSH and the mRNA of GSH-related enzymes were determined. Microcystin markedly depleted liver GSH by 60-70% in Nrf2 and WT mice but only 35% in Keap1-HKO mice. The mRNAs of GSH conjugation and peroxide reduction enzymes, such as Gstα1, Gstα4, Gstμ, and Gpx2 were higher in livers of Keap1-HKO mice, together with higher expression of the rate-limiting enzyme for GSH synthesis (Gclc). Organic anion transport polypeptides were increased by microcystin with the most increase in Keap1-HKO mice. In conclusion, this study demonstrates that higher basal levels of Nrf2 and GSH-related genes in Keap1-HKO mice prevented microcystin-induced oxidative stress and liver injury.

  15. Overexpression of Nrf2 protects against microcystin-induced hepatotoxicity in mice.

    Directory of Open Access Journals (Sweden)

    Yuan-Fu Lu

    Full Text Available Oxidative stress and glutathione (GSH depletion are implicated in mycocystin hepatotoxicity. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2 in microcystin-induced liver injury, Nrf2-null, wild-type, and Keap1-hepatocyte knockout (Keap1-HKO mice were treated with microcystin (50 μg/kg, i.p.. Blood and liver samples were collected 8 h thereafter. Microcystin increased serum alanine aminotransferase and aspartate aminotransferase activities, and caused extensive inflammation and necrosis in Nrf2-null and wild-type mice, but not in Keap1-HKO mice. Oxidative stress and inflammation are implicated in microcystin-induced hepatotoxicity, as evidenced by increased lipid peroxidation and increased expression of pro-inflammatory genes, such as neutrophil-specific chemokines mKC and MIP-2, and pro-inflammatory cytokines IL-1β and IL-6. The increased expression of these pro-inflammatory genes was attenuated in Keap1-HKO mice. Nrf2 and Nqo1 mRNA and protein were higher in Keap1-HKO mice at constitutive levels and after microcystin. To further investigate the mechanism of the protection, hepatic GSH and the mRNA of GSH-related enzymes were determined. Microcystin markedly depleted liver GSH by 60-70% in Nrf2 and WT mice but only 35% in Keap1-HKO mice. The mRNAs of GSH conjugation and peroxide reduction enzymes, such as Gstα1, Gstα4, Gstμ, and Gpx2 were higher in livers of Keap1-HKO mice, together with higher expression of the rate-limiting enzyme for GSH synthesis (Gclc. Organic anion transport polypeptides were increased by microcystin with the most increase in Keap1-HKO mice. In conclusion, this study demonstrates that higher basal levels of Nrf2 and GSH-related genes in Keap1-HKO mice prevented microcystin-induced oxidative stress and liver injury.

  16. Red Seaweed (Hypnea Bryodies and Melanothamnus Somalensis) Extracts Counteracting Azoxymethane-Induced Hepatotoxicity in Rats

    Science.gov (United States)

    Ibrahim Waly, Mostafa; Al Alawi, Ahmed Ali; Al Marhoobi, Insaaf Mohammad; Rahman, Mohammad Shafiur

    2016-12-01

    Background: Azoxymethane (AOM) is a well-known colon cancer-inducing agent in experimental animals via mechanisms that include oxidative stress in rat colon and liver tissue. Few studies have investigated AOM-induced oxidative stress in rat liver tissue. Red seaweeds of the genera Hypnea Bryodies and Melanothamnus Somalensis are rich in polyphenolic compounds that may suppress cancer through antioxidant properties, yet limited research has been carried out to investigate their anti-carcinogenic and antioxidant influence against AOM-induced oxidative stress in rat liver. Objective: This study aims to determine protective effects of red seaweed (Hypnea Bryodies and Melanothamnus Somalensis) extracts against AOM-induced hepatotoxicity and oxidative stress. Materials and Methods: Sprague–Dawley rats received intraperitoneal injections of AOM, 15 mg/kg body weight, once a week for two consecutive weeks and then orally administered red seaweed (100 mg/kg body-weight) extracts for sixteen weeks. At the end of the experiment all animals were overnight fasted then sacrificed and blood and liver tissues were collected. Results: AOM treatment significantly decreased serum liver markers and induced hepatic oxidative stress as evidenced by increased liver tissue homogenate levels of nitric oxide and malondialdehyde, decreased total antioxidant capacity and glutathione, and inhibition of antioxidant enzymes (catalase, glutathione peroxidase, glutathione S-transferase, glutathione reductase and superoxide dismutase). Both red seaweed extracts abolished the AOM-associated oxidative stress and protected against liver injury as evidenced by increased serum levels of liver function markers. In addition, histological findings confirmed protective effects of the two red seaweed extracts against AOM-induced liver injury. Conclusion: Our findings indicate that red seaweed (Hypnea Bryodies and Melanothamnus Somalensis) extracts counteracted oxidative stress-induced hepatotoxicity in a

  17. Effect of glycyrrhizic acid on titanium dioxide nanoparticles-induced hepatotoxicity in rats.

    Science.gov (United States)

    Orazizadeh, Mahmoud; Fakhredini, Fereshtesadat; Mansouri, Esrafil; Khorsandi, Layasadat

    2014-09-05

    Many recent studies demonstrate that most nanoparticles (NPs) have an adverse or toxic action on liver. The aim of this study was to investigate the hepatoprotective effect of glycyrrhizic acid (GA) against hepatic injury induced by titanium dioxide nanoparticles (NTiO2) in rats. Thirty-two Wistar rats were randomly divided into 4 groups. NTiO2-intoxicated rats received 300 mg/kg of NTiO2 for 14 days by gavage method. Protection group pretreated with GA for 7 days before NTiO2 administration. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were detected as biomarkers in the blood to indicate hepatic injury. Product of lipid peroxidation (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were evaluated for oxidative stress in hepatic injury. Light microscopy for histopathological studies and TUNEL assay was also done. Administration of NTiO2 induced a significant elevation in plasma AST, ALT and ALP. In the liver, NTiO2 increased oxidative stress through the increase in lipid peroxidation and decrease in SOD and GPx enzymes. Histopathological studies showed that treatment with NTiO2 caused liver damage including centrilobular necrosis, which was accompanied by congestion and accumulation of inflammatory cells. Apoptotic index was also significantly increased in this group. Pretreatment of GA significantly decreased ALT, AST and ALP, attenuated the histopathology of hepatic injury, decreased apoptotic index, ameliorated oxidative stress in hepatic tissue, and increased the activities of SOD and GPx. These findings indicate that GA effectively protects against NTiO2-induced hepatotoxicity. GA has a potent protective effect against the NPs induced hepatotoxicity and might be clinically useful.

  18. Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

    Science.gov (United States)

    Spruiell, Krisstonia; Gyamfi, Afua A.; Yeyeodu, Susan T.; Richardson, Ricardo M.; Gonzalez, Frank J.

    2015-01-01

    Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXR-humanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor α, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females. PMID:26159875

  19. Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Youssef Dgachi

    2016-05-01

    Full Text Available We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM, good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

  20. Identification of urine tauro-β-muricholic acid as a promising biomarker in Polygoni Multiflori Radix-induced hepatotoxicity by targeted metabolomics of bile acids.

    Science.gov (United States)

    Zhao, Dong-Sheng; Jiang, Li-Long; Fan, Ya-Xi; Dong, Lei-Chi; Ma, Jiang; Dong, Xin; Xu, Xiao-Jun; Li, Ping; Li, Hui-Jun

    2017-02-24

    Polygoni Multiflori Radix (PMR) has been widely used as a tonic for centuries. However, hepatotoxicity cases linked to PMR have been frequently reported and appropriate biomarkers for clinical diagnosis are currently lacking. Here, an approach using UPLC-QqQ/MS-based targeted metabolomics of bile acids (BAs) complemented with biochemistry and histopathology was applied to characterize the development and recovery processes of PMR-induced hepatotoxicity in rats and to identify biomarkers. The expression of bile salt export pump (Bsep) and sodium taurocholate cotransporting polypeptide (Ntcp) were evaluated to investigate the underlying mechanism. Steatosis and inflammatory cell infiltration were observed in PMR-treated rats, which were accompanied by the elevation of serum biochemistry. The metabolic profiles of BAs were analyzed by Principal Component Analysis, hyodeoxycholic acid (HDCA) in serum and tauro-β-muricholic acid (TβMCA) in urine were identified as potential biomarkers for PMR-induced hepatotoxicity. The elevated expression of Bsep and decreased expression of Ntcp in the liver of PMRtreated rats indicated that hepatotoxicity was related to the disorders of BAs metabolism. Our study demonstrated that BAs may be used for clinical diagnosis of PMR-induced hepatotoxicity. Urine TβMCA was identified as a promising biomarker to facilitate the clinical monitoring of PMR-induced hepatotoxicity and may serve as potential therapeutic target.

  1. Acute Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCIPP) Causes Hepatic Inflammation and Leads to Hepatotoxicity in Zebrafish

    Science.gov (United States)

    Liu, Chunsheng; Su, Guanyong; Giesy, John P.; Letcher, Robert J.; Li, Guangyu; Agrawal, Ira; Li, Jing; Yu, Liqin; Wang, Jianghua; Gong, Zhiyuan

    2016-01-01

    Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been frequently detected in environmental media and has adverse health effect on wildlife and humans. It has been implicated to have hepatotoxicity, but its molecular mechanisms remain unclear. In the present study, adult male zebrafish were exposed to TDCIPP and global hepatic gene expression was examined by RNA-Seq and RT-qPCR in order to understand the molecular mechanisms of TDCIPP-induced hepatotoxicity. Our results indicated that TDCIPP exposure significantly up-regulated the expression of genes involved in endoplasmic reticulum stress and Toll-like receptor (TLR) pathway, implying an inflammatory response, which was supported by up-regulation of inflammation-related biomaker genes. Hepatic inflammation was further confirmed by histological observation of increase of infiltrated neutrophils and direct observation of liver recruitment of neutrophils labeled with Ds-Red fluorescent protein of Tg(lysC:DsRed) zebrafish upon TDCIPP exposure. To further characterize the hepatotoxicity of TDCIPP, the expression of hepatotoxicity biomarker genes, liver histopathology and morphology were examined. The exposure to TDCIPP significantly up-regulated the expression of several biomarker genes for hepatotoxicity (gck, gsr and nqo1) and caused hepatic vacuolization and apoptosis as well as increase of the liver size. Collectively, our results suggest that exposure to TDCIPP induces hepatic inflammation and leads to hepatotoxicity in zebrafish.

  2. Investigation of Dose-Dependent Tissue Protective Effects of Vitamin C

    Directory of Open Access Journals (Sweden)

    Hasan Kilicgun

    2014-03-01

    Full Text Available Aim: Vitamin C is an excellent antioxidant in biological systems. However, It is also widely used as a pro-oxidant. This paradoxical behavior results because it is an excellent reducing agent. As for carbon tetrachloride, the incidence of carbon tetrachloride-induced hepatotoxicity is reported to be on the increase. In this study, it is aimed to test, whether additional intake of different concentrations of vitamin C improves antioxidative protection on lipid peroxidation, alanine transaminase, aspartate transaminase, glutathione and protein oxidation levels in single dose carbon tetrachloride-treated male Wistar rats. Material and Method: Two control groups and four treatment groups totaly sixty Wistar albino rats were used in this study. The control groups were fed via oral route a placebo (4 ml of distilled water, while test groups 100 mg /kg, 200 mg/kg, 400 mg/kg and 800 mg/kg body weight of vitamin C in 4ml of distilled water was given via gastric intubation. Results: The administration of vitamin C for 40 days produced a significant decrease with increasing concentrations from 100 to 400 mg/kg of vitamin C in differnt parameters carbon tetrachloride-treated rats. But, the same protection was not observed at higher concentration of vitamin C. Moreover, it has showed hazardous activity at 800 mg/kg concentration as much as carbon tetrachloride-induced toxicity. Discussion: These results showed that vitamin C had not the potential to be used as tissue protective agent at higher doses. Also, results suggest that the same substannces that optimizes antioxidant capacity may also act as prooxidant dependent on its concentration.

  3. Development of Blood-Brain Barrier Permeable Nitrocatechol-Based Catechol O-Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity.

    Science.gov (United States)

    Silva, Tiago; Mohamed, Tarek; Shakeri, Arash; Rao, Praveen P N; Martínez-González, Loreto; Pérez, Daniel I; Martínez, Ana; Valente, Maria João; Garrido, Jorge; Uriarte, Eugenio; Serrão, Paula; Soares-da-Silva, Patrício; Remião, Fernando; Borges, Fernanda

    2016-08-25

    Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 μM with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts.

  4. Protective and curative effect of poly herbal formulation containing indigenous medicinal plants against various hepatotoxic agents in rats

    Institute of Scientific and Technical Information of China (English)

    Sunil Mistry; Kunduri Rajeswar Dutt; Sashi Bhusan Biswal; Jyotirmoyee Jena

    2012-01-01

    Objective: To evaluate the protective and curative potential of PHF, a polyherbal formulation, against two experimentally induced hepatotoxicity models in rats. Methods: Hepatoprotective activity of the PHF containing three indigenous medicinal plants extracts Coccinia indica, Sidacordata and Scoparia dulcis, was screened against CCl4 and paracetamol induced hepatotoxicity in rats. Result: Administration of hepatotoxins (CCl4 and paracetamol) shows significant morphological, biochemical and histopathological deteriorations in the liver of experimental animals. Pretreatment with PHF had significant protection against hepatic damage by maintaining the morphological parameters within normal range and normalizing the elevated levels of biochemical parameters (SGPT, SGOT, ALP and total bilirubin), which were evidently showed in histopathological study. Conclusions: The PHF has highly significant hepatoprotective effect at 100 and 200 mg/kg, p.o. on the liver of all the two experimental animal models. The liver protection due to combined action of all plant extracts along with their phytoconstituents.

  5. Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer′s Disease Therapy

    Directory of Open Access Journals (Sweden)

    Houssem Boulebd

    2016-03-01

    Full Text Available Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-ylethan-1-one (4 is non-hepatotoxic (cell viability assay on HepG2 cells, a selective but moderately potent EeAChE inhibitor (IC50 = 38.7 ± 1.7 μM, and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 μmol·Trolox/μmol compound.

  6. High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort.

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    Alan T Clarke

    Full Text Available Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment.The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions.Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4-2.6]. High dose was classified as 40-80mg daily and low dose 10-20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2-12.7] for HDA, 1.4 [0.9-2.0] for LDA and 1.5 [1.0-2.2] for HDS.The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small.

  7. The Potential Role of Azadirachta indica Treatment on Cisplatin-Induced Hepatotoxicity and Oxidative Stress in Female Rats

    OpenAIRE

    Mohamed A Dkhil; Saleh Al-Quraishy; Aref, Ahmed M.; Othman, Mohamed S.; Kamal M. El-Deib; Ahmed E Abdel Moneim

    2013-01-01

    Azadirachta indica A. Juss. (neem, family: Meliaceae) is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt) on rats treated with cisplatin (CDDP)-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative...

  8. Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals.

    Science.gov (United States)

    Rodrigues, Robim M; De Kock, Joery; Branson, Steven; Vinken, Mathieu; Meganathan, Kesavan; Chaudhari, Umesh; Sachinidis, Agapios; Govaere, Olivier; Roskams, Tania; De Boe, Veerle; Vanhaecke, Tamara; Rogiers, Vera

    2014-01-01

    Human skin-derived precursors (hSKP) are postnatal stem cells with neural crest properties that reside in the dermis of human skin. These cells can be easily isolated from small (fore) skin segments and have the capacity to differentiate into multiple cell types. In this study, we show that upon exposure to hepatogenic growth factors and cytokines, hSKP acquire sufficient hepatic features that could make these cells suitable in vitro tools for hepatotoxicity screening of new chemical entities and already existing pharmaceutical compounds. Indeed, hepatic differentiated hSKP [hSKP-derived hepatic progenitor cells (hSKP-HPC)] express hepatic progenitor cell markers (EPCAM, NCAM2, PROM1) and adult hepatocyte markers (ALB), as well as key biotransformation enzymes (CYP1B1, FMO1, GSTA4, GSTM3) and influx and efflux drug transporters (ABCC4, ABCA1, SLC2A5). Using a toxicogenomics approach, we could demonstrate that hSKP-HPC respond to acetaminophen exposure in a comparable way to primary human hepatocytes in culture. The toxicological responses "liver damage", "liver proliferation", "liver necrosis" and "liver steatosis" were found to be significantly enriched in both in vitro models. Also genes associated with either cytotoxic responses or induction of apoptosis (BCL2L11, FOS, HMOX1, TIMP3, and AHR) were commonly upregulated and might represent future molecular biomarkers for hepatotoxicity. In conclusion, our data gives a first indication that hSKP-HPC might represent a suitable preclinical model for in vitro screening of hepatotoxicity. To the best of our knowledge, this is the first report in which human postnatal stem cells derived from skin are described as a potentially relevant cell source for in vitro hepatotoxicity testing of pharmaceutical compounds.

  9. Chemical Diversity Investigation of Hepatotoxic Pyrrolizidine Alkaloids in Qianliguang (Senecio scandens and Related Species by UHPLC-QTOF-MS

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    Lin Zhu

    2015-04-01

    Full Text Available Objective: Qianliguang (Senecio scandens is a common Chinese medicinal herb. Qianliguang-containing herbal proprietary products are registered as over-the-counter remedies in China and exported to Western countries. The presence of hepatotoxic pyrrolizidine alkaloids (PAs has raised concerns about the safety of using Qianliguang and its products. The present study aims at investigation of different types of PAs present in Qianliguang collected from representative locations in China.

  10. Alteration of cytochrome oxidase subunit I labeling is associated with severe mitochondriopathy in NRTI-related hepatotoxicity in HIV patients.

    Science.gov (United States)

    Duong Van Huyen, Jean-Paul; Batisse, Dominique; Heudes, Didier; Belair, Marie-France; Piketty, Christophe; Gonzalez-Canali, Gustavo; Weiss, Laurence; Kazatchkine, Michel D; Bruneval, Patrick

    2006-10-01

    Liver mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) in human immunodeficiency virus (HIV) patients has been associated with a wide range of liver involvement ranging from low-grade hepatotoxicity, asymptomatic lactacidemia to severe liver insufficiency, with massive steatosis and life-threatening lactic acidosis. Considerable efforts have been made in the last few years to establish clinical guidelines to avoid life-threatening NRTI-associated lactic acidosis. However, the important issue of low-grade NRTI-associated hepatotoxicity still needs to be unravelled since its natural history is largely unknown. We have recently reported a series of 13 monoinfected HIV patients with low-grade NRTI-associated toxicity. Our results outlined the heterogeneity of NRTI-induced hepatotoxicity and raised the question of its diagnosis. The present study evaluates the expression of cytochrome oxidase (COX) subunits I and IV, encoded by mitochondrial and nuclear DNA, respectively, in NRTI hepatotoxicity. The aim of our study was to compare the detection rate of mitochondrial abnormalities of immunohistochemistry for COX subunit I with electron microscopy. COX subunit I and IV labeling was performed together with light microscopy and ultrastructural analysis in a series of 55 liver biopsies from HIV monoinfected and HIV-hepatitis C virus coinfected patients. Clinical data were also recorded. Our major findings were: (i) decreased COX subunit I labeling is associated with severe ultrastructural mitochondrial alterations and may represent overt NRTI-induced mitochondrial cytopathy; (ii) mild ultrastructural damage associated with normal COX subunit I labeling is of unknown clinical significance. The results of the study suggest that COX subunit I labeling may be a valuable tool for the diagnosis of mitochondrial liver disease in HIV patients.

  11. Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits

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    Maysaa B Zubairi

    2014-01-01

    Full Text Available Objectives: To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. Materials and Methods : Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally, group 3, 4,5 and 6 were treated at a dose in (mg/kg/day of the following: Carvedilol (10 mg, prazosin (0.5 mg, metoprolol (10 mg, and a combination of metoprolol (10 mg and prazosin (0.5 mg respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA and glutathione (GSH in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. Results: Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. Conclusion : Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection.

  12. Human Skin-Derived Stem Cells as a Novel Cell Source for In Vitro Hepatotoxicity Screening of Pharmaceuticals

    OpenAIRE

    Rodrigues, Robim M.; De Kock, Joery; Branson, Steven; Vinken, Mathieu; Meganathan, Kesavan; Chaudhari, Umesh; Sachinidis, Agapios; Govaere, Olivier; Roskams, Tania; De Boe, Veerle; Vanhaecke, Tamara; Rogiers, Vera

    2014-01-01

    Human skin-derived precursors (hSKP) are postnatal stem cells with neural crest properties that reside in the dermis of human skin. These cells can be easily isolated from small (fore) skin segments and have the capacity to differentiate into multiple cell types. In this study, we show that upon exposure to hepatogenic growth factors and cytokines, hSKP acquire sufficient hepatic features that could make these cells suitable in vitro tools for hepatotoxicity screening of new chemical entities...

  13. Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

    OpenAIRE

    Ma, Lei-Lei; Wu, Zhi-tao; Wang, Le; Zhang, Xue-Feng; Wang, Jing; Chen, Chen; Ni, Xuan; Lin, Yun-fei; Cao, Yi-yi; Luan, Yang; Pan, Guo-yu

    2016-01-01

    Aim: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. Methods: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro...

  14. Early Stage HIV Management and Reduction of Stavudine-Induced Hepatotoxicity in Rats by Experimentally Developed Biodegradable Nanoparticles.

    Science.gov (United States)

    Ghosh, Saikat; Mondal, Laboni; Chakraborty, Samrat; Mukherjee, Biswajit

    2017-04-01

    The objectives of this research work were to develop optimized nanoparticulate formulations of poly (d,l-lactic-co-glycolic acid) (PLGA) (85:15) with an anti-AIDS drug stavudine and to evaluate their in-vitro uptake by the macrophages and hepatotoxicity in-vivo. Nanoparticles were prepared by nanoprecipitation method based on a factorial design with varying parameters such as the amounts of polymer and stabilizer used. Physicochemical characterizations such as drug-excipient interaction, surface morphology, particle size, and zeta potential measurements were carried out. The best formulation was selected and tagged with fluorescein isothiocyanate (FITC) for cellular uptake study of the formulation. In-vitro uptake of nanoparticles by macrophages was carried out. Formulation-induced hepatotoxicity was assessed by analyzing some serum hepatotoxic parameters and hepatic histology following 10-day treatment in comparison with the free drug. Nanoparticles exhibited smooth surface with particle size 84-238 nm, high entrapment efficiency (approx 85%), and negative surface charge. Formulations showed a sustained drug release pattern over the study period. In-vitro uptake study by macrophages exhibited a time-dependent profile. In-vivo studies on rats showed improvement in the serum parameters and maintenance of the integrity of the hepatic architecture indicating decreased hepatotoxicity with the formulations as compared to the free drug. The experimental results showed a positive outcome in the development of antiretroviral drug carrier exhibiting sustained drug release, macrophage-targeted delivery characteristics, and having reduced hepatoxicity. This could be beneficial for the management of early stage of HIV infection besides reducing the drug load for effective treatment, thereby offering an attractive option in AIDS therapy.

  15. REPEATED EXPOSURE OF SODIUM TELLURITE ON THE RAT LIVER AND ON THE POTENTIAL MECHANISMS OF THE METALLOID-INDUCED HEPATOTOXICITY.

    Science.gov (United States)

    Safhi, Mohammed M; Alam, Mohammad Firoz; Khuwaja, Gulrana; Islam, Farah; Hussain, Sohail; Fageeh, Mohsen Mohammed; Anwer, Tarique; Islam, Fakhrul

    2016-01-01

    Tellurium (Te) is a semiconductor and is frequently doped with copper, tin, gold or silver. It is also used to color glass and ceramics and is one of the primary ingredients in blasting caps. Little is known about Te biological activity but it is well known for toxicity to human and animals. It has inhibited the lipids profiles and oxidative stress in the brain of mice. Sodium tellurite 4.15, 8.3 and 16.6 mg/kg (1/20, 1/10 and 1/5 of LD50, respectively) was given to male Wistar rats orally in saline for a period of 15 days. On day 16, the blood was collected and the livers were dissected out for biochemical assays. The hepatotoxicity biomarkers [bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)] were elevated significantly and dose dependently in the serum of Te treated groups as compared to control group. The content of thiobarbituric reactive substances in Te treated groups was increased significantly and dose-dependently as compared to control group. Conversely, the content of glutathione and activities of antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione-S-transferase, superoxide dismutase and catalase) were decreased significantly in Te treated groups as compared to control group. No data of inorganic Te compounds on the liver toxicity of rats are available. The aim of the present study was to evaluate the hepatotoxicity of inorganic Te compound. In conclusion, Te accelerated hepatotoxicity and oxidative stress in liver tissue of rats.

  16. Diallyl trisulfide ameliorates arsenic-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats.

    Science.gov (United States)

    Sumedha, N C; Miltonprabu, S

    2015-05-01

    The present study investigates the possible ameliorative effects of diallyl trisulfide (DATS) against arsenic (As)-induced hepatotoxicity and oxidative stress in rats. The four experimental groups evaluated include: (1) vehicle control; (2) As (5 mg/kg/day); (3) DATS (80 mg/kg/day) + As; and (4) DATS. Induction of As in rats caused severe hepatotoxicity as evidenced by an elevation of serum aspartate aminotransferase and alanine aminotransferase activities and increased total bilirubin concentration, indicating hepatic function abnormalities. Histopathological examination revealed various structural changes in the liver, characterized by hepatocyte degeneration/necrosis, congestion, sinusoidal dilatation, vacuolation, and inflammatory cell infiltration. The significant decrease in reduced glutathione content, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities and the significant increase in lipid peroxidation (thiobarbituric acid reactive substance) and protein oxidation (protein carbonyl) contents indicated that As-induced hepatotoxicity was mediated through oxidative stress. As intoxication also elevated the levels of Cas-3 and nitric oxide and increased the expression of nuclear factor-κB p65 in the liver. In contrast, DATS pretreatment significantly improved As-induced serum biochemical, immunohistochemical, and histopathological alterations reflecting hepatic dysfunction. These results may contribute to a better understanding of the hepatoprotective role of DATS, emphasizing the influence of this garlic trisulfide in the diet for human health, possibly preventing the hepatic injury associated with As intoxication, presumably due to its ability to inhibit lipid peroxidation, protein oxidation, and restoration of antioxidant status.

  17. In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System

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    Fanny Knöspel

    2016-04-01

    Full Text Available Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR, while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.

  18. In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System.

    Science.gov (United States)

    Knöspel, Fanny; Jacobs, Frank; Freyer, Nora; Damm, Georg; De Bondt, An; van den Wyngaert, Ilse; Snoeys, Jan; Monshouwer, Mario; Richter, Marco; Strahl, Nadja; Seehofer, Daniel; Zeilinger, Katrin

    2016-04-16

    Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.

  19. Effect of captopril and telmisartan on methotrexate-induced hepatotoxicity in rats: impact of oxidative stress, inflammation and apoptosis.

    Science.gov (United States)

    Kelleni, Mina T; Ibrahim, Salwa A; Abdelrahman, Aly M

    2016-06-01

    Methotrexate (MTX) is a commonly used antineoplastic and anti-rheumatoid drug whose efficacy is limited by its hepatotoxicity. The aim of this study was to investigate the possible protective role of captopril (100 mg/kg/day, p.o. for seven days), an angiotensin converting enzyme inhibitor, and telmisartan (10 mg/kg/day p.o. for seven days), an angiotensin II receptor blocker with peroxisome proliferative receptor gamma (PPARγ) agonism, in a model of MTX (single dose 20 mg/kg i.p. at the fifth day) induced hepatotoxicity in rats. Results of the present study revealed MTX-induced hepatotoxicity as demonstrated by increased level of liver enzymes and confirmed by histopathology. Pretreatment with captopril or telmisartan produced a significant hepatic protection manifested as a significant (p < 0.05) decrease in serum levels of alanine transferase (ALT) and aspartate transferase (AST) and alkaline phosphatase (ALP) enzymes; hepatic malondialdehyde (MDA) and total nitrites and nitrates (NOx) levels; as well as a significant increase in hepatic superoxide dismutase (SOD) activity. In addition, there was a remarkable improvement in the histopathological features and a significant reduction in the expression of COX-2, iNOS and caspase-3 enzymes as compared with the MTX group. We recommend considering captopril/Telmisartan, if tolerated and not contraindicated, as preferable antihypertensive agents in patients receiving MTX in their chemotherapy protocols.

  20. Dose-response effects of Elephantopus scaber methanolic extract on N-nitrosodiethylamine-induced hepatotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    A.Linza; P.J.Wills; P.N.Ansil; S.P.Prabha; A.Nitha; B.Latha; K.O.Sheeba; M.S.Latha

    2013-01-01

    AIM:A decoction of Elephantopus scaber (Asteraceae) root is used to treat liver disorders in Indian and Chinese traditional medicine.The study was designed to examine the dose response effects of E.scaber methanolic extract on rats exposed to N-nitrosodiethylamine (NDEA) induced hepatotoxicity (0.02% NDEA in water five days per week,per oral) in preventive and curative models.METHODS:In preventive groups,NDEA was administered for six weeks.Daily doses of E.scaber methanolic extract (200 and 100mg·kg-1) started one week before the onset of NDEA intoxication and continued for six weeks.In curative animals,NDEA was administered for six weeks followed by treatment with the methanolic n-hexane extract of E.scaber (200 and 100mg·kg-1) for ten days.RESULTS:E.scaber extract treatment significantly (P≤0.05) reduced the levels of AST,ALT,and MDA in both experimental groups.The extract also enhanced the antioxidant enzyme and protein levels in rats intoxicated with NDEA.Treatment with the extract dose dependently protected the liver from NDEA-induced hepatotoxicity with normal hepatocytes and uniform sinusoids,but in some areas showed degenerating hepatic cells in both treatment groups.CONCLUSION:E.scaber methanolic extract dose dependently prevented and reversed the hepatotoxicity induced by NDEA in both experimental models.

  1. Alpha-glucosidase inhibitors and hepatotoxicity in type 2 diabetes: a systematic review and meta-analysis

    Science.gov (United States)

    Zhang, Longhao; Chen, Qiyan; Li, Ling; Kwong, Joey S. W.; Jia, Pengli; Zhao, Pujing; Wang, Wen; Zhou, Xu; Zhang, Mingming; Sun, Xin

    2016-09-01

    Alpha-glucosidase inhibitors (AGIs) was reported to be associated with several rare adverse hepatic events, but with inconsistent results. We aimed to investigate the risk of hepatotoxicity associated with the use of AGIs in patients with type 2 diabetes mellitus (T2DM), and performed a systematic review and meta-analysis. Fourteen studies (n = 2881) were eligible, all of which were RCTs. Meta-analysis of data regarding elevation of more than 3-fold the upper limit of normal (ULN) of AST and ALT showed statistically significant differences between AGIs treatment versus control (OR 6.86, 95% CI 2.50 to 18.80; OR 6.48, 95% CI 2.40 to 17.49). Subgroup analyses of elevation of more than 1.8-fold ULN of AST and ALT by dose of AGIs showed differential effects on AST and ALT (AST: OR 0.38 vs 7.31, interaction P = 0.003 ALT: OR 0.32 vs 4.55, interaction p = 0.02). Meta-analysis showed that AGIs might increase the risk of hepatotoxicity, and higher dose appeared to be associated with higher risk of hepatotoxicity. However, the evidence is limited with surrogate measures (i.e. ALT and AST), and no clinically important adverse events were observed.

  2. Hepatotoxicity related to agomelatine and other new antidepressants: a case/noncase approach with information from the Portuguese, French, Spanish, and Italian pharmacovigilance systems.

    Science.gov (United States)

    Montastruc, François; Scotto, Stefania; Vaz, Ines Ribeiro; Guerra, Leonor Nogueira; Escudero, Antonio; Sáinz, María; Falomir, Teresa; Bagheri, Haleh; Herdeiro, Maria Teresa; Venegoni, Mauro; Montastruc, Jean Louis; Carvajal, Alfonso

    2014-06-01

    Antidepressants have been associated with a low incidence of idiosyncratic hepatic injury. Some of them, nefazodone or amineptine, were observed to induce severe hepatic injury and withdrawn from the market. Recently, some cases of this severe condition have been reported in association with agomelatine use. Therefore, the objective of this study is to learn the risk of hepatic damage with agomelatine as compared with other new antidepressants. We took data from the Spanish, French, Italian, and Portuguese pharmacovigilance system databases. A case/noncase approach to assess the strength of the association between whichever antidepressant and hepatotoxicity was performed; cases were defined as reports of hepatotoxicity; noncases were reports of all reactions other than hepatotoxicity. Exposure was the recording of a new antidepressant in a report, whether or not it was suspected of causing the reaction. During the period surveyed, 3300 cases of hepatotoxicity were collected for the antidepressants assessed. They represent 10.3% of all cases collected for these drugs; the corresponding figure for all drugs was 6.0%. Meanwhile, 63 cases of hepatotoxicity associated with agomelatine were collected since its introduction until the end of the period studied; they account for a percentage of 14.6. Agomelatine was statistically associated with hepatotoxicity in Spain [reporting odds ratio (ROR), 4.9 (95% confidence interval [CI], 2.4-9.7)], France (ROR, 2.4 [95% CI, 1.5-3.7]), and Italy (ROR, 5.1 [95% CI, 1.7-14.0]). Current results support the idea of agomelatine to be related to a higher hepatotoxicity risk. Physicians should consider early discontinuation if the condition is suspected; health authorities should promptly explore the best regulatory actions to be taken.

  3. Factors associated with anti-TB drug-induced hepatotoxicity and genetic polymorphisms in indigenous and non-indigenous populations in Brazil.

    Science.gov (United States)

    Heinrich, Melissa M; Zembrzuski, Verônica M; Ota, Marcos M; Sacchi, Flavia P; Teixeira, Raquel L F; Cabello Acero, Pedro H; Cunha, Geraldo Marcelo; Souza-Santos, Reinaldo; Croda, Julio; Basta, Paulo C

    2016-12-01

    Anti-tuberculosis (TB) drugs are responsible for the occurrence of several adverse drug reactions (ADRs), including hepatotoxicity. The aim was to estimate the incidence of hepatotoxicity and its association with genetic polymorphisms and clinical-epidemiological factors by comparing indigenous and non-indigenous TB patients. We investigated clinical-epidemiological variables, serum levels of liver enzymes and NAT2, CYP2E1 and GSTM1 polymorphisms. A non-conditional logistic regression was used to identify the factors associated with hepatotoxicity. Odds ratios were used as the association measures. The incidence of hepatotoxicity was 19.7% for all patients. The risk of hepatotoxicity was almost four times higher in indigenous patients, comparing to non-indigenous. We identified a new nonsynonymous single nucleotide polymorphism of NAT2 in indigenous patients. In total, 54.6% of the patients expressed a slow acetylation phenotype profile. The frequency of the null genotype of GSTM1 was higher in non-indigenous patients (p = 0.002), whereas no significant differences in relation to polymorphisms of CYP2E1 were observed between the groups. Hepatotoxicity was associated with patients older than 60 and indigenous (OR = 26.0; 95%CI:3.1-217.6; OR = 3.8; 95%CI:1.3-11.1, respectively). Furthermore, hepatotoxicity was associated with a slow acetylation profile in indigenous patients (OR = 10.7; 95%CI:1.2-97.2). Our findings suggest that there are distinct acetylation profiles in the Brazilian population, emphasizing the importance of pharmacogenetic analyses for achieving personalized therapeutic schemes and better outcomes.

  4. HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Camilla Stephens

    Full Text Available BACKGROUND AND AIM: The genotype-phenotype interaction in drug-induced liver injury (DILI is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. METHODS: High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. RESULTS: The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7 and B*1801 (P/Pc = 0.008/0.22, OR 2.9 were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0 was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019 and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2 and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15 were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07. CONCLUSIONS: HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

  5. Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice

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    Hagiya, Yoshifumi; Kamata, Shotaro; Mitsuoka, Saya; Okada, Norihiko; Yoshida, Saori; Yamamoto, Junya; Ohkubo, Rika [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Abiko, Yumi [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Yamada, Hidenori [Jobu Hospital for Respiratory Diseases, Maebashi 371-0048 (Japan); Akahoshi, Noriyuki [Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543 (Japan); Kasahara, Tadashi [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Kumagai, Yoshito [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Ishii, Isao, E-mail: isao-ishii@umin.ac.jp [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan)

    2015-01-15

    The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs{sup +/−} or Cth{sup +/−}) and homozygous (Cth{sup −/−}) knockout mice. At 4 h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth{sup −/−} mice at 150 mg/kg dose, and also in Cbs{sup +/−} or Cth{sup +/−} mice at 250 mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth{sup −/−} mice but not wild-type mice, although glutamate–cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth{sup −/−} mice with lower K{sub m} values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150 mg acetaminophen/kg into Cth{sup −/−} mice; the profiles were similar to 1000 mg acetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200–300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities. - Highlights: • Cbs{sup +/−}, Cth{sup +/−}, and

  6. Antioxidant and hepatoprotective properties of dried fig against oxidative stress and hepatotoxicity in rats.

    Science.gov (United States)

    Turan, Abdullah; Celik, Ismail

    2016-10-01

    The aim of this study was to investigate the hepatoprotective effect and antioxidant role of dried fig (DF) (Ficus carica L.) against ethanol-induced oxidative stress. Experiment was designed as normal Control, 20% ethanol, 10% DF and 10% DF+20% ethanol groups. The hepatoprotective and antioxidant role of the dried DF supplementation feed against ethanol induced oxidatif stress were evaluated by liver histopathological changes, measuring liver damage serum enzymes (LDSE), antioxidant defense system (ADS) and malondialdehyde (MDA) content in various tissues of rats following the exposure of experimental for 50days. The biochemical analysis showed a considerable increase the LDSE in the ethanol group as compared to that of control group whereas, decreased in 10% DF+20% ethanol group as compared to that of ethanol group. In addition, the DF supplementation diet restored the ethanol-induced MDA and ADS towards to control. The hepatoprotection of DF is further substantiated by the almost normal histologic findings of liver in 10% DF+20% ethanol group against degenerative changes in ethanol group. The results indicated that the DF could be as important as diet-derived antioxidants and antihepatotoxicity in preventing oxidative damage in the tissues by inhibiting the production of ethanol-induced free radicals and hepatotoxicity in rats.

  7. Ameliorative effects of 7-methylcoumarin and 7-methoxycoumarin against CCl4-induced hepatotoxicity in rats.

    Science.gov (United States)

    Sancheti, Sandesh; Sancheti, Shruti; Seo, Sung-Yum

    2013-01-01

    The available conventional remedies for the treatment of drug-induced liver diseases are highly inadequate and possess serious adverse effects; therefore, the development of new, effective drugs is considered necessary. This article explores the hepatoprotective and antioxidant potential of 7-methylcoumarin (MC) and 7-methoxycoumarin (MOC) in CCl(4)-induced hepatotoxicity in rats. MC and MOC individually, at doses of 50 and 100 mg/kg body weight, were administered orally once-daily for 7 days. The hepatoprotective activity was assessed using various biochemical parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum bilirubin (TB), total protein (TP), and albumin (TA). Serum antioxidant enzyme [e.g., superoxide dismutase (SOD) and catalase (CAT)] levels were determined. Also, thiobarbituric-acid-related substances (TBARS) levels, along with histopathological studies of liver tissue, were scrutinized. Pretreatment with MC and MOC significantly decreased ALT, AST, and TB in the serum of CCl(4)-induced liver damaged rats in a dose-dependent manner. TA and TP levels in the serum were also restored significantly in all presupplemented MC and MOC groups. In addition, oxidative stress induced by CCl(4) was prevented significantly; thereby, increasing SOD and CAT levels and decreasing TBARS levels in liver homogenates. Histopathological studies revealed the ameliorative natures of both the compounds. This study demonstrates the strong hepatoprotective activity of MC and MOC, which could be attributed to their potent antioxidant effects.

  8. Oxidative Stress and Liver Morphology in Experimental Cyclosporine A-Induced Hepatotoxicity

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    Agnieszka Korolczuk

    2016-01-01

    Full Text Available Cyclosporine A is an immunosuppressive drug used after organ’s transplantation. The adverse effects on such organs as kidney or liver may limit its use. Oxidative stress is proposed as one of the mechanisms of organs injury. The study was designed to elucidate CsA-induced changes in liver function, morphology, oxidative stress parameters, and mitochondria in rat’s hepatocytes. Male Wistar rats were used: group A (control receiving physiological saline, group B cyclosporine A in a dose of 15 mg/kg/day subcutaneously, and group C the CsA-vehicle (olive oil. On the 28th day rats were anesthetized. The following biochemical changes were observed in CsA-treated animals: increased levels of ALT, AST, and bilirubin in the serum, statistically significant changes in oxidative stress parameters, and lipid peroxidation products in the liver supernatants: MDA+4HAE, GSH, GSSG, caspase 3 activity, and ADP/ATP, NAD+/NADH, and NADP+/NADPH ratios. Microscopy of the liver revealed congestion, sinusoidal dilatation, and focal hepatocytes necrosis with mononuclear cell infiltration. Electron microscope revealed marked mitochondrial damage. Biochemical studies indicated that CsA treatment impairs liver function and triggers oxidative stress and redox imbalance in rats hepatocytes. Changes of oxidative stress markers parallel with mitochondrial damage suggest that these mechanisms play a crucial role in the course of CsA hepatotoxicity.

  9. Protective effect of quercetin in the regression of ethanol-induced hepatotoxicity

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    Vidhya A

    2009-01-01

    Full Text Available This study examined the protective effects of quercetin on chronic ethanol-induced liver injury. Rats were treated with ethanol at a dose of 4 g/100 g/day for 90 days. After ethanol intoxication, levels of serum amino transferases were significantly elevated. Decreased activity of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase was also observed on ethanol administration. Increased amounts of lipid peroxidation products viz. hydroperoxides, conjugated dienes and malodialdehyde were observed on ethanol intoxication. Ethanol administration resulted in significant decrease in liver glutathione content. After 90 days, the control animals were divided into two groups, the control group and the control+quercetin group. Ethanol-treated group was divided into two groups, abstention group and quercetin-supplemented group. After 30 days, the animals were sacrificed and various biochemical parameters were analyzed. The changes in enzyme activities as well as levels of lipid peroxidation products were reversed to a certain extent by quercetin. Quercetin supplementation resulted in increase of glutathione content to a significant level compared to normal abstention group. Quercetin supplemented group showed a faster recovery than abstention group. This shows the protective effect of quercetin against chronic ethanol induced hepatotoxicity. Histopathological study is also in line with these results.

  10. Chemical composition and hepatotoxic effect of Geranium schiedeanum in a thioacetamide-induced liver injury model

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    Juan Gayosso-De-Lucio

    2014-01-01

    Full Text Available One of the major components of some geraniums is geraniin, described by its discoverer as crystallizable tannin, well known as an excellent antioxidant, and also found in fruits such as pomegranate. Recently, natural antioxidants have attracted great attention from consumers over the world due to their lower toxicity than synthetics. But geraniin is not a stable compound, and also is difficult to obtain, that is why in the present study we obtained acetonylgeraniin from Geranium schideanum (Gs, a stable acetone condensate of geraniin. In the present study the effect of Gs acetone-water extract was studied in reference to postnecrotic liver regeneration induced by thioacetamide (TA in rats. Two months male rats were pretreated with daily dose of Gs extract for 4 days (300 mg/kg and the last day also were intraperitoneally injected with TA (6.6 mmol/kg. Samples of blood were obtained from rats at 0, 24, 48, 72 and 96 h following TA intoxication. The pre-treatment with the crude extract in the model of thioacetamide-induced hepatotoxicity in rats decreased and delayed liver injury by 66% at 24 h. This result suggests that Gs extract may be used as an alternative for reduction of liver damage. On the other hand, acute toxicity study revealed that the LD 50 value of the Gs extract is more than the dose 5000 mg/kg in rats, according to the Lorke method.

  11. Anti-hepatotoxic and anti-oxidant defense potential of Tridax procumbens

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    Hemalatha Reddipalli

    2008-01-01

    Full Text Available Tridax procumbens is a widely occurring medicinal herb used by ethnomedical practitioners. With increased use of chemicals and alcohol besides growing incidence of viruses and autoimmune diseases, the incidence of liver injury is growing for which conventional drugs used for treatment are often inadequate. Various models are adopted in pharmological studies for inducing hepatitis/ liver injury similar to those observed in human viral hepatitis, diabetes and oxidative stress. D-galactosamine with lipopolysacchride (LPS, carbontetrachloride (CCl 4 and paracetamol intoxication, diabetes induced with alloxan are widely used on rodents for this purpose. In vitro studies on Tridax procumbens (TP revealed the anti-oxidant potential of the herb with chloroform fraction of the ethanolic extract showing maximum activity. It is also reported to possess anti-oxidant minerals such as iron, magnesium, copper and zinc. In vivo studies on rodents on the anti-oxidant potential of TP induced through LPS, CCl 4, alloxan and paracetamol intoxication induced hepatitis confirmed the results from in vitro studies as a potential anti-hepatotoxic herb.

  12. Circadian variation in murine hepatotoxicity to the antituberculosis agent «Isoniazide».

    Science.gov (United States)

    Souayed, Nouha; Chennoufi, Malek; Boughattas, Fida; Haouas, Zohra; Maaroufi, Khira; Miled, Abdelhedi; Ben-Attia, Mosaddok; Aouam, Karim; Reinberg, Alain; Boughattas, Naceur A

    2015-01-01

    The circadian time is an important process affecting both pharmacokinetics and pharmacodynamics of drugs. Consequently, the desired and/or undesired effects vary according to the time of drug administration in the 24 h scale. This study investigates whether the toxicity in liver as well as oxidative stress varies according to the circadian dosing-time of isoniazid (INH) in mice. A potentially toxic INH dose (120 mg/kg) was injected by i.p. route to different groups of animals at three different circadian times: 1, 9, and 17 Zeitgeber time (ZT). INH administration at 1 ZT resulted in a maximum hepatotoxicity assessed by the significant increase in both serum transaminase (ALAT: alanine aminotransferase) and (ASAT: aspartate aminotransferase) and antioxidant enzyme activities (catalase: CAT and superoxide dismutase: SOD). The highest malondialdehyde (MDA) level indicating an induction of lipid peroxidation resulting in oxidative damage was also observed at 1 ZT. Liver histopathology from INH groups at 9 ZT and at 1 ZT showed moderate to severe cytoplasma vacuolation, hepatocyte hypertrophy, ballooning, and necrosis. The circadian variation in INH toxicity may help realize a chronotherapy protocol in humans based on the selection of the best time associated to optimal tolerance or least side effects.

  13. Protective effect of apigenin against N-nitrosodiethylamine (NDEA)-induced hepatotoxicity in albino rats.

    Science.gov (United States)

    Ali, Fahad; Rahul; Naz, Falaq; Jyoti, Smita; Siddique, Yasir Hasan

    2014-06-01

    A number of pharmacological properties have been attributed to apigenin. In the present study the effect of apigenin was investigated with respect to hepatotoxicity induced by N-nitrosodiethylamine (NDEA), a compound that is present in many food stuffs and has been reported to be a hepatocarcinogen. Male rats were exposed to NDEA (0.1mg/ml) dissolved in drinking-water separately, and with 10, 20, or 40mg/ml of apigenin for 21 days. The activity of glutamic-oxaloacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) was measured in blood serum. Lipid peroxidation, protein carbonyl content and micronucleus frequency were determined in hepatocytes. To assess the effect on DNA damage, the comet assay was performed on hepatocytes, blood lymphocytes and bone-marrow cells of the exposed rats. The results of the study reveal that the treatment of NDEA together with apigenin showed a significant dose-dependent decrease in the serum concentration of the enzymes SGOT, SGPT, ALP and LDH (papigenin. A significant dose-dependent reduction in lipid peroxidation and protein carbonyl content was observed in rats exposed to NDEA (0.1mg/ml) together with apigenin (papigenin as an anti-genotoxic and hepatoprotective agent.

  14. Effects of erdosteine on cyclosporine-A-induced hepatotoxicity in rats.

    Science.gov (United States)

    Erarslan, Elife; Ekiz, Fuat; Uz, Burak; Koca, Cemile; Turkcu, Ummuhani Ozel; Bayrak, Reyhan; Delibasi, Tuncay

    2011-01-01

    Cyclosporine A (CsA) is a potent immunosuppressive agent used for organ transplantations and various autoimmune disorders. However, hepatotoxicity due to CsA remains one of the major side effects. The use of antioxidants reduces the adverse effects of CsA. The aim of this study was to determine the protective effects of erdosteine on CsA-induced liver injury through tissue oxidant/antioxidant parameters and to evaluate light microscopic alterations in rat-liver tissues. Rats were randomly divided into four experimental groups: The control group received sunflower oil (2 mL/kg/day, per orally; p.o.), while the other groups were treated with CsA (25 mg/kg/day, p.o.) or erdosteine (10 mg/kg/day, p.o.) or CsA+erdosteine, respectively. Serum aspartate aminotransferase and alanine aminotransferase levels, tissue malondialdehyde and nitric oxide levels, and superoxide dismutase, glutathione peroxidase and catalase enzyme activities were measured. Histological examination was performed. CsA caused a significant deterioration in the hepatic function tests, morphology, and gave rise to severe oxidative stress in the liver. Erdostein significantly improved the functional and histological parameters and attenuated the oxidative stresss induced by CsA. Erdostein protects liver tissue against oxygen free radicals and prevents hepatic dysfunction and morphological abnormalities associated with chronic CsA administration.

  15. Antioxidant effect of vitamin E and selenium on hepatotoxicity induced by dimethoate in female adult rats.

    Science.gov (United States)

    Ben Amara, Ibtissem; Soudani, Nejla; Troudi, Afef; Bouaziz, Hanen; Boudawara, Tahia; Zeghal, Najiba

    2011-05-01

    Acute exposure to pesticides can cause hepatotoxicity. Our study pertains to the potential ability of selenium and/or vitamin E, used as nutritional supplements, to alleviate oxidative stress induced by dimethoate. Female Wistar rats were randomly divided into seven groups of six each: group I served as controls; group II received in their drinking water dimethoate (2 g L(-1)); group III received both dimethoate and selenium (0.5 mg/kg of diet); group IV was treated with dimethoate and vitamin E (100 mg/kg of diet); group V received dimethoate+selenium+vitamin E and groups VI and VII received either selenium or vitamin E. The exposure of rats to dimethoate for 30 days promoted oxidative stress with an increase in malondialdehyde and a decrease in glutathione and non-protein thiol levels. A decrease in glutathione peroxidase, superoxide dismutase and catalase activities was also observed. While, plasma transaminases, lactate dehydrogenase activities and bilirubin levels increased. Co-administration of selenium and/or vitamin E through diet improved the biochemical parameters cited above. Liver histological studies confirmed biochemical parameters and the beneficial roles of selenium and vitamin E.

  16. Immunization of Mice with Anthrax Protective Antigen Limits Cardiotoxicity but Not Hepatotoxicity Following Lethal Toxin Challenge.

    Science.gov (United States)

    Devera, T Scott; Prusator, Dawn K; Joshi, Sunil K; Ballard, Jimmy D; Lang, Mark L

    2015-06-25

    Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand α-galactosylceramide (αGC) to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI), and hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST), it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities.

  17. CYP2E1-dependent hepatotoxicity and oxidative damage after ethanol administration in human primary hepatocytes

    Institute of Scientific and Technical Information of China (English)

    Lie-Gang Liu; Hong Yan; Ping Yao; Wen Zhang; Li-Jun Zou; Fang-Fang Song; Ke Li; Xiu-Fa Sun

    2005-01-01

    AIM: To observe the relationship between ethanol-induced oxidative damage in human primary cultured hepatocytes and cytochrome P450 2E1 (CYP2E1) activity, in order to address if inhibition of CYP2E1 could attenuate ethanol-induced cellular damage.METHODS: The dose-dependent (25-100 mmol/L) and time-dependent (0-24 h) exposures of primary human cultured hepatocytes to ethanol were carried out. CYP2E1 activity and protein expression were detected by spectrophotometer and Western blot analysis respectively.Hepatotoxicity was investigated by determination of lactate dehydrogenase (LDH) and aspartate transaminase (AST) level in hepatocyte culture supernatants, as well as the intracellular formation of malondialdehyde (MDA).RESULTS: A dose-and time-dependent response between ethanol exposure and CYP2E1 activity in human hepatocytes was demonstrated. Moreover, there was a time-dependent increase of CYP2E1 protein after 100 mmol/L ethanol exposure. Meanwhile, ethanol exposure of hepatocytes caused a time-dependent increase of ceilular MDA level, LDH, and AST activities in supernatants.Furthermore, the inhibitor of CYP2E1, diallyl sulfide (DAS) could partly attenuate the increases of MDA, LDH, and AST in human hepatocytes.CONCLUSION: A positive relationship between ethanol-induced oxidative aamage in human primary cultured hepatocytes and CYP2E1 activity was exhibited, and the inhibition of CYP2E1 could partly attenuate ethanol-induced oxidative damage.

  18. Prophylactic and Therapeutic Potential of Acetyl-L-carnitine against Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Alotaibi, Salman A; Alanazi, Abdulrazaq; Bakheet, Saleh A; Alharbi, Naif O; Nagi, Mahmoud N

    2016-01-01

    Prophylactic and therapeutic effects of acetylcarnitine against acetaminophen-induced hepatotoxicity were studied in mice. To evaluate the prophylactic effects of acetylcarnitine, mice were supplemented with acetylcarnitine (2 mmol/kg/day per oral (p.o.) for 5 days) before a single dose of acetaminophen (350 mg/kg intraperitoneal (i.p.)). Animals were sacrificed 6 h after acetaminophen injection. Acetaminophen significantly increased the markers of liver injury, hepatic reactive oxygen species, and nitrate/nitrite, and decreased hepatic glutathione (GSH) and the antioxidant enzymes. Acetylcarnitine supplementation resulted in reversal of all biochemical parameters toward the control values. To explore the therapeutic effects of acetylcarnitine, mice were given a single dose of acetylcarnitine (0.5, 1, and 2 mmol/kg p.o.) 1.5 h after acetaminophen. Animals were sacrificed 6 h after acetaminophen. Acetylcarnitine administration resulted in partial reversal of liver injury only at 2 mmol/kg p.o. At equimolar doses, N-acetylcystiene was superior as therapeutic agent to acetylcarnitine. However, acetylcarnitine potentiated the effect of N-acetylcystiene in the treatment of acetaminophen toxicity.

  19. Hepatotoxic Seafood Poisoning (HSP Due to Microcystins: A Threat from the Ocean?

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    Evangelos Briasoulis

    2013-08-01

    Full Text Available Cyanobacterial blooms are a major and growing problem for freshwater ecosystems worldwide that increasingly concerns public health, with an average of 60% of blooms known to be toxic. The most studied cyanobacterial toxins belong to a family of cyclic heptapeptide hepatotoxins, called microcystins. The microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cell damage following cellular uptake via organic anion-transporting proteins (OATP. Their intracellular biologic effects presumably involve inhibition of catalytic subunits of protein phosphatases (PP1 and PP2A and glutathione depletion. The microcystins produced by cyanobacteria pose a serious problem to human health, if they contaminate drinking water or food. These toxins are collectively responsible for human fatalities, as well as continued and widespread poisoning of wild and domestic animals. Although intoxications of aquatic organisms by microcystins have been widely documented for freshwater ecosystems, such poisonings in marine environments have only occasionally been reported. Moreover, these poisonings have been attributed to freshwater cyanobacterial species invading seas of lower salinity (e.g., the Baltic or to the discharge of freshwater microcystins into the ocean. However, recent data suggest that microcystins are also being produced in the oceans by a number of cosmopolitan marine species, so that Hepatotoxic Seafood Poisoning (HSP is increasingly recognized as a major health risk that follows consumption of contaminated seafood.

  20. Effects of gomisin A on liver functions in hepatotoxic chemicals-treated rats.

    Science.gov (United States)

    Maeda, S; Takeda, S; Miyamoto, Y; Aburada, M; Harada, M

    1985-08-01

    The effects of gomisin A, which is a lignan component of schizandra fruits, on liver functions in various experimental liver injuries and on bile secretion in CCl4-induced liver injury were studied. Gomisin A weakly accelerated the disappearance of plasma ICG by itself at a high dose (100 mg/kg, i.p.). All of the hepatotoxic chemicals used in this study inhibited the excretion of ICG from plasma. Gomisin A showed a tendency to prevent the delays of the disappearance of plasma ICG induced by CCl4, d-galactosamine and orotic acid, but not that by ANIT. Bile flow and biliary outputs of total bile acids and electrolytes (Na+, K+, Cl- and HCO3-) were decreased in CCl4-treated rats. Gomisin A maintained bile flow and biliary output of each electrolyte nearly to the level of the vehicle-treated group, but did not affect biliary output of total bile acids. These findings suggest that gomisin A possesses a liver function-facilitating property in normal and liver injured rats and that its preventive action on CCl4-induced cholestasis is due to maintaining the function of the bile acids-independent fraction.

  1. Oxidative stress and hepatotoxicity in rats induced by poisonous pufferfish (Lagocephalus lagocephalus meat

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    M Saoudi

    2009-01-01

    Full Text Available This study was undertaken to evaluate the effect of pufferfish (Lagocephalus lagocephalus meat poisoning on hepatic functions of Wistar rats. For this purpose, groups of rats (Lcr, Lcu+b and Lcu-b received diet supplemented with 10% of raw or cooked meat, respectively, with or without cooking water of L. lagocephalus while groups Mcr and Mcu+b received diet supplemented with 10% of raw or cooked meat of Liza aurata, which were used as a negative control. In Lcu+b group, ALT, AST and ALP rates (hepatic enzyme markers decreased after two months of treatment, indicating liver damage. We also observed an increase of 54 and 65% of thiobarbituric acid reactive substances (TBARS in their livers respectively 48 hours and two months after treatment compared to controls. The catalase (CAT activity in group Lcu+b decreased (p < 0.05 after two periods of treatment, whereas metallothionein (MT level significantly increased and decreased, respectively after 48 hours and two months. In fact, in the histological analysis of the livers from Lcu+b treated group, we observed an increase in vacuolisation, necrosis, hepatocytes ballooning and sinusoids dilation. These results indicate that L. lagocephalus meat cooked with water produces hepatotoxicity and oxidative damage.

  2. Protective effects of pterostilbene against acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    El-Sayed, El-Sayed M; Mansour, Ahmed M; Nady, Mohamed E

    2015-01-01

    The present study was undertaken to evaluate the protective effect of pterostilbene against acetaminophen-induced hepatotoxicity. Silymarin was used as a standard hepatoprotective agent. A single dose of acetaminophen (800 mg/kg i.p.), injected to male rats, caused significant increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, total cholesterol, triglycerides, tumor necrosis factor alpha, and hepatic contents of malondialdehyde, nitric oxide, caspase-3, hydroxyproline, with significant decreases in serum HDL-cholesterol, total proteins, albumin, and hepatic activities of reduced glutathione, superoxide dismutase and catalase as compared with the control group. On the other hand, administration of each of pterostilbene (50 mg/kg, p.o.) and silymarin (100 mg/kg, p.o.) for 15 days before acetaminophen ameliorated liver function and oxidative stress parameters. Histopathological evidence confirmed the protection offered by pterostilbene from the tissue damage caused by acetaminophen. In conclusion, pterostilbene possesses multimechanistic hepatoprotective activity that can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.

  3. Ameliorative effect of Leucas cephalotes extract on isoniazid and rifampicin induced hepatotoxicity

    Institute of Scientific and Technical Information of China (English)

    Bhini Bais; Payal Saiju

    2014-01-01

    Objective:To investigate ameliorative effect of alcoholic extract of whole herb of Lucas cephalotes (L. cephalotes) on isoniazid and rifampicin induced hepatotoxicity. Methods: Hepatoprotective potential of alcoholic extract of L. cephalotes was ascertained at 200 mg/kg and 400 mg/kg in Sprague Dawley rats. Animals were intoxicated with isoniazid and rifampicin (100 mg/kg each, i.p.) for 21 d. Assessment was done on the basis of liver function test (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase and bilirubin);effect on enzymes involved in oxidative stress (lipid peroxidase, superoxide dismutase, glutathione and catalase) and histology of liver were assessed as well. Comparison among different treatment group was done using One way ANOVA followed by Benferroni’s t test. Results: It was observed that at both of the selected doses extract exhibited significant ameliorative effect. In animals treated with the extract at both doses, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, bilirubin and lipid peroxidase level was found to be significantly less (P Conclusions:From the present study it can be concluded that alcoholic extract of L. cephalotes possesses significant hepatoprotective potential against isoniazid and rifampicin induced heptoxicity.

  4. Protective effect of Genistein against N-nitrosodiethylamine (NDEA)-induced hepatotoxicity in Swiss albino rats

    Institute of Scientific and Technical Information of China (English)

    Fahad Ali; Rahul; Falaq Naz; Smita Jyoti; Yasir Hasan Siddique

    2015-01-01

    In the present study, we studied the effect of Genistein against the hepatotoxicity induced by N-nitrosodiethylamine (NDEA). NDEA is present in almost all kinds of food stuff and has been reported to be a hepatocarcinogen. The male rats were exposed to NDEA (0.1 mg/mL) dissolved in drinking water separately and along with 25, 50, 100 mg/mL of Genistein for 21 days. The activities of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were measured in blood serum. Lipid peroxidation, protein carbonyl content, micronucleus frequency and DNA damage (Comet assay) were performed on rat hepatocytes. The results of the study reveal that the treatment of NDEA along with Genistein showed a significant dose-dependent decrease in the levels of blood serum enzymes i.e., SGOT, SGPT, ALP and LDH (Po0.05). The HE staining of histological sections of the liver also revealed a protective effect of Genistein. A significant dose-dependent reduction in the lipid peroxidation and protein carbonyl content was observed in rats exposed to NDEA (0.1 mg/mL) along with Genistein (Po0.05). The results obtained for the comet assay in rat hepatocytes showed a significant dose-dependent decrease in the mean tail length (Po0.05). Thus the present study supports the hepatoprotective role of Genistein.

  5. In Vitro Antioxidant Activity and Hepatoprotective Effects of Lentinula edodes against Paracetamol-Induced Hepatotoxicity

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    Sreenivasan Sasidharan

    2010-06-01

    Full Text Available Background: The objective of this study was to investigate the antioxidant and hepatoprotective effects of methanolic extracts of L. edodes and the determination of their total phenolics content. Results: The amount of total phenolics was estimated to be 70.83 mg Gallic Acid Equivalent (GAE per gram of dry extract. The antioxidant activity of the L. edodes extract was 39.0% at a concentration of 1 mg/mL and was also concentration dependant, with an EC50 value of 4.4 mg/mL. Different groups of animals (Wister albino mice were administered paracetamol (1 g/kg, p.o.. L. edodes extract at a dose of 200 mg/kg was administered to the paracetamol treated mice for seven days. The effects of L. edodes extract on serum transaminases (SGOT, SGPT, alkaline phosphatase (ALP and bilirubin were measured in the paracetamol-induced hepatotoxic mice. L. edodes extract produced significant (p < 0.05 hepatoprotective effects by decreasing the activity of serum enzymes and bilirubin. Conclusions: From these results, it was suggested that L. edodes extract could perhaps protect liver cells from paracetamol-induced liver damage by its antioxidative effect on hepatocytes, hence diminishing or eliminating the harmful effects of toxic metabolites of paracetamol.

  6. Anti-proliferative activities of sinigrin on carcinogen-induced hepatotoxicity in rats.

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    Jie, Meng; Cheung, Wan Man; Yu, Vivian; Zhou, Yanling; Tong, Pak Ho; Ho, John W S

    2014-01-01

    Liver cancer is one of the leading causes of cancer death worldwide. A very high incidence of new liver cancer cases is diagnosed every year, and metastasis has been found to correlate to poor prognoses in humans. Better treatments for liver cancer are thus clearly needed. Sinigrin is one of the major ingredients present in Brassica nigra, which has been used in combination with other herbs for treatment of various diseases. The anti-proliferative activities of sinigrin were studied in a model of carcinogen-induced hepatotoxicity in rats. Rats were orally administered with sinigrin on a daily basis for three months before sacrifice. Sinigrin was found to significantly inhibit the proliferation of liver tumor cells; the number of surface tumors in the rat liver was dramatically reduced. Sinigrin induced apoptosis of liver cancer cells through up-regulation of p53 and down-regulation of Bcl-2 family members and caspases. Our findings indicated that the liver functions were gradually restored after treatment with sinigrin and that the agent did not cause liver toxicity. Cell cycle analysis indicated that sinigrin caused cell cycle arrest in G0/G1 phase. The results suggest that sinigrin exerts important anti-proliferative activities in carcinogen-induced hepatocarcinogenesis in rats, and highlight the potential of sinigrin as an anti-cancer agent for liver cancer.

  7. Anti-hepatotoxic potential of Hedyotis corymbosa against D-galactosamine-induced hepatopathy in experimental rodents

    Institute of Scientific and Technical Information of China (English)

    Ramesh Kr Gupta; Rajnish Kr Singh; Sudhansu Ranjan Swain; Talib Hussain; Chandana Venkateswara Rao

    2012-01-01

    Objective: To evaluate hepatoprotective potential of the methanolic extract of Hedyotis corymbosa against D-galactosamine-induced hepatopathy in experimental animals. Methods: In the present study, in- vivo hepatoprotective effect of 50% methanolic extract of Hedyotis corymbosa (HCE, 100 and 200 mg/kg body weight) was evaluated using experimental models D-Galactosamine (D-GalN) (200 mg/kg, body weight i.p.) induced hepatotoxicity in experimental animals. The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatise (ALP), γ-glutamyl transferase (γ-GT) and total bilirubin. Meanwhile, in vivo antioxidant activities as lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were screened along with histopathological studies. Results: Obtained results demonstrated that the treatment with HCE signi-cantly (P<0.05-P<0.001) and dose-dependently prevented chemically induced increase in serum levels of hepatic enzymes. Furthermore, HCE signi-cantly (up to P<0.001) reduced the lipid peroxidation in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and catalase towards normal levels. Histopathology of the liver tissue showed that HCE attenuated the hepatocellular necrosis and led to reduction of in ammatory cells in-ltration. Conclusions: The results of this study strongly indicate the protective effect of HCE against acute liver injury which may be attributed to its hepatoprotective activity, and there by scienti-cally support its traditional use.

  8. Enhanced hepatotoxicity induced by repeated exposure to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin in combination in male rats

    Institute of Scientific and Technical Information of China (English)

    Yimei Wang; Chunfeng Lu; Zhiguo Sheng; Gang Liu; Ze Fu; Benzhan Zhu; Shuangqing Peng

    2011-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are among persistent polyhalogenated aromatic hydrocarbons that exist as complex mixtures in the environment worldwide. The present study was attempted to investigate the hepatotoxicity following repeated exposure to TCDD and PCBs in combination in male rats, and to reveal the involvement of potential mechanisms. Male Sprague-Dawley rats were exposed to TCDD (10 μg/kg) and Aroclor 1254 (10 mg/kg, a representative mixture of PCBs) alone or in combination by intragastric administration. After 12-day exposure, all treatments produced significant hepatotoxicity as characterized by changes of plasma biochemistry and histopathological changes. These effects were more prominent in the combined group. Furthermore, all treatments induced hepatic cytochrome P450 1A1 (CYP1A1) expression, and the maximal level of CYP1A1 expression was observed in the combined group, as in the case of the most severe hepatotoxicity evoked by the combined exposure.These findings indicated that the hepatotoxicity induced by TCDD and Aroclor 1254 might be ascribed to the high expression of hepatic CYP1A1. The present study demonstrates the enhanced hepatotoxicity after exposure to TCDD and PCBs in combination in rats.

  9. [Investigation of Predisposition Biomarkers to Identify Risk Factors for Drug-induced Liver Injury in Humans: Analyses of Endogenous Metabolites in an Animal Model Mimicking Human Responders to APAP-induced Hepatotoxicity].

    Science.gov (United States)

    Kobayashi, Akio; Kondo, Kazuma; Sugai, Shoichiro

    2015-01-01

    Drug-induced liver injury is a main reason of regulatory action pertaining to drugs, including restrictions to clinical indications and withdrawal from the marketplace. Acetaminophen (APAP) is a commonly used and effective analgesic/antipyretic agent and relatively safe drug even in long-term treatment. However, it is known that APAP at therapeutic doses may cause hepatotoxicity in some individuals. Hence great efforts have been made to identify risk factors for APAP-induced chronic hepatotoxicity. We investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model. We employed daytime restricted fed (RF) rats as a modified-nutritional state model for human APAP-induced hepatotoxicity. RF and ad libitum fed (ALF) rats were given APAP at 0, 300, and 500 mg/kg for 3 months. Plasma and urinary glutathione-related metabolomes and liver function parameters were measured during the dosing period. Endogenous metabolites forming at different levels between the RF and ALF rats could be potential predisposition biomarkers for APAP-induced hepatotoxicity. In addition, RF rats were considered a useful model to estimate the contribution of nutritional state of patients to APAP-induced chronic hepatotoxicity. In this article we report our current research focusing on nutritional state as risk factor for APAP-induced chronic hepatotoxicity and our findings of hepatotoxicity biomarkers.

  10. Human Upcyte Hepatocytes: Characterization of the Hepatic Phenotype and Evaluation for Acute and Long-Term Hepatotoxicity Routine Testing.

    Science.gov (United States)

    Tolosa, Laia; Gómez-Lechón, M José; López, Silvia; Guzmán, Carla; Castell, José V; Donato, M Teresa; Jover, Ramiro

    2016-07-01

    The capacity of human hepatic cell-based models to predict hepatotoxicity depends on the functional performance of cells. The major limitations of human hepatocytes include the scarce availability and rapid loss of the hepatic phenotype. Hepatoma cells are readily available and easy to handle, but are metabolically poor compared with hepatocytes. Recently developed human upcyte hepatocytes offer the advantage of combining many features of primary hepatocytes with the unlimited availability of hepatoma cells. We analyzed the phenotype of upcyte hepatocytes comparatively with HepG2 cells and adult primary human hepatocytes to characterize their functional features as a differentiated hepatic cell model. The transcriptomic analysis of liver characteristic genes confirmed that the upcyte hepatocytes expression profile comes closer to human hepatocytes than HepG2 cells. CYP activities were measurable and showed a similar response to prototypical CYP inducers than primary human hepatocytes. Upcyte hepatocytes also retained conjugating activities and key hepatic functions, e.g. albumin, urea, lipid and glycogen synthesis, at levels close to hepatocytes. We also investigated the suitability of this cell model for preclinical hepatotoxicity risk assessments using multiparametric high-content screening, as well as transcriptomics and targeted metabolomic analysis. Compounds with well-documented in vivo hepatotoxicity were screened after acute and repeated doses up to 1 week. The evaluation of complex mechanisms of cell toxicity, drug-induced steatosis and oxidative stress biomarkers demonstrated that, by combining the phenotype of primary human hepatocytes and the ease of handling of HepG2 cells, upcyte hepatocytes offer suitable properties to be potentially used for toxicological assessments during drug development.

  11. The Protective Effect of Liquorice Plant Extract on CCl4-Induced Hepatotoxicity in Common Carp (Cyprinus carpio

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    Hassan Malekinejad

    2010-12-01

    Full Text Available The protective effect of liquorice plant extract (LPE on CCl4-induced hepatotoxicity in common carp was evaluated using fifty adult carps. The fish were cultured in a standard environment in terms of water flow rate, oxygen, pH, food and temperature. The fish were assigned into 5 groups (N = 10 as control, sham, and tests. The test groups were pre-treated for 3 h with various concentrations of LPE, 3 days before CCl4 exposure. The control and sham groups received normal saline before and after CCl4 exposure. To induce hepatotoxicity, animals in the sham and test groups were exposed against 100 l L-1 CCl4 for 45 min. The fish in all groups 1 h after CCl4 exposure were anesthetized and the blood samples were collected. Immediately the liver specimens were dissected out and were stored in 10 % formalin for further pathological studies. Determination of serum level of ALP and SGOT revealed that acute form of CCl4 exposure elevated significantly (P < 0.05 the serum level of either tested hepatic marker enzymes. While 3 days pretreatment with LPE prevented from ALP and SGOT enhancement. The pathological evaluation revealed that the CCl4 exposure resulted in a minor pathologic manifestation such as slight congestion, which the LPE pretreated groups showed the remarkable improvement. The anti-oxidant capacity of LPE was assayed by FRAP and DPPH methods. Both provided techniques showed that LPE exerts an excellent anti-oxidant effect. This data suggest that LPE exerts protective effect against CCl4-induced hepatotoxicity. Moreover, the hepatoprotective effect of LPE may attribute to its antioxidant capacity.

  12. A comprehensive study of the association between drug hepatotoxicity and daily dose, liver metabolism, and lipophilicity using 975 oral medications.

    Science.gov (United States)

    Weng, Zuquan; Wang, Kejian; Li, Haibo; Shi, Qiang

    2015-07-10

    It was recently suggested that daily dose, liver metabolism and lipophilicity were associated with an oral drug's potential to cause hepatotoxicity, but this has not been widely accepted. A likely reason is that published data lack comprehensiveness, as they were based on only about one third of all FDA approved single-active-ingredient oral prescription drugs. Here the 975 oral drugs used worldwide which have a Defined Daily Dose (DDD) designated in the World Health Organization's Anatomical Therapeutic Chemical classification system and whose hADRs potential and metabolism data are available in the Micromedex Drugdex® compendium were studied, with their lipophilicity calculated by the partition coefficient LogP. Of the 975 drugs examined, 49% (478) have the potential to induce at least one type of hepatic adverse drug reactions (hADRs) such as fatal hepatotoxicity, acute liver failure, significant ALT/AST elevation, hepatitis, and jaundice. By single factor analysis, a higher DDD (≥100 mg) was found to be associated with all types of hADRs, and extensive liver metabolism (≥50%) was associated with a subset of hADRs including fatal hADRs, hepatitis and jaundice, while LogP showed no relation to any types of hADRs. Contrary to previous reports, none of the combination, neither DDD and liver metabolism, nor DDD and LogP, was found to be more predictive of hADRs than using DDD or liver metabolism alone. These data provide convincing evidence that a higher daily dose and extensive liver metabolism, but not lipophilicity, are independent but not synergistic risk factors for oral drugs to induce hepatotoxicity.

  13. Protective activities of the aqueous root extract of Harungana madagascariensis in acute and repeated acetaminophen hepatotoxic rats

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    Adeneye AA

    2008-09-01

    Full Text Available In this study, the protective effects of 100 – 500 mg/kg/day of the aqueous root extract of Harungana madagascariensisLam. ex Poir were evaluated on the average body weight, relative liver-body weight, serum alanine (ALT and aspartateaminotransferases (AST, alkaline phosphatase (ALP, total (TB and conjugated bilirubin (CB, triglycerides (TG, total cholesterol(TC, cholesterol fractions (HDL-c, LDL-c, VLDL-c, fasting blood glucose (FBG, total protein (TP and albumin (ALB in the acuteand repeated dose acetaminophen hepatotoxic rats. Results showed that acute intraperitoneal injection of 800 mg/kg of acetaminopheninduced significant (p0.05 alterations in the serum levels oflipids, TB and CB. However, pretreatments with 100 - 500 mg/kg of Harungana madagascariensis significantly (p0.05 alterations in the serum lipids.Repeated acetaminophen hepatotoxicity caused similar effects in the measured parameters except that it was associated withsignificant (p<0.001 reduction in the FBG while inducing significant (p<0.05, p<0.001 increases in the serum TB and CB. Oralpretreatments with the extract significantly (p<0.001 enhanced acetaminophen induced hypoglycemia while significantly (p<0.05,p<0.01 attenuating significant elevations in the serum levels of TB and CB, in dose related fashion. The associated histopathologicfeatures of moderate-to-severe hepatic necrosis were also attenuated by the extract. Thus, the overall results of this study confirm thefolkloric use of the extract in the treatment of drug-induced hepatotoxicity.

  14. Anti-inflammatory effects and hepatotoxicity of Tripterygium-loaded solid lipid nanoparticles on adjuvant-induced arthritis in rats.

    Science.gov (United States)

    Xue, Mei; Jiang, Zhen-zhou; Wu, Tao; Li, Ji; Zhang, Liang; Zhao, Yan; Li, Xue-jun; Zhang, Lu-Yong; Yang, Shu-yu

    2012-08-15

    Tripterygium wilfordii Hook f. (TWHF) has been demonstrated to have anti-inflammatory, immunosuppressive effects and its clinical use was restricted to some extent due to some toxic effects on the digestive, urogenital, and blood circulatory systems, especially the male reproductive system. In the previous study, we had confirmed that TWHF-loaded solid lipid nanoparticles (SLN) have protective effects on male reproductive toxicity in rats. Anti-inflammatory effects and hepatotoxicity of TWHF-SLN remain to be unidentified. The present study was focused on the anti-inflammatory effect of complete Freund's adjuvant-induced arthritis in rats treated with TWHF-SLN as well as the effects of SLN delivery system on decreasing the hepatotoxicity induced by tripterygium. Sixty-four healthy male rats were randomly divided into eight groups with eight rats each. From day 18 after FCA injection, TWHF-SLN group (120, 60, 30 mg/kg) and TWHF group (120, 60, 30 mg/kg) were administered by oral gavage for 24 consecutive days. The control group was with saline and model control group was without any treatment. The volume of the right hind paws was evaluated at 0, 4, 8, 12, 18, 24, 30, 36 and 42 days post-injection of FCA by a home-made connected device. The serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total bilirubin (TBIL) and albumin (ALB) levels were evaluated by an autoanalyzer. Activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) malondialdehyde (MDA) and xanthine oxidase (XOD) levels were determined using commercial kits. The PG level in sera was examined by double antibody sandwich method. Tissue histopathology was evaluated with hematoxylin and eosin (H&E). The results show that TWHF-SLN can significantly reduce rat paw volume at 60 mg/kg (pinduced hepatotoxicity.

  15. Construction and analysis of a human hepatotoxicity database suitable for QSAR modeling using post-market safety data.

    Science.gov (United States)

    Zhu, Xiao; Kruhlak, Naomi L

    2014-07-01

    Drug-induced liver injury (DILI) is one of the most common drug-induced adverse events (AEs) leading to life-threatening conditions such as acute liver failure. It has also been recognized as the single most common cause of safety-related post-market withdrawals or warnings. Efforts to develop new predictive methods to assess the likelihood of a drug being a hepatotoxicant have been challenging due to the complexity and idiosyncrasy of clinical manifestations of DILI. The FDA adverse event reporting system (AERS) contains post-market data that depict the morbidity of AEs. Here, we developed a scalable approach to construct a hepatotoxicity database using post-market data for the purpose of quantitative structure-activity relationship (QSAR) modeling. A set of 2029 unique and modelable drug entities with 13,555 drug-AE combinations was extracted from the AERS database using 37 hepatotoxicity-related query preferred terms (PTs). In order to determine the optimal classification scheme to partition positive from negative drugs, a manually-curated DILI calibration set composed of 105 negatives and 177 positives was developed based on the published literature. The final classification scheme combines hepatotoxicity-related PT data with supporting information that optimize the predictive performance across the calibration set. Data for other toxicological endpoints related to liver injury such as liver enzyme abnormalities, cholestasis, and bile duct disorders, were also extracted and classified. Collectively, these datasets can be used to generate a battery of QSAR models that assess a drug's potential to cause DILI.

  16. Zebrafish larva as a reliable model for in vivo assessment of membrane remodeling involvement in the hepatotoxicity of chemical agents.

    Science.gov (United States)

    Podechard, Normand; Chevanne, Martine; Fernier, Morgane; Tête, Arnaud; Collin, Aurore; Cassio, Doris; Kah, Olivier; Lagadic-Gossmann, Dominique; Sergent, Odile

    2016-11-28

    The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases. Copyright © 2016 John Wiley & Sons, Ltd.

  17. P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice.

    Science.gov (United States)

    Hoque, Rafaz; Sohail, Muhammed Adnan; Salhanick, Steven; Malik, Ahsan F; Ghani, Ayaz; Robson, Simon C; Mehal, Wajahat Z

    2012-05-15

    Inflammation contributes to liver injury in acetaminophen (APAP) hepatotoxicity in mice and is triggered by stimulation of immune cells. The purinergic receptor P2X7 is upstream of the nod-like receptor family, pryin domain containing-3 (NLRP3) inflammasome in immune cells and is activated by ATP and NAD that serve as damage-associated molecular patterns. APAP hepatotoxicity was assessed in mice genetically deficient in P2X7, the key inflammatory receptor for nucleotides (P2X7-/-), and in wild-type mice. P2X7-/- mice had significantly decreased APAP-induced liver necrosis. In addition, APAP-poisoned mice were treated with the specific P2X7 antagonist A438079 or etheno-NAD, a competitive antagonist of NAD. Pre- or posttreatment with A438079 significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury in wild-type but not P2X7-/- mice. Pretreatment with etheno-NAD also significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury. In addition, APAP toxicity in mice lacking the plasma membrane ecto-NTPDase CD39 (CD39-/-) that metabolizes ATP was examined in parallel with the use of soluble apyrase to deplete extracellular ATP in wild-type mice. CD39-/- mice had increased APAP-induced hemorrhage and mortality, whereas apyrase also decreased APAP-induced mortality. Kupffer cells were treated with extracellular ATP to assess P2X7-dependent inflammasome activation. P2X7 was required for ATP-stimulated IL-1β release. In conclusion, P2X7 and exposure to the ligands ATP and NAD are required for manifestations of APAP-induced hepatotoxicity.

  18. Does pregnancy increase the risk of ART-induced hepatotoxicity among HIV-positive women?

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    Susie Huntington

    2014-11-01

    Full Text Available Introduction: High rates of hepatotoxicity have been observed among HIV-positive pregnant women using antiretroviral therapy (ART. However, the extent to which pregnancy affects the risk of ART-induced hepatotoxicity is unclear since studies in this area have generated conflicting results. Material and Methods: Combined data from the UK Collaborative HIV Cohort (UK CHIC study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC were used. Alanine aminotransferase (ALT data were assessed according to the Division of AIDS toxicity guidelines to identify factors associated with liver enzyme elevation (LEE (grade 1–4. Women starting ART in 2000–11 aged 16–49 years were included irrespective of pregnancy status at ART start. Cox proportional hazards were used to assess the associations between fixed (ethnicity, exposure group, HBV/HCV co-infection, prior ART use, and age, year, pregnancy status, viral load and CD4 count at ART start and time-dependent covariates (pregnancy status, age, year, CD4 count, viral load, duration on ART and the risk of LEE. Results: Of the 3426 women included, one-quarter (25.0%, n=857 were pregnant during follow-up and 14.4% (n=492 started ART during pregnancy. The rate of LEE was 15/100 person-years (PY during pregnancy and 6.1/100 PY outside pregnancy. The risk of LEE was increased during pregnancy (adjusted hazard ratio (aHR 1.61 [1.26–2.06], p<0.001, including in secondary analysis excluding 493 women pregnant when starting ART. Other factors independently associated with LEE were lower CD4 count (<250 cells/mm3 vs. 251–350 cells/mm3 aHR 1.25 [1.02–1.54], p=0.03, HBV/HCV co-infection (aHR 1.94 [1.58–2.39], p<0.001, HIV acquired via injecting drug use (aHR 1.61 [1.15–2.24], p=0.01 vs. heterosexually and calendar year (aHR 1.05 [1.02–1.08], p<0.001 per one year increase. Three ART drugs were associated with increased risk of LEE (efavirenz aHR 1.27 [1.06–1.50], p-value 0

  19. Mercury-induced hepatotoxicity in zebrafish: in vivo mechanistic insights from transcriptome analysis, phenotype anchoring and targeted gene expression validation

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    Mathavan Sinnakaruppan

    2010-03-01

    Full Text Available Abstract Background Mercury is a prominent environmental contaminant that causes detrimental effects to human health. Although the liver has been known to be a main target organ, there is limited information on in vivo molecular mechanism of mercury-induced toxicity in the liver. By using transcriptome analysis, phenotypic anchoring and validation of targeted gene expression in zebrafish, mercury-induced hepatotoxicity was investigated and a number of perturbed cellular processes were identified and compared with those captured in the in vitro human cell line studies. Results Hepato-transcriptome analysis of mercury-exposed zebrafish revealed that the earliest deregulated genes were associated with electron transport chain, mitochondrial fatty acid beta-oxidation, nuclear receptor signaling and apoptotic pathway, followed by complement system and proteasome pathway, and thereafter DNA damage, hypoxia, Wnt signaling, fatty acid synthesis, gluconeogenesis, cell cycle and motility. Comparative meta-analysis of microarray data between zebrafish liver and human HepG2 cells exposed to mercury identified some common toxicological effects of mercury-induced hepatotoxicity in both models. Histological analyses of liver from mercury-exposed fish revealed morphological changes of liver parenchyma, decreased nucleated cell count, increased lipid vesicles, glycogen and apoptotic bodies, thus providing phenotypic evidence for anchoring of the transcriptome analysis. Validation of targeted gene expression confirmed deregulated gene-pathways from enrichment analysis. Some of these genes responding to low concentrations of mercury may serve as toxicogenomic-based markers for detection and health risk assessment of environmental mercury contaminations. Conclusion Mercury-induced hepatotoxicity was triggered by oxidative stresses, intrinsic apoptotic pathway, deregulation of nuclear receptor and kinase activities including Gsk3 that deregulates Wnt signaling

  20. Analysis of changes in hepatic gene expression in a murine model of tolerance to acetaminophen hepatotoxicity (autoprotection)

    Energy Technology Data Exchange (ETDEWEB)

    O' Connor, Meeghan A., E-mail: meeghan.oconnor@boehringer-ingelheim.com [Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States); Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368 (United States); Koza-Taylor, Petra, E-mail: petra.h.koza-taylor@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Campion, Sarah N., E-mail: sarah.campion@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Aleksunes, Lauren M., E-mail: aleksunes@eohsi.rutgers.edu [Rutgers University, Department of Pharmacology and Toxicology, Environmental and Occupational Health Sciences Institute, Piscataway, NJ 08854 (United States); Gu, Xinsheng, E-mail: xinsheng.gu@uconn.edu [Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States); Enayetallah, Ahmed E., E-mail: ahmed.enayetallah@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Lawton, Michael P., E-mail: michael.lawton@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Manautou, José E., E-mail: jose.manautou@uconn.edu [Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States)

    2014-01-01

    Pretreatment of mice with a low hepatotoxic dose of acetaminophen (APAP) results in resistance to a subsequent, higher dose of APAP. This mouse model, termed APAP autoprotection was used here to identify differentially expressed genes and cellular pathways that could contribute to this development of resistance to hepatotoxicity. Male C57BL/6J mice were pretreated with APAP (400 mg/kg) and then challenged 48 h later with 600 mg APAP/kg. Livers were obtained 4 or 24 h later and total hepatic RNA was isolated and hybridized to Affymetrix Mouse Genome MU430{sub 2} GeneChip. Statistically significant genes were determined and gene expression changes were also interrogated using the Causal Reasoning Engine (CRE). Extensive literature review narrowed our focus to methionine adenosyl transferase-1 alpha (MAT1A), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), flavin-containing monooxygenase 3 (Fmo3) and galectin-3 (Lgals3). Down-regulation of MAT1A could lead to decreases in S-adenosylmethionine (SAMe), which is known to protect against APAP toxicity. Nrf2 activation is expected to play a role in protective adaptation. Up-regulation of Lgals3, one of the genes supporting the Nrf2 hypothesis, can lead to suppression of apoptosis and reduced mitochondrial dysfunction. Fmo3 induction suggests the involvement of an enzyme not known to metabolize APAP in the development of tolerance to APAP toxicity. Subsequent quantitative RT-PCR and immunochemical analysis confirmed the differential expression of some of these genes in the APAP autoprotection model. In conclusion, our genomics strategy identified cellular pathways that might further explain the molecular basis for APAP autoprotection. - Highlights: • Differential expression of genes in mice resistant to acetaminophen hepatotoxicity. • Increased gene expression of Flavin-containing monooxygenase 3 and Galectin-3. • Decrease in MAT1A expression and compensatory hepatocellular regeneration. • Two distinct gene

  1. Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice.

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    Jing-Dun Xie

    Full Text Available Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC. Aspartate transaminase (AST, alanine aminotransferase (ALT, and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl-3,5-diphenylformazan (MTT, and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2 of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided.

  2. Comparison of hepatotoxicity and metabolism of butyltin compounds in the liver of mice, rats and guinea pigs

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    Ueno, Shunji; Kashimoto, Takashige; Susa, Nobuyuki; Ishii, Masamitsu; Chiba, Toshikazu [Laboratory of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Mutoh, Ken-ichiro [Laboratory of Veterinary Anatomy, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Hoshi, Fumio [Laboratory of Veterinary Anatomy, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Suzuki, Takashi [Laboratory of Environmental Health and Toxicology, Kyoto Prefectural University, Hangi-cho, Shimogamo, Sakyo-ku, 606-5822, Kyoto (Japan); Sugiyama, Masayasu [Sugiyama Pharmacy, 1335-1 Shimotama, Tamagawa-cho, 759-3112, Yamaguchi (Japan)

    2003