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Sample records for bilirubin udp-glucuronosyltransferase 1a1

  1. Bilirubin UDP-Glucuronosyltransferase 1A1 (UGT1A1) Gene Promoter Polymorphisms and HPRT, Glycophorin A, and Micronuclei Mutant Frequencies in Human Blood

    Energy Technology Data Exchange (ETDEWEB)

    Grant, D; Hall, I J; Eastmond, D; Jones, I M; Bell, D A

    2004-10-06

    A dinucleotide repeat polymorphism (5-, 6-, 7-, or 8-TA units) has been identified within the promoter region of UDP-glucuronosyltransferase 1A1 gene (UGT1A1). The 7-TA repeat allele has been associated with elevated serum bilirubin levels that cause a mild hyperbilirubinemia (Gilbert's syndrome). Studies suggest that promoter transcriptional activity of UGT1A1 is inversely related to the number of TA repeats and that unconjugated bilirubin concentration increases directly with the number of TA repeat elements. Because bilirubin is a known antioxidant, we hypothesized that UGT1A1 repeats associated with higher bilirubin may be protective against oxidative damage. We examined the effect of UGT1A1 genotype on somatic mutant frequency in the hypoxanthine-guanine phosphoribosyl-transferase (HPRT) gene in human lymphocytes and the glycophorin A (GPA) gene of red blood cells (both N0, NN mutants), and the frequency of lymphocyte micronuclei (both kinetochore (K) positive or micronuclei K negative) in 101 healthy smoking and nonsmoking individuals. As hypothesized, genotypes containing 7-TA and 8-TA displayed marginally lower GPA{_}NN mutant frequency relative to 5/5, 5/6, 6/6 genotypes (p<0.05). In contrast, our analysis showed that lower expressing UGT1A1 alleles (7-TA and 8-TA) were associated with modestly increased HPRT mutation frequency (p<0.05) while the same low expression genotypes were not significantly associated with micronuclei frequencies (K-positive or K-negative) when compared to high expression genotypes (5-TA and 6-TA). We found weak evidence that UGT1A1 genotypes containing 7-TA and 8-TA were associated with increased GPA{_}N0 mutant frequency relative to 5/5, 5/6, 6/6 genotypes (p<0.05). These data suggest that UGT1A1 genotype may modulate somatic mutation of some types, in some cell lineages, by a mechanism not involving bilirubin antioxidant activity. More detailed studies examining UGT1A1 promoter variation, oxidant/antioxidant balance and

  2. Early modification of sickle cell disease clinical course by UDP-glucuronosyltransferase 1A1 gene promoter polymorphism

    OpenAIRE

    Martins, R.; Morais, A.; Dias, A; Soares, I; Rolão, C; Ducla-Soares, J; Braga, L.; Seixas, T.; Nunes, B.; Olim, G; Romão, L; Lavinha, J; Faustino, P

    2008-01-01

    Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinaemia and, in a subset of patients, cholelithiasis occurs. We investigated whether the (TA)n promoter polymorphism in the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) may modify bilirubin metabolism, influencing bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in a group of 153 young SCD patients (mean age 12.0 +/- 9.0 years) predominantly of Bantu beta S haplotype. ...

  3. Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity.

    Science.gov (United States)

    Hirashima, Rika; Michimae, Hirofumi; Takemoto, Hiroaki; Sasaki, Aya; Kobayashi, Yoshinori; Itoh, Tomoo; Tukey, Robert H; Fujiwara, Ryoichi

    2016-09-01

    Anticonvulsants can increase the risk of developing neurotoxicity in infants; however, the underlying mechanism has not been elucidated to date. Thyroxine [3,5,3',5'-l-tetraiodothyronine (T4)] plays crucial roles in the development of the central nervous system. In this study, we hypothesized that induction of UDP-glucuronosyltransferase 1A1 (UGT1A1)-an enzyme involved in the metabolism of T4-by anticonvulsants would reduce serum T4 levels and cause neurodevelopmental toxicity. Exposure of mice to phenytoin during both the prenatal and postnatal periods significantly induced UGT1A1 and decreased serum T4 levels on postnatal day 14. In the phenytoin-treated mice, the mRNA levels of synaptophysin and synapsin I in the hippocampus were lower than those in the control mice. The thickness of the external granule cell layer was greater in phenytoin-treated mice, indicating that induction of UGT1A1 during the perinatal period caused neurodevelopmental disorders. Exposure to phenytoin during only the postnatal period also caused these neurodevelopmental disorders. A T4 replacement attenuated the increase in thickness of the external granule cell layer, indicating that the reduced T4 was specifically associated with the phenytoin-induced neurodevelopmental disorder. In addition, these neurodevelopmental disorders were also found in the carbamazepine- and pregnenolone-16-α-carbonitrile-treated mice. Our study is the first to indicate that UGT1A1 can control neurodevelopment by regulating serum T4 levels. PMID:27413119

  4. Gilbert's syndrome: High frequency of the (TA)7 TAA allele in India and its interaction with a novel CAT insertion in promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 gene

    Institute of Scientific and Technical Information of China (English)

    Shabana Farheen; Sanghamitra Sengupta; Amal Santra; Suparna Pal; Gopal Krishna Dhali; Meenakshi Chakravorty; Partha P Majumder; Abhijit Chowdhury

    2006-01-01

    AIM: To identify the variants in UDP-glucuronosyltransferase 1 (UGT1A1) gene in Gilbert's syndrome (GS) and to estimate the association between homozygosity for TA insertion and GS in India, as well as the frequency of TA insertion and its impact among normal controls in India.METHODS: Ninety-five GS cases and 95 normal controls were selected. Liver function and other tests were done. The promoter and all 5 exons of UGT1A1 gene were resequenced. Functional assessment of a novel trinucleotide insertion was done byin silico analysis and by estimating UGT1A1 promoter activity carried out by luciferase reporter assay of appropriate constructs in Hep G2 cell line.RESULTS: Among the GS patients, 80% were homozygous for the TA insertion, which was several-fold higher than reports from other ethnic groups. The mean UCB level was elevated among individuals with only one copy of this insertion, which was not significantly different from those with two copies. Many new DNA variants in UGT1A1 gene were discovered, including a trinucleotide (CAT) insertion in the promoter found in a subset (10%) of GS patients, but not among normal controls. In-silico analysis showed marked changes in the DNA-folding of the promoter and functional analysis showed a 20-fold reduction in transcription efficiency of UGT1A1 gene resulting from this insertion, thereby significantly elevating the UCB level.CONCLUSION: The genetic epidemiology of GS is variable across ethnic groups and the epistatic interactions among UGT1A1 promoter variants modulate bilirubin glucuronidation.

  5. Human UDP-Glucuronosyltransferase 1A1 is the Primary Enzyme Responsible for the N-glucuronidation of N-hydroxy-PhIP in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Malfatti, M A; Felton, J S

    2004-04-06

    UDP-Glucuronosyltransferase 1A proteins (UGT1A) catalyze the glucuronidation of many endogenous and xenobiotic compounds including heterocyclic amines and their hydroxylated metabolites (the main topic of this study). Studies have shown that in humans UGT1A mediated glucuronidation is an important pathway in the detoxification of food-borne carcinogenic heterocyclic amines. The biotransformation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most mass abundant heterocyclic amine found in cooked meats, is highly dependent on cytochrome P4501A2 hydroxylation followed by UGT catalyzed glucuronidation of the N-hydroxy-PhIP reactive intermediate. To determine which UGT1A proteins are involved in the glucuronidation of N-hydroxy-PhIP, microsomal preparations from baculovirus infected insect cells that express all of the known functional human UGT1A isozymes (UGT1A1, -1A3, -1A4, -1A6, -1A7, -1A8, -1A9, -1A10) were exposed to N-hydroxy-PhIP and the reaction products were isolated by HPLC. All UGT1A proteins except UGT1A6 showed some degree of activity towards N-hydroxy-PhIP. The formation of both N-hydroxy-PhIP-N{sup 2}-glucuronide and N-hydroxy-PhIP-N3-glucuronide was both time and substrate concentration dependent in all the microsomal incubations that showed appreciable activity. UGT1A1 was the most efficient in converting N-hydroxy-PhIP to both conjugates producing 5 times more of the N{sup 2}-conjugate than UGT1A4, the next active UGT, and 286 times more than UGT1A7, the least active UGT. With an apparent Km of 52 {micro}M and a K{sub cat} of 114 min-1, UGT1A1 was also the most catalytically efficient in forming N-hydroxy-PhIP-N{sup 2}-glucuronide. Catalytic constants for UGT1A4, UGT1A8 and UGT1A9 were 52 min-1, 35 min{sup -1} and 3.7 min{sup -1}, respectively. The catalytic efficiency for N-hydroxy-PhIP-N3-glucuronide formation was 8, 10, and 6 times lower for UGT1A1, -1A4, and -1A8, respectively, when compared to the k{sub cat} values for N

  6. The Effect of UDP-glucuronosyltransferase 1A1 Expression on the Mutagenicity and Metabolism of the Cooked-Food Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4-5,b]pyridine in CHO cells

    Energy Technology Data Exchange (ETDEWEB)

    Malfatti, M A; Wu, R W; Felton, J S

    2004-08-13

    UDP-glucuronosyltransferase proteins (UGT) catalyze the glucuronidation of both endogenous and xenobiotic compounds. In previous studies UGT1A1 has been implicated in the detoxification of certain food-borne-carcinogenic-heterocyclic amines. To determine the importance of UDP-glucuronosyltransferase 1A1 (UGT1A1) in the biotransformation of the cooked-food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), genetically modified CHO cells that are nucleotide excision repair-deficient, and express cytochrome P4501A2 (UV5P3 cell line) were transfected with a cDNA plasmid of human UGT1A1 to establish the UDPglucuronosyltransferase 1A1 expressing 5P3hUGT1A1 cell line. Expression of the UGT1A1 gene was verified by screening neogene expressing clonal isolates (G-418 resistant) for their sensitivity to cell killing from PhIP exposure. Five of eleven clones were chosen for further analysis due to their resistance to cell killing. Western blot analysis was used to confirm the presence of the UGT1A1 and CYP1A2 proteins. All five clones displayed a 52 kDa protein band, which corresponded to a UGT1A1 control protein. Only four of the clones had a protein band that corresponded to the CYP1A2 control protein. Correct fragment size of the cDNAs in the remaining 4 clones was confirmed by RT-PCR and quantification of the mRNA product was accomplished by real-time RT-PCR. Expression of UGT1A1 in the transfected cells was 10{sup 4}-10{sup 5} fold higher relative to the UV5P3 parental cells. One clone (No.14) had a 10 fold higher increase in expression at 1.47 x 10{sup 5} over the other three clones. This clone was also the most active in converting N-hydroxy-PhIP to N-hydroxy-PhIP glucuronide conjugates in microsomal metabolism assays. Based on the D{sub 50} values, the cytotoxic effect of PhIP was decreased {approx}350 fold in the 5P3hUGT1A1 cells compared to the UV5P3 control cells. In addition no significant increase in mutation frequency was observed in the

  7. Hepatic UDP-glucuronosyltransferase is responsible for eslicarbazepine glucuronidation.

    Science.gov (United States)

    Loureiro, Ana I; Fernandes-Lopes, Carlos; Bonifácio, Maria J; Wright, Lyndon C; Soares-da-Silva, Patricio

    2011-09-01

    Eslicarbazepine acetate (ESL) is a once-daily novel antiepileptic drug approved in Europe for use as adjunctive therapy for refractory partial-onset seizures with or without secondary generalization. Metabolism of ESL consists primarily of hydrolysis to eslicarbazepine, which is then subject to glucuronidation followed by renal excretion. In this study, we have identified that human liver microsomes (HLM) enriched with uridine 5'-diphosphoglucuronic acid give origin to a single Escherichia coli β-glucuronidase-sensitive eslicarbazepine glucuronide (most likely the O-glucuronide). The kinetics of eslicarbazepine glucuronidation in HLM was investigated in the presence and absence of bovine serum albumin (BSA). The apparent K(m) were 412.2 ± 63.8 and 349.7 ± 74.3 μM in the presence and absence of BSA, respectively. Incubations with recombinant human UDP glucuronosyltransferases (UGTs) indicated that UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 appear to be involved in eslicarbazepine conjugation. The UGT with the highest affinity for conjugation was UGT2B4 (K(m) = 157.0 ± 31.2 and 28.7 ± 10.1 μM, in the absence and presence of BSA, respectively). There was a significant correlation between eslicarbazepine glucuronidation and trifluoperazine glucuronidation, a typical UGT1A4 substrate; however, no correlation was found with typical substrates for UGT1A1 and UGT1A9. Diclofenac inhibited eslicarbazepine glucuronidation in HLM with an IC(50) value of 17 μM. In conclusion, glucuronidation of eslicarbazepine results from the contribution of UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17, but the high-affinity component of the UGT2B4 isozyme may play a major role at therapeutic plasma concentrations of unbound eslicarbazepine. PMID:21673130

  8. Efflux Transport Characterization of Resveratrol Glucuronides in UDP-Glucuronosyltransferase 1A1 Transfected HeLa Cells: Application of a Cellular Pharmacokinetic Model to Decipher the Contribution of Multidrug Resistance-Associated Protein 4.

    Science.gov (United States)

    Wang, Shuai; Li, Feng; Quan, Enxi; Dong, Dong; Wu, Baojian

    2016-04-01

    Resveratrol undergoes extensive metabolism to form biologically active glucuronides in humans. However, the transport mechanisms for resveratrol glucuronides are not fully established. Here, we aimed to characterize the efflux transport of resveratrol glucuronides using UGT1A1-overexpressing HeLa cells (HeLa1A1 cells), and to determine the contribution of multidrug resistance-associated protein (MRP) 4 to cellular excretion of the glucuronides. Two glucuronide isomers [i.e., resveratrol 3-O-glucuronide (R3G) and resveratrol 4'-O-glucuronide (R4'G)] were excreted into the extracellular compartment after incubation of resveratrol (1-100 μM) with HeLa1A1 cells. The excretion rate was linearly related to the level of intracellular glucuronide, indicating that glucuronide efflux was a nonsaturable process. MK-571 (a dual inhibitor of UGT1A1 and MRPs) significantly decreased the excretion rates of R3G and R4'G while increasing their intracellular levels. Likewise, short-hairpin RNA (shRNA)-mediated silencing of MRP4 caused a significant reduction in glucuronide excretion but an elevation in glucuronide accumulation. Furthermore, β-glucuronidase expressed in the cells catalyzed the hydrolysis of the glucuronides back to the parent compound. A cellular pharmacokinetic model integrating resveratrol transport/metabolism with glucuronide hydrolysis/excretion was well fitted to the experimental data, allowing derivation of the efflux rate constant values in the absence or presence of shRNA targeting MRP4. It was found that a large percentage of glucuronide excretion (43%-46%) was attributed to MRP4. In conclusion, MRP4 participated in cellular excretion of R3G and R4'G. Integration of mechanistic pharmacokinetic modeling with transporter knockdown was a useful method to derive the contribution percentage of an exporter to overall glucuronide excretion. PMID:26758854

  9. Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity

    OpenAIRE

    Basu, Nikhil K.; Kovarova, Martina; Garza, Amanda; Kubota, Shigeki; Saha, Tapas; Mitra, Partha S.; Banerjee, Rajat; Rivera, Juan; Owens, Ida S.

    2005-01-01

    UDP-glucuronosyltransferase (UGT) isozymes catalyze detoxification of numerous chemical toxins present in our daily diet and environment by conjugation to glucuronic acid. The special properties and enzymatic mechanism(s) that enable endoplasmic reticulum-bound UGT isozymes to convert innumerable structurally diverse lipophiles to excretable glucuronides are unknown. Inhibition of cellular UGT1A7 and UGT1A10 activities and of [33P]orthophosphate incorporation into immunoprecipitable proteins ...

  10. Interaction between oblongifolin C and UDP-glucuronosyltransferase isoforms in human liver and intestine microsomes.

    Science.gov (United States)

    Gao, Cui; Shi, Rong; Wang, Tianming; Tan, Hongsheng; Xu, Hongxi; Ma, Yueming

    2015-01-01

    1. Oblongifolin C (OC) is a potential natural anticancer candidate, and its metabolic profile has not yet been established. 2. One major OC glucuronidation metabolite (OCG) has been identified in a pool of human liver microsomes (HLMs). Chemical inhibition experiments suggested that OCG was mainly formed by UGT1A. A screen of recombinant UDP-glucuronosyltransferase isoforms (UGTs) indicated that UGT1A1 primarily mediates OC conjugation, with minor contributions from UGT1A3 and UGT1A8. Enzyme kinetic studies showed that UGT1A1 was the main UGT isoform involved in OCG in HLMs. 3. Further investigation suggested that OC is a broad inhibitor of UGTs. Additionally, OC competitively inhibited UGT1A6 with a Ki value of 3.49 ± 0.57 μM, whereas non-competitively inhibited UGT1A10 with a Ki value of 2.12 ± 0.18 μM. 4. Understanding the interaction between OC and UGTs will greatly contribute to future investigations regarding the inter-individual differences in OC metabolism in clinical trials and potential drug-drug interactions. PMID:25714435

  11. Potential Cardiovascular Risk Protection of Bilirubin in End-Stage Renal Disease Patients under Hemodialysis

    OpenAIRE

    Maria do Sameiro-Faria; Michaela Kohlova; Sandra Ribeiro; Petronila Rocha-Pereira; Laetitia Teixeira; Henrique Nascimento; Flávio Reis; Vasco Miranda; Elsa Bronze-da-Rocha; Alexandre Quintanilha; Luís Belo; Elísio Costa; Alice Santos-Silva

    2014-01-01

    We evaluated the potential cardiovascular risk protection of bilirubin in hemodialysis (HD) patients. An enlarged set of studies were evaluated in 191 HD patients, including hematological study, lipid profile, iron metabolism, nutritional, inflammatory markers, and dialysis adequacy. The TA duplication screening in the UDP-glucuronosyltransferase 1 A1 (UGT1A1) promoter region was also performed. The UGT1A1 genotype frequencies in HD patients were 49.2%, 42.4%, and 8.4% for 6/6, 6/7, and 7/7 g...

  12. UDP-glucuronosyltransferase expression in mouse liver is increased in obesity- and fasting-induced steatosis.

    Science.gov (United States)

    Xu, Jialin; Kulkarni, Supriya R; Li, Liya; Slitt, Angela L

    2012-02-01

    UDP-glucuronosyltransferases (Ugt) catalyze phase II conjugation reactions with glucuronic acid, which enhances chemical polarity and the elimination from the body. Few studies have addressed whether Ugt expression and activity are affected by liver disease, such as steatosis. The purpose of this study was to determine whether steatosis induced by obesity or fasting could affect liver Ugt mRNA expression and activity. Male C57BL/6J and Lep(ob/ob) (ob/ob) mice were fed ad libitum or food was withheld for 24 h. In steatotic livers of ob/ob mice, Ugt1a1, -1a6, -1a9, -2a3, -3a1, and -3a2 mRNA expression increased. Fasting, which also induced steatosis, increased hepatic Ugt1a1, -1a6, -1a7, -1a9, -2b1, -2b5, -2a3, -3a1, and -3a2 mRNA expression in mouse liver. Likewise, acetaminophen glucuronidation increased by 47% in hepatic microsomes from ob/ob mice compared with that in C57BL/6J mice, but not after fasting. In both steatosis models, Ugt induction was accompanied by increased aryl hydrocarbon receptor, constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor (PPAR)-α, pregnane X receptor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and peroxisome proliferator-activated receptor-γ coactivator-1α mRNA expression. In addition, fasting increased CAR, PPAR, and Nrf2 binding activity. The work points to hepatic triglyceride concentrations corresponding with nuclear receptor and Ugt expression. The findings indicate that steatosis significantly alters hepatic Ugt expression and activity, which could have a significant impact on determining circulating hormone levels, drug efficacy, and environmental chemical clearance. PMID:22031624

  13. Bioactivation of Heterocyclic Aromatic Amines by UDP Glucuronosyltransferases.

    Science.gov (United States)

    Cai, Tingting; Yao, Lihua; Turesky, Robert J

    2016-05-16

    2-Amino-9H-pyrido[2,3-b]indole (AαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic heterocyclic aromatic amines (HAA) that arise during the burning of tobacco and cooking of meats. UDP-glucuronosyltransferases (UGT) detoxicate many procarcinogens and their metabolites. The genotoxic N-hydroxylated metabolite of AαC, 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-AαC), undergoes glucuronidation to form the isomeric glucuronide (Gluc) conjugates N(2)-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HON(2)-Gluc) and O-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN(2)-O-Gluc). AαC-HON(2)-Gluc is a stable metabolite but AαC-HN(2)-O-Gluc is a biologically reactive intermediate, which covalently adducts to DNA at levels that are 20-fold higher than HONH-AαC. We measured the rates of formation of AαC-HON(2)-Gluc and AαC-HN(2)-O-Gluc in human organs: highest activity occurred with liver and kidney microsomes, and lesser activity was found with colon and rectum microsomes. AαC-HN(2)-O-Gluc formation was largely diminished in liver and kidney microsomes, by niflumic acid, a selective inhibitor UGT1A9. In contrast, AαC-HON(2)-Gluc formation was less affected and other UGT contribute to N(2)-glucuronidation of HONH-AαC. UGT were reported to catalyze the formation of isomeric Gluc conjugates at the N(2) and N3 atoms of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), the genotoxic metabolite of PhIP. However, we found that the N3-Gluc of HONH-PhIP also covalently bound to DNA at higher levels than HONH-PhIP. The product ion spectra of this Gluc conjugate acquired by ion trap mass spectrometry revealed that the Gluc moiety was linked to the oxygen atom of HONH-PhIP and not the N3 imidazole atom of the oxime tautomer of HONH-PhIP as was originally proposed. UGT1A9, an abundant UGT isoform expressed in human liver and kidney, preferentially forms the O-linked Gluc conjugates of HONH

  14. The Inhibition of the Components from Shengmai Injection towards UDP-Glucuronosyltransferase

    OpenAIRE

    Li-Peng Jiang; Jin Zhao; Yun-Feng Cao; Mo Hong; Dong-Xue Sun; Xiao-Yu Sun; Jun Yin; Zhi-Tu Zhu; Zhong-Ze Fang

    2014-01-01

    The mechanism of shengmai injection- (SMI-) related drug-drug interaction remains unclear. Evaluation of the inhibition potential of SMI’s ingredients towards UDP-glucuronosyltransferases (UGTs) activity will provide a new insight to understand SMI-related drug-drug interaction. In vitro incubation system to model UGT reaction was used. Recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reactions were empl...

  15. Cloning and substrate specificity of a human phenol UDP-glucuronosyltransferase expressed in COS-7 cells

    International Nuclear Information System (INIS)

    A rat kidney phenol UDP-glucuronosyltransferase cDNA was used to isolate a human liver phenol UDP-glucuronosyltransferase cDNA by screening of a human liver cDNA library in the expression vector λgt11. The 2.4-kilobase cDNA contained an open reading frame of 1,593 base pairs coding for a protein of 531 residues. The human liver cDNA was subcloned into the vector pKCRH2. Transfection of this recombinant plasmid into COS-7 cells allowed the expression of a protein of ∼ 55 kDa. The enzyme synthesized was a glycoprotein, as indicated by a reduction in molecular mass of ∼ 3 kDa after biosynthesis in the presence of tunicamycin. The expressed enzyme rapidly catalyzed the glucuronidation of 1-naphthol, 4-methylumbelliferone, and 4-nitrophenol. The use of a related series of simple phenols provided an outline description of the substituent restrictions imposed upon the phenolic structures accepted as substrates. The glucuronidation of testosterone, androsterone, and estrone was not catalyzed by this cloned UDP-glucuronosyltransferase

  16. Effect of Honokiol on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

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    Yong Yeon Cho

    2013-09-01

    Full Text Available Honokiol is a bioactive component isolated from the medicinal herbs Magnolia officinalis and Magnolia grandiflora that has antioxidative, anti-inflammatory, antithrombotic, and antitumor activities. The inhibitory potentials of honokiol on eight major human cytochrome P450 (CYP enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, and four UDP-glucuronosyltransferases (UGTs 1A1, 1A4, 1A9, and 2B7 in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. Honokiol strongly inhibited CYP1A2-mediated phenacetin O-deethylation, CYP2C8-mediated amodiaquine N-deethylation, CYP2C9-mediated diclofenac 4-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4-hydroxylation, and UGT1A9-mediated propofol glucuronidation with Ki values of 1.2, 4.9, 0.54, 0.57, and 0.3 μM, respectively. Honokiol also moderately inhibited CYP2B6-mediated bupropion hydroxylation and CYP2D6-mediated bufuralol 1'-hydroxylation with Ki values of 17.5 and 12.0 μM, respectively. These in vitro results indicate that honokiol has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and UGT1A9.

  17. UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients

    International Nuclear Information System (INIS)

    UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes are involved in removing sex hormones from circulation. Polymorphic variation in five UGT and SULT genes – UGT1A1 ((TA)6/(TA)7), UGT2B4 (Asp458Glu), UGT2B7 (His268Tyr), UGT2B15 (Asp85Tyr), and SULT1A1 (Arg213His) – may be associated with circulating sex hormone concentrations, or the risk of an estrogen receptor-negative (ER-) or progesterone receptor-negative (PR-) tumor. Logistic regression analysis was used to estimate the odds ratios of an ER- or PR- tumor associated with polymorphisms in the genes listed above for 163 breast cancer patients from a population-based cohort study of women in western Washington. Adjusted geometric mean estradiol, estrone, and testosterone concentrations were calculated within each UGT and SULT genotype for a subpopulation of postmenopausal breast cancer patients not on hormone therapy 2–3 years after diagnosis (n = 89). The variant allele of UGT1A1 was associated with reduced risk of an ER- tumor (P for trend = 0.03), and variants of UGT2B15 and SULT1A1 were associated with non-statistically significant risk reductions. There was some indication that plasma estradiol and testosterone concentrations varied by UGT2B15 and SULT1A1 genotypes; women with the UGT2B15 Asp/Tyr and Tyr/Tyr genotypes had higher concentrations of estradiol than women with the Asp/Asp genotype (P = 0.004). Compared with women with the SULT1A1 Arg/Arg and Arg/His genotypes, women with the His/His genotype had elevated concentrations of testosterone (P = 0.003). The risk of ER- breast cancer tumors may vary by UGT or SULT genotype. Further, plasma estradiol and testosterone concentrations in breast cancer patients may differ depending on some UGT and SULT genotypes

  18. Isolation and purification of rat liver morphine UDP-glucuronosyltransferase

    International Nuclear Information System (INIS)

    The enhancement of rat liver microsomal morphine (M) and 4-hydroxybiphenyl (4-HBP) UDP-glucuronyltransferase (UDPGT) activities by phenobarbital treatment has been proposed to represent increased activity of a single enzyme form, GT-2. They have separated M and 4-HBP UDPGT activities from Emulgen 911-solubilized microsomes obtained from livers of phenobarbital-treated Wistar rats. A sensitive assay procedure was developed to quantify M-UDPGT and 4-HBP-UDPGT activities using 14C-UDP-glucuronic acid (UDPGA) and reversed phase C-18 minicolumns whereby the radioactive glucuronides were differentially eluted from labeled UDPGA. Trisacryl DEAE, and chromatofocusing procedures were employed to separate M-UDPGT and 4-HBP-UDPGT in the presence of exogenous phosphatidylcholine (PC). The PC is necessary to stabilize UDPGT activities. M-UDPGT was isolated to apparent homogeneity and displayed a monomeric molecular weight of 56,000 daltons on SDS-PAGE. It reacted with M but not with 4-HBP, bilirubin, p-nitrophenol, testosterone, androsterone, estrone, 4-aminobiphenyl or α-naphthylamine. 4-HBP-UDPGT did not react with M. Therefore, M and 4-HBP glucuronidations are catalyzed by separate enzymes in rat liver microsomes

  19. Isolation and purification of rat liver morphine UDP-glucuronosyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Puig, J.F.; Tephly, T.R.

    1986-03-05

    The enhancement of rat liver microsomal morphine (M) and 4-hydroxybiphenyl (4-HBP) UDP-glucuronyltransferase (UDPGT) activities by phenobarbital treatment has been proposed to represent increased activity of a single enzyme form, GT-2. They have separated M and 4-HBP UDPGT activities from Emulgen 911-solubilized microsomes obtained from livers of phenobarbital-treated Wistar rats. A sensitive assay procedure was developed to quantify M-UDPGT and 4-HBP-UDPGT activities using /sup 14/C-UDP-glucuronic acid (UDPGA) and reversed phase C-18 minicolumns whereby the radioactive glucuronides were differentially eluted from labeled UDPGA. Trisacryl DEAE, and chromatofocusing procedures were employed to separate M-UDPGT and 4-HBP-UDPGT in the presence of exogenous phosphatidylcholine (PC). The PC is necessary to stabilize UDPGT activities. M-UDPGT was isolated to apparent homogeneity and displayed a monomeric molecular weight of 56,000 daltons on SDS-PAGE. It reacted with M but not with 4-HBP, bilirubin, p-nitrophenol, testosterone, androsterone, estrone, 4-aminobiphenyl or ..cap alpha..-naphthylamine. 4-HBP-UDPGT did not react with M. Therefore, M and 4-HBP glucuronidations are catalyzed by separate enzymes in rat liver microsomes.

  20. Intestinal excretion of unconjugated bilirubin in man and rats with inherited unconjugated hyperbilirubinemia

    NARCIS (Netherlands)

    Kotal, P; VanderVeere, CN; Sinaasappel, M; Elferink, RO; Vitek, L; Brodanova, M; Jansen, PLM; Fevery, J

    1997-01-01

    Patients with Crigler-Najjar syndrome and Gunn rats cannot form bilirubin glucuronides owing to a lack of bilirubin UDP-glucuronosyltransferase activity. Because increased serum and tissue bilirubin levels remain constant, an alternative excretory route has to substitute for this deficiency. Gunn ra

  1. PPARα: A Master Regulator of Bilirubin Homeostasis

    Directory of Open Access Journals (Sweden)

    Cyril Bigo

    2014-01-01

    Full Text Available Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR α to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARα agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC and coronary artery smooth muscle cells (CASMC were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin synthesizing heme oxygenase- (HO- 1 and biliverdin reductase (BVR enzymes were determined. Human hepatocytes (HH and HepG2 cells sustained similar treatments, except that the expression of the bilirubin conjugating UDP-glucuronosyltransferase (UGT 1A1 enzyme and multidrug resistance-associated protein (MRP 2 transporter was analyzed. In HUVECs, gemfibrozil, fenofibrate, and Wy14,643 upregulated HO-1 mRNA expression without affecting BVR. Wy14,643 and fenofibrate also caused HO-1 protein accumulation, while gemfibrozil and fenofibrate favored the secretion of bilirubin in cell media. Similar positive regulations were also observed with the 3 PPARα ligands in CASMCs where HO-1 mRNA and protein levels were increased. In HH and HepG2 cells, both UGT1A1 and MRP2 transcripts were also accumulating. These observations indicate that PPARα ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed.

  2. The UDP-Glucuronosyltransferase (UGT) 1A Polymorphism c.2042C>G (rs8330) Is Associated with Increased Human Liver Acetaminophen Glucuronidation, Increased UGT1A Exon 5a/5b Splice Variant mRNA Ratio, and Decreased Risk of Unintentional Acetaminophen-Induced Acute Liver FailureS⃞

    OpenAIRE

    Court, Michael H; Freytsis, Marina; Wang, Xueding; Peter, Inga; Guillemette, Chantal; Hazarika, Suwagmani; Duan, Su X.; Greenblatt, David J; Lee, William M.

    2013-01-01

    Acetaminophen is cleared primarily by hepatic glucuronidation. Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose. In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15). Of th...

  3. Characterization of Human Hepatic and Extrahepatic UDP-Glucuronosyltransferase Enzymes Involved in the Metabolism of Classic Cannabinoids

    OpenAIRE

    Mazur, Anna; Lichti, Cheryl F.; Prather, Paul L.; Zielinska, Agnieszka K.; Bratton, Stacie M.; Gallus-Zawada, Anna; Finel, Moshe; Miller, Grover P.; Radomińska-Pandya, Anna; Moran, Jeffery H.

    2009-01-01

    Tetrahydrocannabinol (Δ9-THC), the primary psychoactive ingredient in marijuana, is subject to cytochrome P450 oxidation and subsequent UDP-glucuronosyltransferase (UGT)-dependent glucuronidation. Many studies have shown that CYP2C9 and CYP3A4 are the primary enzymes responsible for these cytochrome P450-dependent oxidations, but little work has been done to characterize phase II metabolic pathways. In this study, we test the hypothesis that there are specific human UG...

  4. Gastrointestinally distributed UDP-glucuronosyltransferase 1A10, which metabolizes estrogens and nonsteroidal anti-inflammatory drugs, depends upon phosphorylation.

    Science.gov (United States)

    Basu, Nikhil K; Kubota, Shigeki; Meselhy, Meselhy R; Ciotti, Marco; Chowdhury, Bhabadeb; Hartori, Masao; Owens, Ida S

    2004-07-01

    Among gastrointestinal distributed isozymes encoded at the UGT1 locus, UDP-glucuronosyltransferase 1A10 (UGT1A10) metabolizes a number of important chemicals. Similar to broad conversion of phytoestrogens (Basu, N. K., Ciotti, M., Hwang, M. S., Kole, L., Mitra, P. S., Cho, J. W., and Owens, I. S. (2004) J. Biol. Chem. 279, 1429-1441), UGT1A10 metabolized estrogens and their derivatives, whereas UGT1A1, -1A3, -1A7, and -1A8 differentially exhibited reduced activity toward the same. UGT1A10 compared with UGT1A7, -1A8, and -1A3 generally exhibited high activity toward acidic nonsteroidal anti-inflammatory drugs and natural benzaldehyde derivatives, while UGT1A3 metabolized most efficiently aromatic transcinnamic acids known to be generated from flavonoid glycosides by microflora in the lower gastrointestinal tract. Finally UGT1A10, -1A7, -1A8, and -1A3 converted plant-based salicylic acids; methylsalicylic acid was transformed at high levels, and acetylsalicylic (aspirin) and salicylic acid were transformed at moderate to low levels. Atypically UGT1A10 transformed estrogens between pH 6 and 8 but acidic structures preferentially at pH 6.4. Furthermore evidence indicates UGT1A10 expressed in COS-1 cells depends upon phosphorylation; UGT1A10 versus its single, double, and triple mutants at three predicted protein kinase C phosphorylation sites incorporated [(33)P]-orthophosphate and showed a progressive decrease with no detectable label or activity for the triple T73A/T202A/S432G-1A10 mutant. Single and double mutants revealed either null/full activity or null/additive activity, respectively. Additionally UGT1A10-expressing cultures glucuronidated 17beta-[(14)C]estradiol, whereas cultures containing null mutants at protein kinase C sites showed no estrogen conversion. Importantly UGT1A10 in cells supported 10-fold higher glucuronidation of 17beta-estradiol than UGT1A1. In summary, our results suggest gastrointestinally distributed UGT1A10 is important for detoxifying

  5. Structure–inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs)

    International Nuclear Information System (INIS)

    The wide utilization of ginseng provides the high risk of herb–drug interaction (HDI) with many clinical drugs. The inhibition of ginsenosides towards drug-metabolizing enzymes (DMEs) has been regarded as an important reason for herb–drug interaction (HDI). Compared with the deep studies on the ginsenosides' inhibition towards cytochrome P450 (CYP), the inhibition of ginsenosides towards the important phase II enzymes UDP-glucuronosyltransferases (UGTs) remains to be unclear. The present study aims to evaluate the inhibition behavior of ginsenosides towards important UGT isoforms located in the liver and intestine using in vitro methods. The recombinant UGT isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed as in vitro probe reaction. The results showed that structure-dependent inhibition existed for the inhibition of ginsenosides towards UGT isoforms. To clarify the possibility of in vivo herb–drug interaction induced by this kind of inhibition, the ginsenoside Rg3 was selected as an example, and the inhibition kinetic type and parameters (Ki) were determined. Rg3 competitively inhibited UGT1A7, 2B7 and 2B15-catalyzed 4-MU glucuronidation reaction, and exerted noncompetitive inhibition towards UGT1A8-catalyzed 4-MU glucuronidation. The inhibition parameters (Ki values) were calculated to be 22.6, 7.9, 1.9, and 2.0 μM for UGT1A7, 1A8, 2B7 and 2B15. Using human maximum plasma concentration of Rg3 (400 ng/ml (0.5 μM)) after intramuscular injection of 60 mg Rg3, the area under the plasma concentration-time curve (AUC) was extrapolated to increase by 2.2%, 6.3%, 26.3%, and 25% for the co-administered drugs completely undergoing the metabolism catalyzed by UGT1A7, 1A8, 2B7 and 2B15, respectively. All these results indicated that the ginsenosides' inhibition towards UGT isoforms might be an important reason for ginseng–drug interaction. - Highlights: ► Structure-dependent inhibition of ginsenoside towards UDP-glucuronosyltransferases

  6. Structure–inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs)

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Zhong-Ze [The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001 (China); Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of Sciences and The first Affiliated Hospital of Liaoning Medical University, No.457, Zhongshan Road, Dalian 116023 (China); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (United States); Cao, Yun-Feng [Key Laboratory of Contraceptives and Devices Research(NPFPC),Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai 200032 (China); Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of Sciences and The first Affiliated Hospital of Liaoning Medical University, No.457, Zhongshan Road, Dalian 116023 (China); Hu, Cui-Min [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (United States); Hong, Mo; Sun, Xiao-Yu [Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of Sciences and The first Affiliated Hospital of Liaoning Medical University, No.457, Zhongshan Road, Dalian 116023 (China); Ge, Guang-Bo; Liu, Yong; Zhang, Yan-Yan; Yang, Ling [Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023 Dalian (China); Sun, Hong-Zhi, E-mail: zzfang228@gmail.com [The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001 (China)

    2013-03-01

    The wide utilization of ginseng provides the high risk of herb–drug interaction (HDI) with many clinical drugs. The inhibition of ginsenosides towards drug-metabolizing enzymes (DMEs) has been regarded as an important reason for herb–drug interaction (HDI). Compared with the deep studies on the ginsenosides' inhibition towards cytochrome P450 (CYP), the inhibition of ginsenosides towards the important phase II enzymes UDP-glucuronosyltransferases (UGTs) remains to be unclear. The present study aims to evaluate the inhibition behavior of ginsenosides towards important UGT isoforms located in the liver and intestine using in vitro methods. The recombinant UGT isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed as in vitro probe reaction. The results showed that structure-dependent inhibition existed for the inhibition of ginsenosides towards UGT isoforms. To clarify the possibility of in vivo herb–drug interaction induced by this kind of inhibition, the ginsenoside Rg{sub 3} was selected as an example, and the inhibition kinetic type and parameters (K{sub i}) were determined. Rg{sub 3} competitively inhibited UGT1A7, 2B7 and 2B15-catalyzed 4-MU glucuronidation reaction, and exerted noncompetitive inhibition towards UGT1A8-catalyzed 4-MU glucuronidation. The inhibition parameters (K{sub i} values) were calculated to be 22.6, 7.9, 1.9, and 2.0 μM for UGT1A7, 1A8, 2B7 and 2B15. Using human maximum plasma concentration of Rg{sub 3} (400 ng/ml (0.5 μM)) after intramuscular injection of 60 mg Rg{sub 3}, the area under the plasma concentration-time curve (AUC) was extrapolated to increase by 2.2%, 6.3%, 26.3%, and 25% for the co-administered drugs completely undergoing the metabolism catalyzed by UGT1A7, 1A8, 2B7 and 2B15, respectively. All these results indicated that the ginsenosides' inhibition towards UGT isoforms might be an important reason for ginseng–drug interaction. - Highlights: ► Structure

  7. Metabolic inactivation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview

    International Nuclear Information System (INIS)

    The breast tissue is the site of major metabolic conversions of estradiol (E2) mediated by specific cytochromes P450 hydroxylations and methylation by catechol-O-methytransferase. In addition to E2 itself, recent findings highlight the significance of 4-hydroxylated estrogen metabolites as chemical mediators and their link to breast cancer development and progression, whereas, in opposition, 2-methoxylated estrogens appear to be protective. Recent data also indicate that breast tissue possesses enzymatic machinery to inactivate and eliminate E2 and its oxidized and methoxylated metabolites through conjugation catalyzed by UDP-glucuronosyltransferases (UGTs), which involves the covalent addition of glucuronic acid. In opposition to other metabolic pathways of estrogen, the UGT-mediated process leads to the formation of glucuronides that are devoid of biologic activity and are readily excreted from the tissue into the circulation. This review addresses the most recent findings on the identification of UGT enzymes that are responsible for the glucuronidation of E2 and its metabolites, and evidence regarding their potential role in breast cancer

  8. Comparison of the inhibitory effects of tolcapone and entacapone against human UDP-glucuronosyltransferases.

    Science.gov (United States)

    Lv, Xia; Wang, Xin-Xin; Hou, Jie; Fang, Zhong-Ze; Wu, Jing-Jing; Cao, Yun-Feng; Liu, Shu-Wen; Ge, Guang-Bo; Yang, Ling

    2016-06-15

    Tolcapone and entacapone are two potent catechol-O-methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities. However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease, while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants (Ki) of tolcapone and entacapone against bilirubin-O-glucuronidation in human liver microsomes (HLM) are determined as 0.68μM and 30.82μM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin-O-glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1. PMID:27089846

  9. Potential Cardiovascular Risk Protection of Bilirubin in End-Stage Renal Disease Patients under Hemodialysis

    Directory of Open Access Journals (Sweden)

    Maria do Sameiro-Faria

    2014-01-01

    Full Text Available We evaluated the potential cardiovascular risk protection of bilirubin in hemodialysis (HD patients. An enlarged set of studies were evaluated in 191 HD patients, including hematological study, lipid profile, iron metabolism, nutritional, inflammatory markers, and dialysis adequacy. The TA duplication screening in the UDP-glucuronosyltransferase 1 A1 (UGT1A1 promoter region was also performed. The UGT1A1 genotype frequencies in HD patients were 49.2%, 42.4%, and 8.4% for 6/6, 6/7, and 7/7 genotypes, respectively. Although no difference was found in UGT1A1 genotype distribution between the three tertiles of bilirubin, significant differences were found with increasing bilirubin levels, namely, a decrease in platelet, leukocyte, and lymphocyte counts, transferrin, oxidized low-density lipoprotein (ox-LDL, ox-LDL/low-density lipoprotein cholesterol ratio, apolipoprotein (Apo A, Apo B, and interleukin-6 serum levels and a significant increased concentration of hemoglobin, hematocrit, erythrocyte count, iron, transferrin saturation, Apo A/Apo B ratio, adiponectin, and paraoxonase 1 serum levels. After adjustment for age these results remained significant. Our data suggest that higher bilirubin levels are associated with beneficial effects in HD patients, by improving lipid profile and reducing the inflammatory grade, which might contribute to increase in iron availability. These results suggest a potential cardiovascular risk protection of bilirubin in HD patients.

  10. Photoaffinity labeling of rat liver microsomal morphine UDP-glucuronosyltransferase by [3H]flunitrazepam

    International Nuclear Information System (INIS)

    Benzodiazepines have been shown to competitively inhibit morphine glucuronidation in rat and human hepatic microsomes. Flunitrazepam exerted a potent competitive inhibition of rat hepatic morphine UDP-glucuronosyltransferase (UDPGT) activity (Ki = 130 microM). It has no effect on the activity of p-nitrophenol, 17 beta-hydroxysteroid, 3 alpha-hydroxysteroid, or 4-hydroxybiphenyl UDPGTs. Because flunitrazepam is an effective photoaffinity label for benzodiazepine receptors, studied were performed in solubilized rat hepatic microsomes and with partially purified preparations of morphine UDPGT to determine the enhancement of flunitrazepam inhibition and binding to morphine UDPGT promoted by exposure to UV light. Under UV light, flunitrazepam inhibition was markedly enhanced. UV light exposure also led to a marked increase in binding of [3H]flunitrazepam to microsomal protein, which was protected substantially by preincubation with morphine. Testosterone, androsterone, and UDP-glucuronic acid did not protect against UV-enhanced flunitrazepam binding, and morphine did not reverse flunitrazepam binding once binding had occurred. As morphine UDPGT was purified, a good correlation was found between the increases in specific activity of morphine UDPGT and flunitrazepam binding to protein. Chromatofocusing chromatography showed that flunitrazepam bound only to fractions containing active morphine UDPGT, and no binding to 4-hydroxybiphenyl UDPGT was observed. Fluorography of a sodium dodecyl sulfate-polyacrylamide electrophoresis gel of solubilized hepatic microsomes that had been treated with [3H] flunitrazepam under UV light revealed a band with a monomeric molecular weight between 54,000 and 58,000. This monomeric molecular weight compares favorably with the reported monomeric molecular weight of homogeneous morphine UDPGT (56,000)

  11. Photoaffinity labeling of rat liver microsomal morphine UDP-glucuronosyltransferase by ( sup 3 H)flunitrazepam

    Energy Technology Data Exchange (ETDEWEB)

    Thomassin, J.; Tephly, T.R. (Univ. of Iowa, Iowa City (USA))

    1990-09-01

    Benzodiazepines have been shown to competitively inhibit morphine glucuronidation in rat and human hepatic microsomes. Flunitrazepam exerted a potent competitive inhibition of rat hepatic morphine UDP-glucuronosyltransferase (UDPGT) activity (Ki = 130 microM). It has no effect on the activity of p-nitrophenol, 17 beta-hydroxysteroid, 3 alpha-hydroxysteroid, or 4-hydroxybiphenyl UDPGTs. Because flunitrazepam is an effective photoaffinity label for benzodiazepine receptors, studied were performed in solubilized rat hepatic microsomes and with partially purified preparations of morphine UDPGT to determine the enhancement of flunitrazepam inhibition and binding to morphine UDPGT promoted by exposure to UV light. Under UV light, flunitrazepam inhibition was markedly enhanced. UV light exposure also led to a marked increase in binding of (3H)flunitrazepam to microsomal protein, which was protected substantially by preincubation with morphine. Testosterone, androsterone, and UDP-glucuronic acid did not protect against UV-enhanced flunitrazepam binding, and morphine did not reverse flunitrazepam binding once binding had occurred. As morphine UDPGT was purified, a good correlation was found between the increases in specific activity of morphine UDPGT and flunitrazepam binding to protein. Chromatofocusing chromatography showed that flunitrazepam bound only to fractions containing active morphine UDPGT, and no binding to 4-hydroxybiphenyl UDPGT was observed. Fluorography of a sodium dodecyl sulfate-polyacrylamide electrophoresis gel of solubilized hepatic microsomes that had been treated with (3H) flunitrazepam under UV light revealed a band with a monomeric molecular weight between 54,000 and 58,000. This monomeric molecular weight compares favorably with the reported monomeric molecular weight of homogeneous morphine UDPGT (56,000).

  12. Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Arctiin and Arctigenin.

    Science.gov (United States)

    Zhang, Hui; Zhao, Zhenying; Wang, Tao; Wang, Yijia; Cui, Xiao; Zhang, Huijuan; Fang, Zhong-Ze

    2016-07-01

    Arctiin is the major pharmacological ingredient of Fructus Arctii, and arctigenin is the metabolite of arctiin formed via the catalysis of human intestinal bacteria. The present study aims to investigate the inhibition profile of arctiin and arctigenin on important phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs), indicating the possible herb-drug interaction. In vitro screening experiment showed that 100 μM of arctiin and arctigenin inhibited the activity of UGT1A3, 1A9, 2B7, and 2B15. Homology modeling-based in silico docking of arctiin and arctigenin into the activity cavity of UGT2B15 showed that hydrogen bonds and hydrophobic interactions contributed to the strong binding free energy of arctiin (-8.14 kcal/mol) and arctigenin (-8.43 kcal/mol) with UGT2B15. Inhibition kinetics study showed that arctiin and arctigenin exerted competitive and noncompetitive inhibition toward UGT2B15, respectively. The inhibition kinetic parameters (Ki ) were calculated to be 16.0 and 76.7 μM for the inhibition of UGT2B15 by arctiin and arctigenin, respectively. Based on the plasma concentration of arctiin and arctigenin after administration of 100 mg/kg of arctiin, the [I]/Ki values were calculated to be 0.3 and 0.007 for arctiin and arctigenin, respectively. Based on the inhibition evaluation standard ([I]/Ki   1, high possibility), arctiin might induce drug-drug interaction with medium possibility. Based on these results, clinical monitoring the utilization of Fructus Arctii is very important and necessary. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27145339

  13. UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia.

    Science.gov (United States)

    Carpenter, Shannon L; Lieff, Susan; Howard, Thad A; Eggleston, Barry; Ware, Russell E

    2008-10-01

    Genetic modifiers contribute to phenotypic variability in patients with sickle cell anemia (SCA). The influence of the bilirubin UDP-glucuronosyltransferase (UGT) 1A1 (TA)(n)TAA promoter polymorphism on bilirubin levels and gallbladder disease in SCA was examined using prospectively collected data from the Cooperative Study of Sickle Cell Disease. A total of 324 children with HbSS (median age 6.9 years) had UGT1A1 genotyping; 243 (75%) had common (TA)(6) or (TA)(7) alleles, whereas 81 (25.0%) had variant (TA)(5) or (TA)(8) alleles. The UGT1A1 genotype significantly influenced average bilirubin levels for the common alleles: 6/6 genotype = 2.36 +/- 1.13 mg/dL, 6/7 genotype = 2.90 +/- 1.54 mg/dL, and 7/7 genotype = 4.24 +/- 2.11 mg/dL (P < 0.0001). Thirty-nine percent of children with the 7/7 genotype had documented gallbladder disease, compared with 18.2% with the 6/7 genotype and only 9.9% with the wildtype 6/6 UGT1A1 genotype (P = 0.001). To analyze the (TA)(5) and (TA)(8) variant alleles, three groups were generated, showing increasing bilirubin levels with increasing TA repeats and age. Group 3 (genotypes 6/8, 7/7, and 7/8) had a significantly greater rate of bilirubin change than Groups 1 (genotypes 5/6, 5/7, and 6/6) or 2 (genotype 6/7). These results validate previous smaller studies and confirm that the UGT1A1 promoter polymorphism exerts a powerful influence on bilirubin levels and the development of gallbladder disease in children with SCA. UGT1A1 genotyping should be considered as a screening tool for predicting children most likely to develop gallbladder disease at a young age. PMID:18756540

  14. Cloning and expression of human UDP-glucuronosyltransferase 1A4 in Bac-to-Bac system

    International Nuclear Information System (INIS)

    UDP-glucuronosyltransferases (UGTs) catalyze the transfer of glucuronic acid from uridine diphosphate-glucuronic acid (UDP-GA) to compounds with amine, hydroxyl, and carboxylic acid moieties. N-glucuronidation is an important pathway for elimination of many tertiary amine therapeutic agents used in humans. UGT1A4 has been reported to be specific for glucuronidating primary, secondary, and tertiary amines, forming N-glucuronides. To further investigate the drugs metabolized by UGT1A4, the Bac-to-Bac expression system was used to express the recombinant UGT1A4 with His-tag on the C-terminal. The His-tagged recombinant UGT1A4 expressed in Spodoptera frugiperda (Sf9) cells were detected using anti-His antibody and the molecular weight of the recombinant protein was approximately 55 kDa. The enzyme activity towards imipramine in cell homogenate protein was found to be 83.14 ± 15 pmol/min/mg protein (n=3) with 0.5 mM imipramine by HPLC, but was not detectable in blank Sf9 cells. It paved the way for the further studies for drug glucuronidation by UGT1A4. The purification of the UGT1A4 can be done by Ni-resin. This is helpful to do research on the structure of the UFT1A4

  15. Unravelling the transcriptomic landscape of the major phase II UDP-glucuronosyltransferase drug metabolizing pathway using targeted RNA sequencing.

    Science.gov (United States)

    Tourancheau, A; Margaillan, G; Rouleau, M; Gilbert, I; Villeneuve, L; Lévesque, E; Droit, A; Guillemette, C

    2016-02-01

    A comprehensive view of the human UDP-glucuronosyltransferase (UGT) transcriptome is a prerequisite to the establishment of an individual's UGT metabolic glucuronidation signature. Here, we uncover the transcriptome landscape of the 10 human UGT gene loci in normal and tumoral metabolic tissues by targeted RNA next-generation sequencing. Alignment on the human hg19 reference genome identifies 234 novel exon-exon junctions. We recover all previously known UGT1 and UGT2 enzyme-coding transcripts and identify over 130 structurally and functionally diverse novel UGT variants. We further expose a revised genomic structure of UGT loci and provide a comprehensive repertoire of transcripts for each UGT gene. Data also uncover a remodelling of the UGT transcriptome occurring in a tissue- and tumor-specific manner. The complex alternative splicing program regulating UGT expression and protein functions is likely critical in determining detoxification capacity of an organ and stress-related responses, with significant impact on drug responses and diseases. PMID:25869014

  16. Effect of a New Prokinetic Agent DA-9701 Formulated with Corydalis Tuber and Pharbitidis Semen on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

    Directory of Open Access Journals (Sweden)

    Hye Young Ji

    2012-01-01

    Full Text Available DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP enzymes and four UDP-glucuronosyltransferase (UGT enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC50 values of 188 and 290 μg/mL, respectively. DA-9701 inhibited CYP2D6-catalyzed bufuralol 1′-hydroxylation with an inhibition constant (Ki value of 6.3 μg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol 1′-hydroxylation, with a Ki value of 3.7 μg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC50 equivalent concentration (volume per dose index value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate the in vivo extent of the observed in vitro interactions.

  17. Altered life cycle in Arabidopsis plants expressing PsUGT1, a UDP-glucuronosyltransferase-encoding gene from pea.

    Science.gov (United States)

    Woo, Ho-Hyung; Faull, Kym F; Hirsch, Ann M; Hawes, Martha C

    2003-10-01

    Alfalfa (Medicago sativa) and Arabidopsis were used as model systems to examine molecular mechanisms underlying developmental effects of a microsomal UDP-glucuronosyltransferase-encoding gene from pea (Pisum sativum; PsUGT1). Alfalfa expressing PsUGT1 antisense mRNA under the control of the cauliflower mosaic virus (CaMV) 35S promoter exhibited delayed root emergence, reduced root growth, and increased lateral root development. The timing of root emergence in wild-type and antisense plants was correlated with the transient accumulation of auxin at the site of root emergence. Cell suspension cultures derived from the antisense alfalfa plants exhibited a delay in cell cycle from 24-h in the wild-type plants to 48-h in the antisense plants. PsUGT1::uidA was introduced into Arabidopsis to demonstrate that, as in alfalfa and pea, PsUGT1 expression occurs in regions of active cell division. This includes the root cap and root apical meristems, leaf primordia, tips of older leaves, and the transition zone between the hypocotyl and the root. Expression of PsUGT1::uidA colocalized with the expression of the auxin-responding reporter DR5::uidA. Co-expression of DR5::uidA in transgenic Arabidopsis lines expressing CaMV35S::PsUGT1 revealed that ectopic expression of CaMV35S::PsUGT1 is correlated with a change in endogenous auxin gradients in roots. Roots of ecotype Columbia expressing CaMV35S::PsUGT1 exhibited distinctive responses to exogenous naphthalene acetic acid. Completion of the life cycle occurred in 4 to 6 weeks compared with 6 to 7 weeks for wild-type Columbia. Inhibition of endogenous ethylene did not correct this early senescence phenotype. PMID:12972656

  18. Serum bilirubin concentration in healthy adult North-Europeans is strictly controlled by the UGT1A1 TA-repeat variants.

    Directory of Open Access Journals (Sweden)

    Marianne K Kringen

    Full Text Available The major enzyme responsible for the glucuronidation of bilirubin is the uridine 5'-diphosphoglucose glucuronosyltransferase A1 (UGT1A1 enzyme, and genetic variation in the UGT1A1 gene is reported to influence the bilirubin concentration in the blood. In this study, we have investigated which gene-/haplotype variants may be useful for genetic testing of Gilbert's syndrome. Two groups of samples based on serum bilirubin concentrations were obtained from the Nordic Reference Interval Project Bio-bank and Database (NOBIDA: the 150 individuals with the highest bilirubin (>17.5 µmol/L and the 150 individuals with normal bilirubin concentrations (TA7 variant in the UGT1A1 promoter and 7 tag-SNPs in an extended promoter region of UGT1A1 (haplotype analysis and in selected SNPs in candidate genes (SLCO1B3, ABCC2 and NUP153. We found significant odds ratios for high bilirubin level for all the selected UGT1A1 variants. However, in stepwise multivariate logistic regression analysis of all genetic variants together with age, sex, country of origin and fasting time, the repeat variants of UGT1A1 TA6>TA7 and SLCO1B3 rs2117032 T>C were the only variants significantly associated with higher bilirubin concentrations. Most individuals with high bilirubin levels were homozygous for the TA7-repeat (74% while only 3% were homozygous for the TA7-repeat in individuals with normal bilirubin levels. Among individuals heterozygous for the TA7-repeat, a low frequent UGT1A1-diplotype harboring the rs7564935 G-variant was associated with higher bilirubin levels. In conclusion, our results demonstrate that in testing for Gilbert's syndrome, analyzing for the homozygous TA7/TA7-genotype would be appropriate.

  19. Identification of the UDP-glucuronosyltransferase responsible for bucolome N-glucuronide formation in rats.

    Science.gov (United States)

    Kanoh, H; Okada, K; Mohri, K

    2010-11-01

    Bucolome N-glucuronide (BCP-NG), a major metabolite of bucolome (BCP), is the first unique N-glucuronide of barbituric acid derivatives to be reported. The purpose of the present study was to identify the UGT isoform(s) responsible for BCP-NG formation in rats. A pharmacokinetic study of BCP and the biliary excretion of BCP-NG was carried out in Wistar rats pretreated with phenobarbital (PB) (PB-pretreated rats), and the results were compared with those of Wistar rats not pretreated with PB (untreated rats). BCP N-glucuronidation activities were studied using hepatic microsomes prepared from Wistar rats pretreated with PB (primarily induces UGT1A1, 1A6 and 2B1) or with clofibric acid (CF, primarily induces UGT1A1 and 1A6), and from Gunn rats (deficiency of UGT1A family), and the results were compared with those of untreated rat microsomes.The plasma elimination clearance value of BCP in PB-pretreated rats was approximately 1.4 times greater than that of untreated rats. The cumulative amount (20.4 +/- 5.9 % of dose) of BCP-NG excreted in PB-pretreated rat bile was approximately 1.5-fold higher than that (13.4 +/- 2.5% of dose) in untreated rat bile, and BCP-NG (5.9 +/- 3.0%) and BCP (3.0 +/- 2.6%) excreted in PB-pretreated rat urine were approximately 3.0- and 1.8-fold higher than those in untreated rat urine (BCP-NG: 2.0 +/- 1.4%; BCP: 1.7 +/- 1.3%), respectively.BCP N-glucuronidation activities in PB- and CF-pretreated microsomes were approximately 1.5- and 1.6-fold higher than in untreated microsomes, respectively. BCP N-glucuronidation activity in the microsomes of Gunn rats was markedly reduced by approximately 8.5% in untreated rat microsomes. The results suggest that UGT 1A1 is primarily responsible for BCP N-glucuronide formation in rats. PMID:21155392

  20. Regioselectivity of Human UDP-Glucuronsyltransferase 1A1 in the Synthesis of Flavonoid Glucuronides Determined by Metal Complexation and Tandem Mass Spectrometry

    OpenAIRE

    Davis, Barry D.; Brodbelt, Jennifer S.

    2007-01-01

    A three-part tandem mass spectrometric strategy that entails MSn analysis and a post-column LC-MS cobalt complexation method is developed to identify flavonoid monoglucuronide metabolites synthesized using the 1A1 isozyme of human UDP-glucuronosyltransferase (UGT). Ten flavonoid aglycons were used as substrates, spanning the subclasses of flavones, flavonols and flavanones. The products were characterized by LC-MS and LC-MSn, with post-column cobalt complexation employed to pinpoint the speci...

  1. UGT1A1 and UGT1A9 functional variants, meat intake, and colon cancer, among Caucasians and African Americans

    OpenAIRE

    Girard, Hugo; Butler, Lesley M.; Villeneuve, Lyne; Millikan, Robert C.; Sinha, Rashmi; Sandler, Robert S.; Guillemette, Chantal

    2008-01-01

    Glucuronidation by the UDP-glucuronosyltransferase enzymes (UGTs) is one of the primary detoxification pathways of dietary heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). In a population-based case-control study of 537 cases and 866 controls, we investigated whether colon cancer was associated with genetic variations in UGT1A1 and UGT1A9 genes and we determined if those variations modify the association between colon cancer and dietary HCA and PAH exposure. We measured...

  2. Coupling of UDP-glucuronosyltransferases and multidrug resistance-associated proteins is responsible for the intestinal disposition and poor bioavailability of emodin

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Wei; Feng, Qian; Li, Ye; Ye, Ling [Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong (China); Hu, Ming, E-mail: mhu@uh.edu [Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong (China); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 1441 Moursund Street, Houston, TX 77030 (United States); Liu, Zhongqiu, E-mail: liuzq@smu.edu.cn [Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong (China)

    2012-12-15

    Emodin is a poorly bioavailable but promising plant-derived anticancer drug candidate. The low oral bioavailability of emodin is due to its extensive glucuronidation in the intestine and liver. Caco-2 cell culture model was used to investigate the interplay between UDP-glucuronosyltransferases (UGTs) and efflux transporters in the intestinal disposition of emodin. Bidirectional transport assays of emodin at different concentrations were performed in the Caco-2 monolayers with or without multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP) efflux transporter chemical inhibitors. The bidirectional permeability of emodin and its glucuronide in the Caco-2 monolayers was determined. Emodin was rapidly metabolized to emodin glucuronide in Caco-2 cells. LTC4, a potent inhibitor of MRP2, decreased the efflux of emodin glucuronide and also substantially increased the intracellular glucuronide level in the basolateral-to-apical (B–A) direction. MK-571, chemical inhibitor of MRP2, MRP3, and MRP4, significantly reduced the efflux of glucuronide in the apical-to-basolateral (A–B) and B–A directions in a dose-dependent manner. However, dipyridamole, a BCRP chemical inhibitor demonstrated no effect on formation and efflux of emodin glucuronide in Caco-2 cells. In conclusion, UGT is a main metabolic pathway for emodin in the intestine, and the MRP family is composed of major efflux transporters responsible for the excretion of emodin glucuronide in the intestine. The coupling of UGTs and MRP efflux transporters causes the extensive metabolism, excretion, and low bioavailability of emodin. -- Highlights: ► Glucuronidation is the main reason for the poor oral bioavailability of emodin. ► Efflux transporters are involved in the excretion of emodin glucuronide. ► The intestine is the main organ for metabolism of emodin.

  3. Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Hai-Ying, E-mail: cmu4h-mhy@126.com [The Fourth Affiliated Hospital of China Medical University, Shenyang 110032 (China); Sun, Dong-Xue [School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016 (China); Cao, Yun-Feng [The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001 (China); Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023 (China); Ai, Chun-Zhi [Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023 (China); Qu, Yan-Qing [Thyroid Surgery, Yantaishan Hospital, Yantai, Shandong (China); Hu, Cui-Min [Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023 (China); Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057 (United States); Jiang, Changtao [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (United States); Dong, Pei-Pei [Academy of Integrative Medicine, Dalian Medical University, Dalian 116044 (China); Sun, Xiao-Yu; Hong, Mo [Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023 (China); Tanaka, Naoki; Gonzalez, Frank J. [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (United States); and others

    2014-05-15

    Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (K{sub i}) were determined for the compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (K{sub i}) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7. - Highlights: • Specific inhibition of andrographolide derivatives towards UGT2B7. • Herb-drug interaction related withAndrographis paniculata. • Guidance for design of UGT2B7 specific inhibitors.

  4. Involvement of hepatocyte nuclear factor 1 in the regulation of the UDP-glucuronosyltransferase 1A7 (UGT1A7) gene in rat hepatocytes.

    Science.gov (United States)

    Metz, R P; Auyeung, D J; Kessler, F K; Ritter, J K

    2000-08-01

    UDP-glucuronosyltransferase 1A7 (UGT1A7) is a major UGT contributing to the glucuronidation of xenobiotic phenols in rats. Its expression in rat liver is tightly regulated, with low constitutive and high inducible expression in response to aryl hydrocarbon receptor ligands and oltipraz. Previously, we reported the absence of 3-methylcholanthrene- or oltipraz-responsive elements in the 1.6-kbp region flanking the UGT1A7 promoter. However, potential binding sites were noted for several liver-enriched transcription factors. Here we show that deletion of the hepatic nuclear factor (HNF)3, HNF4, and CCAAT-enhancer binding protein-like binding sites had no effect on the expression of a UGT1A7 reporter plasmid, p(-965/+56)1A7-Luc, in primary rat hepatocytes. The full activity of the promoter was contained in the region between bases -157 and +76. Two sites of binding by rat liver nuclear proteins were detected in this region by DNase footprinting. PR-1 corresponded to the HNF1-like binding site between bases -52 and -38, whereas PR-2 was located between -30 to -6. Gel retardation studies supported the presence of HNF1alpha in the PR-1 DNA-liver nuclear protein complex. Mutation of PR-1 inhibited binding in the gel shift assay, prevented activation by overexpressed HNF1 in human embryonic kidney cells, and reduced by >80% the maximal luciferase activities expressed from basal and 3-methylcholanthrene-responsive UGT1A7 gene reporter constructs in primary rat hepatocytes. These data provide evidence for an important stimulatory role of HNF1 in promoting UGT1A7 gene expression in rat liver. PMID:10908299

  5. Transcriptomic analysis identified up-regulation of a solute carrier transporter and UDP glucuronosyltransferases in dogs with aggressive cutaneous mast cell tumours.

    Science.gov (United States)

    Giantin, Mery; Baratto, Chiara; Marconato, Laura; Vascellari, Marta; Mutinelli, Franco; Dacasto, Mauro; Granato, Anna

    2016-06-01

    Gene expression analyses have been recently used in cancer research to identify genes associated with tumorigenesis and potential prognostic markers or therapeutic targets. In the present study, the transcriptome of dogs that had died because of mast cell tumours (MCTs) was characterised to identify a fingerprint having significant influence on prognosis determination and treatment selection. A dataset (GSE50433) obtained using a commercial canine DNA microarray platform was used. The transcriptome of seven biopsies obtained from dogs with histologically confirmed, surgically removed MCTs, treated with chemotherapy, and dead for MCT-related causes, was compared with the transcriptional portrait of 40 samples obtained from dogs with histologically confirmed, surgically removed MCTs and that were still alive at the end of the follow-up period. Among the differentially expressed genes (DEGs), eight transcripts were validated by quantitative real time PCR and their mRNA levels were measured in a cohort of 22 additional MCTs. Statistical analysis identified 375 DEGs (fold change 2, false discovery rate 5%). The functional annotation analysis indicated that the DEGs were associated with drug metabolism and cell cycle pathways. Particularly, members of solute carrier transporter (SLC) and UDP glucuronosyltransferase (UGT) gene families were identified as dysregulated. Principal component analysis (PCA) of the 22 additional MCTs identified the separate cluster dogs dead for MCT-related causes. SLCs and UGTs have been recently recognised in human cancer as important key factors in tumour progression and chemo-resistance. An in-depth analysis of their roles in aggressive canine MCT is warranted in future studies. PMID:27256023

  6. Coupling of UDP-glucuronosyltransferases and multidrug resistance-associated proteins is responsible for the intestinal disposition and poor bioavailability of emodin

    International Nuclear Information System (INIS)

    Emodin is a poorly bioavailable but promising plant-derived anticancer drug candidate. The low oral bioavailability of emodin is due to its extensive glucuronidation in the intestine and liver. Caco-2 cell culture model was used to investigate the interplay between UDP-glucuronosyltransferases (UGTs) and efflux transporters in the intestinal disposition of emodin. Bidirectional transport assays of emodin at different concentrations were performed in the Caco-2 monolayers with or without multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP) efflux transporter chemical inhibitors. The bidirectional permeability of emodin and its glucuronide in the Caco-2 monolayers was determined. Emodin was rapidly metabolized to emodin glucuronide in Caco-2 cells. LTC4, a potent inhibitor of MRP2, decreased the efflux of emodin glucuronide and also substantially increased the intracellular glucuronide level in the basolateral-to-apical (B–A) direction. MK-571, chemical inhibitor of MRP2, MRP3, and MRP4, significantly reduced the efflux of glucuronide in the apical-to-basolateral (A–B) and B–A directions in a dose-dependent manner. However, dipyridamole, a BCRP chemical inhibitor demonstrated no effect on formation and efflux of emodin glucuronide in Caco-2 cells. In conclusion, UGT is a main metabolic pathway for emodin in the intestine, and the MRP family is composed of major efflux transporters responsible for the excretion of emodin glucuronide in the intestine. The coupling of UGTs and MRP efflux transporters causes the extensive metabolism, excretion, and low bioavailability of emodin. -- Highlights: ► Glucuronidation is the main reason for the poor oral bioavailability of emodin. ► Efflux transporters are involved in the excretion of emodin glucuronide. ► The intestine is the main organ for metabolism of emodin.

  7. Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

    International Nuclear Information System (INIS)

    Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (Ki) were determined for the compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (Ki) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7. - Highlights: • Specific inhibition of andrographolide derivatives towards UGT2B7. • Herb-drug interaction related withAndrographis paniculata. • Guidance for design of UGT2B7 specific inhibitors

  8. Effects of aqueous extract of Ruta graveolens and its ingredients on cytochrome P450, uridine diphosphate (UDP-glucuronosyltransferase, and reduced nicotinamide adenine dinucleotide (phosphate (NAD(PH-quinone oxidoreductase in mice

    Directory of Open Access Journals (Sweden)

    Yune-Fang Ueng

    2015-09-01

    Full Text Available Ruta graveolens (the common rue has been used for various therapeutic purposes, including relief of rheumatism and treatment of circulatory disorder. To elucidate the effects of rue on main drug-metabolizing enzymes, effects of an aqueous extract of the aerial part of rue and its ingredients on cytochrome P450 (P450/CYP, uridine diphosphate (UDP-glucuronosyltransferase, and reduced nicotinamide adenine dinucleotide (phosphate (NAD(PH:quinone oxidoreductase were studied in C57BL/6JNarl mice. Oral administration of rue extract to males increased hepatic Cyp1a and Cyp2b activities in a dose-dependent manner. Under a 7-day treatment regimen, rue extract (0.5 g/kg induced hepatic Cyp1a and Cyp2b activities and protein levels in males and females. This treatment increased hepatic UDP-glucuronosyltransferase activity only in males. However, NAD(PH:quinone oxidoreductase activity remained unchanged. Based on the contents of rutin and furanocoumarins of mouse dose of rue extract, rutin increased hepatic Cyp1a activity and the mixture of furanocoumarins (Fmix increased Cyp2b activities in males. The mixture of rutin and Fmix increased Cyp1a and Cyp2b activities. These results revealed that rutin and Fmix contributed at least in part to the P450 induction by rue.

  9. Inhibitory effects of commonly used herbal extracts on UDP-glucuronosyltransferase 1A4, 1A6, and 1A9 enzyme activities.

    Science.gov (United States)

    Mohamed, Mohamed-Eslam F; Frye, Reginald F

    2011-09-01

    The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC(50)) and the volume in which the dose could be diluted to generate an IC(50)-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC(50) value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC(50) values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC(50) values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC(50)-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions. PMID:21632963

  10. Cadmium and arsenic override NF-κB developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia.

    Science.gov (United States)

    Liu, Miao; Chen, Shujuan; Yueh, Mei-Fei; Fujiwara, Ryoichi; Konopnicki, Camille; Hao, Haiping; Tukey, Robert H

    2016-06-15

    Humanized UDP-glucuronosyltransferase (UGT)-1 (hUGT1) mice encode the UGT1 locus including the UGT1A1 gene. During neonatal development, delayed expression of the UGT1A1 gene leads to hyperbilirubinemia as determined by elevated levels of total serum bilirubin (TSB). We show in this report that the redox-sensitive NF-κB pathway is crucial for intestinal expression of the UGT1A1 gene and control of TSB levels. Targeted deletion of IKKβ in intestinal epithelial cells (hUGT1/Ikkβ(ΔIEC) mice) leads to greater neonatal accumulation of TSB than observed in control hUGT1/Ikkβ(F/F) mice. The elevation in TSB levels in hUGT1/Ikkβ(ΔIEC) mice correlates with a reduction in intestinal UGT1A1 expression. As TSB levels accumulate in hUGT1/Ikkβ(ΔIEC) mice during the neonatal period, the increase over that observed in hUGT1/Ikkβ(F/F) mice leads to weight loss, seizures and eventually death. Bilirubin accumulates in brain tissue from hUGT1/Ikkβ(ΔIEC) mice inducing an inflammatory state as shown by elevated TNFα, IL-1β and IL-6, all of which can be prevented by neonatal induction of hepatic or intestinal UGT1A1 and lowering of TSB levels. Altering the redox state of the intestines by oral administration of cadmium or arsenic to neonatal hUGT1/Ikkβ(F/F) and hUGT1/Ikkβ(ΔIEC) mice leads to induction of UGT1A1 and a dramatic reduction in TSB levels. Microarray analysis following arsenic treatment confirms upregulation of oxidation-reduction processes and lipid metabolism, indicative of membrane repair or synthesis. Our findings indicate that the redox state in intestinal epithelial cells during development is important in maintaining UGT1A1 gene expression and control of TSB levels. PMID:27060662

  11. SERUM TOTAL BILIRUBIN, NOT CHOLELITHIASIS, IS INFLUENCED BY UGT1A1 POLYMORPHISM, ALPHA THALASSEMIA AND S GENOTYPE: FIRST REPORT ON COMPARISON BETWEEN ARAB-INDIAN AND AFRICAN S GENES

    Directory of Open Access Journals (Sweden)

    Said Y ALkindi

    2015-10-01

    Full Text Available Background: We explored the potential relationship between steady state serum bilirubin levels and the incidence of cholelithiasis in the context of UGT1A1 gene A(TAnTAA promoter polymorphism in Omani sickle cell anemia (SCA patients, homozygotes for African (Benin and Bantu and Arab-Indian bS haplotypes, but sharing the same microgeographical environment and comparable life style factors.   Methods: 136 SCA patients were retrospectively studied in whom imaging data including abdominal CT scan, MRI or Ultrasonography was routinely available. Available data on the mean steady state hematological/biochemical parameters (n=136,  bs haplotypes(n=136, a globin gene status (n=105 and UGT1A1 genotypes(n=133 were reviewed from the respective medical records.   Results: The mean serum total bilirubin level was significantly higher in the homozygous UGT1A1(AT7 group as compared to  UGT1A1(AT6 group. Strikingly, cholelithiasis was not influenced by age, gender, alpha globin genotype or bS haplotypes in this SCA cohort.   Conclusion: As observed in other population groups, the UGT1A1 (AT7 homozygosity was significantly associated with raised serum total bilirubin level, but the prevalence of gallstones in the Omani SCA patients was not associated with a thalassaemia, UGT1A1 polymorphism, or bs haplotypes.

  12. UDP-glucuronosyltransferase (UGT) 1A9-overexpressing HeLa cells is an appropriate tool to delineate the kinetic interplay between breast cancer resistance protein (BRCP) and UGT and to rapidly identify the glucuronide substrates of BCRP.

    Science.gov (United States)

    Jiang, Wen; Xu, Beibei; Wu, Baojian; Yu, Rong; Hu, Ming

    2012-02-01

    The interplay between phase II enzymes and efflux transporters leads to extensive metabolism and low bioavailability for flavonoids. To investigate the simplest interplay between one UDP-glucuronosyltransferase isoform and one efflux transporter in flavonoid disposition, engineered HeLa cells stably overexpressing UGT1A9 were developed, characterized, and further applied to investigate the metabolism of two model flavonoids (genistein and apigenin) and excretion of their glucuronides. The results indicated that the engineered HeLa cells overexpressing UGT1A9 rapidly excreted the glucuronides of genistein and apigenin. The kinetic characteristics of genistein or apigenin glucuronidation were similar with the use of UGT1A9 overexpressed in HeLa cells or the commercially available UGT1A9. Small interfering (siRNA)-mediated UGT1A9 silencing resulted in a substantial decrease in glucuronide excretion (>75%, p MRP) 2 and MRP3 did not affect excretion of flavonoid glucuronides. In conclusion, the engineered HeLa cells overexpressing UGT1A9 is an appropriate model to study the kinetic interplay between UGT1A9 and BCRP in the phase II disposition of flavonoids. This simple cell model should also be very useful to rapidly identify whether a phase II metabolite is the substrate of BCRP. PMID:22071170

  13. Bilirubin Test

    Science.gov (United States)

    ... Bilirubin; Indirect Bilirubin; Unconjugated Bilirubin Formal name: Bilirubin - blood Related tests: Liver Panel ; GGT ; ALP ; AST ; ALT ; Hepatitis A ; Hepatitis B ; Hepatitis C ; Complete Blood Count ; Urinalysis ; Direct Antiglobulin ...

  14. Differential effect of over-expressing UGT1A1 and CYP1A1 on xenobiotic assault in MCF-7 cells

    International Nuclear Information System (INIS)

    Gene mutation has been considered as a major step of carcinogenesis. Some defective genes may induce spontaneous tumorigenesis, while others are required to interact with the environment to induce cancer. CYP1A1 and UGT1A1 are encoded for the respective phase I and II drug-metabolizing enzymes. Their expressions have been associated with breast cancer incidence in women, and some xenobiotics are substrates of these two enzymes. In the current study, cytochrome P450 (CYP) 1A1 and UDP-glucuronosyltransferase (UGT) 1A1 were over-expressed in the breast cancer MCF-7 cells, and potential interactions between these enzymes and estrogen or polycyclic aromatic hydrocarbon were evaluated. Compared with control cells (MCF-7VEC), reduced cell proliferation was seen in cells expressing UGT1A1 (MCF-7UGT1A1) under estradiol treatment. 7,12-Dimethylbenz[a]anthracene (DMBA) is an established breast cancer initiator in animal model. Over-expressing UGT1A1 reduced the binding of DMBA to DNA, and increased MCF-7UGT1A1 intact cells under DMBA treatment was verified by comet assay. On the other hand, intensified DMBA binding and damages were observed in MCF-7CYP1A1 cells. This study supported that UGT1A1 but not CYP1A1 expression could protect against xenobiotic assault

  15. Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9.

    Science.gov (United States)

    Kishi, Naoki; Takasuka, Akane; Kokawa, Yuki; Isobe, Takashi; Taguchi, Maho; Shigeyama, Masato; Murata, Mikio; Suno, Manabu; Hanioka, Nobumitsu

    2016-04-01

    1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4'-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intestinal microsomes and recombinant UGT enzymes (UGT1A1, UGT1A8 and UGT1A9). 2. Although the Km and CLint values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in Vmax values (liver microsomes, humans > monkeys; intestinal microsomes, humans  UGT1A8 >UGT1A9 for humans, and UGT1A8 > UGT1A1 > UGT1A9 for monkeys. The activities of 4'-glucuronidation were UGT1A8 > UGT1A1 > UGT1A9 in humans and monkeys. 4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys. PMID:26247833

  16. Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1

    Directory of Open Access Journals (Sweden)

    Edavana VK

    2011-11-01

    Full Text Available Vineetha Koroth Edavana1, Xinfeng Yu1, Ishwori B Dhakal1, Suzanne Williams1, Baitang Ning2, Ian T Cook3, David Caldwell1, Charles N Falany3, Susan Kadlubar11Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Division of Personalized Nutrition and Medicine, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA; 3Department of Pharmacology, University of Alabama, Birmingham, AL, USAAbstract: Fulvestrant (Faslodex™ is a pure antiestrogen that is approved to treat hormone receptor-positive metastatic breast cancer in postmenopausal women. Previous studies have demonstrated that fulvestrant metabolism in humans involves cytochromes P450 and UDP-glucuronosyltransferases (UGTs. To date, fulvestrant sulfation has not been characterized. This study examined fulvestrant sulfation with nine recombinant sulfotransferases and found that only SULT1A1 and SULT1E1 displayed catalytic activity toward this substrate, with Km of 4.2 ± 0.99 and 0.2 ± 0.16 µM, respectively. In vitro assays of 104 human liver cytosols revealed marked individual variability that was highly correlated with β-naphthol sulfation (SULT1A1 diagnostic substrate; r = 0.98, P < 0.0001, but not with 17ß-estradiol sulfation (SULT1E1 diagnostic substrate; r = 0.16, P = 0.10. Fulvestrant sulfation was correlated with both SULT1A1*1/2 genotype (P value = 0.023 and copy number (P < 0.0001. These studies suggest that factors influencing SULT1A1/1E1 tissue expression and/or enzymatic activity could influence the efficacy of fulvestrant therapy.Keywords: fulvestrant, sulfotransferase, genotype, copy number

  17. Cold stress initiates the Nrf2/UGT1A1/L-FABP signaling pathway in chickens.

    Science.gov (United States)

    Chen, X Y; Li, R; Geng, Z Y

    2015-11-01

    Cold stress triggers an anti-oxidative response in animals regulated by Nrf2 (nuclear factor 2-like, NFE2L2) binding to deoxyribonucleic acid-regulatory sequences near stress-responsive genes. To identify chicken Nrf2-regulated genes, 3 genetically related experimental groups (EG) with 40 Huainan partridge chickens in each group were chosen. The chickens were maintained at 20°C environmental temperature from 5 wk of age. At 6 wk of age, 10 chickens from each EG were still maintained at 20°C as control, and the other 30 chickens from each EG were exposed to 6 ± 2°C. Liver samples were collected from the control and from chickens exposed to 6 ± 2°C for 12, 24, and 72 h for co-immuno-precipitation (CoIP) analysis. Chromatin immunoprecipitation (ChIP)-sequencing experiment in liver cells treated with Dimethyl fumarate (DMF) were carried out. A de novo motif was discovered which closely matched the core Nrf2 consensus binding motif. Genes involved in de novo motif discovery were further analyzed for their enrichment in the anti-oxidative response pathway and the lipid anabolism pathway. There were 14 genes found which are related to oxidative stress. To examine the downstream factors of the 14 responsive genes, one of them, UGT1A1 (UDP glucuronosyltransferase), was further analyzed by CoIP experiment and nano LC-ESI-MS/MS analysis. It was detected that fatty acid-binding protein (L-FABP, 127 AA) might be the potential UGT1A1 downstream interaction proteins. In conclusion, it is proposed that chickens under cold stress generate anti-oxidative stress and thus trigger the Nrf2/ARE signaling pathway, which further up-regulates the expression of L-FABP to inactivate lipid peroxidation of the cell membrane and promote fatty acid storage against the cold environment. PMID:26453599

  18. Inherited Disorders of Bilirubin Clearance

    OpenAIRE

    Memon, Naureen; Weinberger, Barry I; Hegyi, Thomas; Aleksunes, Lauren M

    2015-01-01

    Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be due to defective 1) unconjugated bilirubin uptake and intrahepatic storage, 2) conjugation of glucuronic acid to bilirubin (e.g. Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk jaundice), 3) bilirubin excretion into bile (Dubin-Johnson syndrome), or 4) conjugated bilirubin re-uptake (Rotor syndrom...

  19. [Cytoprotective effects of bilirubin].

    Science.gov (United States)

    Vítek, L

    2005-01-01

    Bilirubin, a major product of heme catabolism, belongs to compounds with pleiotropic biologic effects. For a long time bilirubin was considered as a metabolite dangerous for human health, neonatologists know well serious clinical complication of neonatal jaundice called bilirubin encephalopathy. Nevertheless, recent data has demonstrated that bilirubin exhibits potent antioxidant and even anti-inflammatory effects with substantial clinical impacts. The aim of the present study was to summarize present knowledge in this rapidly evolving field and suggest further possible clinical consequences. PMID:15981989

  20. Blood Test: Bilirubin

    Science.gov (United States)

    ... the blood. Babies with high levels may need phototherapy (treatment with a special light that makes bilirubin ... are afraid of needles. Explaining the test in terms your child can understand might help ease some ...

  1. Inherited Disorders of Bilirubin Clearance

    Science.gov (United States)

    Memon, Naureen; Weinberger, Barry I; Hegyi, Thomas; Aleksunes, Lauren M

    2016-01-01

    Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be due to defective 1) unconjugated bilirubin uptake and intrahepatic storage, 2) conjugation of glucuronic acid to bilirubin (e.g. Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk jaundice), 3) bilirubin excretion into bile (Dubin-Johnson syndrome), or 4) conjugated bilirubin re-uptake (Rotor syndrome). In this review, the molecular mechanisms and clinical manifestations of these conditions are described, as well as current approaches to diagnosis and therapy. PMID:26595536

  2. A genome-wide association study identifies UGT1A1 as a regulator of serum cell-free DNA in young adults: The Cardiovascular Risk in Young Finns Study.

    Directory of Open Access Journals (Sweden)

    Juulia Jylhävä

    Full Text Available INTRODUCTION: Circulating cell-free DNA (cf-DNA is a useful indicator of cell death, and it can also be used to predict outcomes in various clinical disorders. Several innate immune mechanisms are known to be involved in eliminating DNA and chromatin-related material as part of the inhibition of potentially harmful autoimmune responses. However, the exact molecular mechanism underlying the clearance of circulating cf-DNA is currently unclear. METHODS: To examine the mechanisms controlling serum levels of cf-DNA, we carried out a genome-wide association analysis (GWA in a cohort of young adults (aged 24-39 years; n = 1841; 1018 women and 823 men participating in the Cardiovascular Risk in Young Finns Study. Genotyping was performed with a custom-built Illumina Human 670 k BeadChip. The Quant-iT(TM high sensitivity DNA assay was used to measure cf-DNA directly from serum. RESULTS: The results revealed that 110 single nucleotide polymorphisms (SNPs were associated with serum cf-DNA with genome-wide significance (p<5×10(-8. All of these significant SNPs were localised to chromosome 2q37, near the UDP-glucuronosyltransferase 1 (UGT1 family locus, and the most significant SNPs localised within the UGT1 polypeptide A1 (UGT1A1 gene region. CONCLUSION: The UGT1A1 enzyme catalyses the detoxification of several drugs and the turnover of many xenobiotic and endogenous compounds by glucuronidating its substrates. These data indicate that UGT1A1-associated processes are also involved in the regulation of serum cf-DNA concentrations.

  3. Evaluation of bisphenol A glucuronidation according to UGT1A1*28 polymorphism by a new LC–MS/MS assay

    International Nuclear Information System (INIS)

    The endocrine disruptor bisphenol A (BPA) is a frequently used chemical in the manufacture of consumer products. In humans, BPA is extensively metabolized to BPA glucuronide (BPAG) by different UDP-glucuronosyltransferase (UGT) isoforms. The study has been performed with the intention to improve the accuracy of published physiologically based pharmacokinetic models and to improve regulatory risk assessments of BPA. In order to gain insight into intestine, kidney, liver, and lung glucuronidation of BPA, human microsomes of all tested organs were used. BPAG formation followed Michaelis–Menten kinetics in the intestine and kidney, but followed substrate inhibition kinetics in the liver. Human lung microsomes did not show glucuronidation activity towards BPA. While the liver intrinsic clearance was very high (857 mL min−1 kg body weight−1), the tissue intrinsic clearances for the kidney and intestine were less than 1% of liver intrinsic clearance. Since BPA is a UGT1A1 substrate, we postulated that the common UGT1A1*28 polymorphism influences BPA glucuronidation, and consequently, BPA detoxification. Hepatic tissue intrinsic clearances for UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28 microsomes were 1113, 1075, and 284 mL min−1 kg body weight−1, respectively. Prior to microsomal experiments, the bioproduction of BPAG and stable isotope-labeled BPAG (BPAGd16) was performed for the purpose of the reliable and accurate quantification of BPAG. In addition, a sensitive LC–MS/MS analytical method for the simultaneous determination of BPA and BPAG based on two stable isotope-labeled internal standards was developed and validated. In conclusion, our in vitro results show that the liver is the main site of BPA glucuronidation (Km 8.9 μM, Vmax 8.5 nmol min−1 mg−1) and BPA metabolism may be significantly influenced by a person's genotype (Km 10.0–13.1 μM, Vmax 3.4–16.2 nmol min−1 mg−1). This discovery may be an important fact for the currently on

  4. Bilirubin measurements in neonates

    Science.gov (United States)

    Newman, Gregory J.

    2000-04-01

    Infant Jaundice is a physiologic condition of elevated bilirubin in the tissue that affects nearly 60 percent of all term newborns and virtually 100 percent of premature infants. The high production of bilirubin in the newborn circulatory system and the inability of the immature liver to process and eliminate it case the condition. When the bilirubin levels rise, it starts to deposit in the baby's skin and in the brain. The deposits in the brain can cause neurologic impairment and death. The BiliCheck is a handheld, battery-powered device that measures the level of jaundice non-invasively using BioPhotonics at the point of care. The result is displayed on an LCD screen immediately, so physicians can now make treatment decision without waiting for results to return from the lab. The BiliCheck System has been marketed worldwide since April of 1998 and has received FDA clearance for use in the USA on pre-photo therapy infants in March of 1999.

  5. In Vitro Metabolism of Montelukast by Cytochrome P450s and UDP-Glucuronosyltransferases.

    Science.gov (United States)

    Cardoso, Josiane de Oliveira; Oliveira, Regina Vincenzi; Lu, Jessica Bo Li; Desta, Zeruesenay

    2015-12-01

    Montelukast has been recommended as a selective in vitro and in vivo probe of cytochrome P450 (P450) CYP2C8 activity, but its selectivity toward this enzyme remains unclear. We performed detailed characterization of montelukast metabolism in vitro using human liver microsomes (HLMs), expressed P450s, and uridine 5'-diphospho-glucuronosyltransferases (UGTs). Kinetic and inhibition experiments performed at therapeutically relevant concentrations reveal that CYP2C8 and CYP2C9 are the principal enzymes responsible for montelukast 36-hydroxylation to 1,2-diol. CYP3A4 was the main catalyst of montelukast sulfoxidation and stereoselective 21-hydroxylation, and multiple P450s participated in montelukast 25-hydroxylation. We confirmed direct glucuronidation of montelukast to an acyl-glucuronide. We also identified a novel peak that appears consistent with an ether-glucuronide. Kinetic analysis in HLMs and experiments in expressed UGTs indicate that both metabolites were exclusively formed by UGT1A3. Comparison of in vitro intrinsic clearance in HLMs suggest that direct glucuronidation may play a greater role in the overall metabolism of montelukast than does P450-mediated oxidation, but the in vivo contribution of UGT1A3 needs further testing. In conclusion, our in vitro findings provide new insight toward montelukast metabolism. The utility of montelukast as a probe of CYP2C8 activity may be compromised owing to involvement of multiple P450s and UGT1A3 in its metabolism. PMID:26374173

  6. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk.

    Science.gov (United States)

    Hu, Dong Gui; Mackenzie, Peter I; McKinnon, Ross A; Meech, Robyn

    2016-01-01

    Identification of genetic polymorphisms that contribute to the risk of developing cancers is important for cancer prevention. The most recent human genome GRCh38/hg38 assembly (2013) reveals thousands of genetic polymorphisms in human uridine diphosphoglucuronosyltransferase (UGT) genes. Among these, a large number of polymorphisms at the UGT1A and UGT2B genes have been shown to modulate UGT gene promoter activity or enzymatic activity. Glucuronidation plays an important role in the metabolism and clearance of endogenous and exogenous carcinogenic compounds, and this reaction is primarily catalyzed by the UGT1A and UGT2B enzymes. Therefore, it has long been hypothesized that UGT polymorphisms that reduce the capacity to glucuronidate carcinogens and other types of cancer-promoting molecules (e.g. sex hormones) are associated with an increased risk of developing cancers. A large number of case-control studies have investigated this hypothesis and these studies identified numerous UGT polymorphisms in UGT1A and UGT2B genes as genetic risk factors for a wide variety of cancers, including bladder, breast, colorectal, endometrial, esophageal, head and neck, liver, lung, prostate, and thyroid. These UGT polymorphisms may be cancer causative polymorphisms, or be linked to as yet undefined causative polymorphisms, either in UGT genes or neighboring genes. This article presents a comprehensive review of these case-control studies, discusses current areas of uncertainty, and highlights future research directions in this field. PMID:26828111

  7. Susceptibility to Exposure to Heterocyclic Amines from Cooked Food: Role of UDP-glucuronosyltransferases

    Energy Technology Data Exchange (ETDEWEB)

    Malfatti, M A; Felton, J S

    2005-08-22

    A number of carcinogenic heterocyclic amines (PhIP, MeIQx, and DiMeIQx) are produced from the condensation of creatinine, hexoses and amino acids during the cooking of meat (1). There are many variables that impact the production and subsequent ingestion of these compounds in our diet. Temperature, type of meat product, cooking method, doneness, and other factors affect the quantity of these carcinogens consumed by humans. Estimates of ingestion of these carcinogens are 1-20 ng/kg body weight per day (2). Human case control studies that correlate meat consumption from well-done cooking practices with cancer incidence indicate excess tumors for breast, colon, stomach, esophagus, and possibly prostate (3-5).

  8. Bilirubin Binding to PPARα Inhibits Lipid Accumulation.

    Science.gov (United States)

    Stec, David E; John, Kezia; Trabbic, Christopher J; Luniwal, Amarjit; Hankins, Michael W; Baum, Justin; Hinds, Terry D

    2016-01-01

    Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. In the present study, we found that bilirubin has a new function as a ligand for PPARα. We show that bilirubin can bind directly to PPARα and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPARα transcriptional activation to known PPARα ligands, WY 14,643 and fenofibrate, it showed that fenofibrate and biliverdin have similar activation properties. Treatment of 3T3-L1 adipocytes with biliverdin suppressed lipid accumulation and upregulated PPARα target genes. We treated wild-type and PPARα KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPARα dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPARα KO mice. These data demonstrate a new function for bilirubin as an agonist of PPARα, which mediates the protection from adiposity afforded by moderate increases in bilirubin. PMID:27071062

  9. PPARα: A Master Regulator of Bilirubin Homeostasis

    OpenAIRE

    Cyril Bigo; Jenny Kaeding; Diala El Husseini; Iwona Rudkowska; Mélanie Verreault; Marie Claude Vohl; Olivier Barbier

    2014-01-01

    Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR) α to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARα agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC) and coronary artery smooth muscle cells (CASMC) were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin...

  10. Intermolecular interactions in the bilirubin-cholate-silica system

    Science.gov (United States)

    Vlasova, N. N.; Golovkova, L. P.; Severinovskaya, O. V.

    2007-06-01

    Bilirubin-cholate interactions in aqueous solutions were studied. The constants of binding of bilirubin with taurocholate dimers and taurodeoxycholate trimers were calculated. The adsorption of bilirubin and cholates on the surface of highly dispersed silica was studied. It was shown that taurine-conjugated cholates are poorly adsorbed from micellar solutions on the silica surface, the specific amount of bilirubin adsorbed decreases with increasing concentration of cholates in the solution, the affinity of free bilirubin for the silica surface is independent of the nature of the cholic acid, and that the affinity of cholate-bilirubin complexes for the silica surface is lower than the affinity of free bilirubin.

  11. Novel associations of UDP-glucuronosyltransferase 2B gene variants with prostate cancer risk in a multiethnic study

    International Nuclear Information System (INIS)

    We have previously shown that a functional polymorphism of the UGT2B15 gene (rs1902023) was associated with increased risk of prostate cancer (PC). Novel functional polymorphisms of the UGT2B17 and UGT2B15 genes have been recently characterized by in vitro assays but have not been evaluated in epidemiologic studies. Fifteen functional SNPs of the UGT2B17 and UGT2B15 genes, including cis-acting UGT2B gene SNPs, were genotyped in African American and Caucasian men (233 PC cases and 342 controls). Regression models were used to analyze the association between SNPs and PC risk. After adjusting for race, age and BMI, we found that six UGT2B15 SNPs (rs4148269, rs3100, rs9994887, rs13112099, rs7686914 and rs7696472) were associated with an increased risk of PC in log-additive models (p < 0.05). A SNP cis-acting on UGT2B17 and UGT2B15 expression (rs17147338) was also associated with increased risk of prostate cancer (OR = 1.65, 95% CI = 1.00-2.70); while a stronger association among men with high Gleason sum was observed for SNPs rs4148269 and rs3100. Although small sample size limits inference, we report novel associations between UGT2B15 and UGT2B17 variants and PC risk. These associations with PC risk in men with high Gleason sum, more frequently found in African American men, support the relevance of genetic differences in the androgen metabolism pathway, which could explain, in part, the high incidence of PC among African American men. Larger studies are required

  12. Characterization of Bucolome N-Glucuronide Formation: Tissue Specificity and Identification of Rat UDP-Glucuronosyltransferase Isoform (s)

    OpenAIRE

    Humihisa Kanoh; Makiko Tada; Shinichi Ikushiro; Kiminori Mohri

    2011-01-01

    Bucolome N-glucuronide (BCP-NG, main metabolite of bucolome (BCP) is the first N-glucuronide of barbituric acid derivatives isolated from rat bile. The objective of this study was to identify the main tissue producing BCP-NG and the molecular species of BCP-NG-producing UGT. Four target tissues were investigated: the liver, small and large intestines, and kidney. To identify the UGT molecular species responsible for BCP-NG formation, yeast microsomes expressing each rat UGT isoform were prepa...

  13. Initial photochemistry of bilirubin probed by femtosecond spectroscopy.

    Science.gov (United States)

    Zietz, Burkhard; Gillbro, Tomas

    2007-10-18

    Bilirubin is a breakdown product from heme catabolism, and reduced excretion of bilirubin can lead to jaundice. Phototherapy is the most common treatment for neonatal jaundice, a condition frequently encountered in newborn infants. Knowledge of the photochemistry of bilirubin, which is dominated by (ultra)fast components, is necessary for the profound understanding of the processes in phototherapy. Here, we report results from femtosecond fluorescence upconversion measurements on bilirubin and half-bilirubin model compounds, as well as pump-probe absorption measurements on bilirubin. A fast component of ca. 120 fs in the multiexponential fluorescence decay, being only visible in the bilirubin molecule, is interpreted as exciton localization within the molecular halves. The slower components of several hundreds of femtoseconds and a few picoseconds, occurring in bilirubin and the half-bilirubin model, are interpreted as relaxation to a (twisted) intermediate, which decays further with ca. 15 ps to the ground state. PMID:17927274

  14. Polymorphic variants of UGT1A1 in neonatal jaundice in southern Brazil.

    Science.gov (United States)

    Carvalho, Clarissa Gutiérrez; Castro, Simone Martins; Santin, Ana Paula; de Azevedo, Laura Alencastro; Pereira, Maria Luiza Saraiva; Giugliani, Roberto

    2010-10-01

    Alterations in the hepatic conjugation of bilirubin due to uridyl-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms have been proposed as risk factors to neonatal jaundice. Herein, we estimated the frequency of genotypes of the promoter region of UGT1A1 gene in newborns and evaluated its association with severe hyperbilirubinemia. Prospective study of cases and controls including all newborns admitted for phototherapy at HCPA, Brazil, during 9 months; 490 babies were enrolled and PCR was performed. Polymorphic genotypes were detected in 16% of the patients and 7 of the 10 possible genotypes were identified with higher prevalence of polymorphisms in Afro-descendants. In this sample, the variants of UGT1A1 were not associated to severe hyperbilirubinemia; other genic factors should be sought in this high miscegenation area of Brazil. PMID:20061399

  15. Prognostic significance of serum bilirubin in stroke

    International Nuclear Information System (INIS)

    Background: Oxidative injury is an important cause of the neurologic lesion in stroke. Serum bilirubin is considered a natural antioxidant that may affect the prognosis of stroke. The purpose of this study was to evaluate the prognostic significance of bilirubin in stroke patients. Methods: A prospective cross-sectional study was conducted in Medical Units of Khyber Teaching Hospital, Peshawar. Inpatients admitted with acute attack of stroke were included in this study. Data regarding serum bilirubin and concurrent cerebrovascular risk factors were collected. National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were used to analyse stroke's severity and functional outcomes, respectively. Results: Hypertension, diabetes mellitus and heart diseases were the most common risk factors. Patients were divided into 3 groups on the basis of serum bilirubin, i.e., =0.6 mg/dl (Group-1), 0.7-0.9 mg/dl (Group-2), and =1.0 mg/dl (Group-3). The mean pre-hospitalisation NIHSS score for Groups 1, 2 and 3 was 5.62, 11.66 and 25.33, respectively; and post-hospitalisation score was 0.875, 3.76 and 16.26, respectively. The pre-hospitalisation mRS score was 4 for Group-1, 4.52 for Group-2 and 4.93 for Group-3; while post-hospitalisation Mrs Score was 1.50, 2.38 and 4.26, respectively. Average serum bilirubin level was significantly higher in patients with poor outcomes as compared with good outcomes (p<0.01). Conclusions: This study suggests that higher serum bilirubin levels were associated with increased stroke severity, longer hospitalisation and poor prognosis. (author)

  16. Serum Bilirubin Levels and Developmental Outcome

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-05-01

    Full Text Available The neurodevlopmental risks associated with neonatal total serum bilirubin levels of 25 mg/dL or higher in 140 affected infants were compared with 419 randomly selected controls from a cohort of term-infants born 1995-1998 in Kaiser Permanente hospitals in northern California.

  17. Mechanisms of bilirubin toxicity: clinical implications.

    Science.gov (United States)

    Hansen, Thor Willy Ruud

    2002-12-01

    The basic mechanism of kernicterus and bilirubin encephalopathy has not been unequivocally determined. Much knowledge has been gained about phenomena that contribute to bilirubin neurotoxicity, and this knowledge has implications for clinical practice. Conditions that impact on blood-brain barrier function, increase brain blood flow, or impact on bilirubin metabolism, including its transport in serum, should be avoided, if possible. Such conditions include drugs and drug stabilizers that compete with bilirubin binding to albumin, or that inhibit P-glycoprotein in the blood-brain barrier, prematurity/immaturity, and clinically significant illness in the infant that involves hemolysis, respiratory and metabolic acidosis, infection, asphyxia, hypoxia and (perhaps) hyperoxia, and hyperosmolality. If these conditions are not avoidable then there should be a more aggressive approach to the treatment of hyperbilirubinemia. The limits of tolerance for hyperbilirubinemia varies among neonates and there are no tools to determine with certainty when a particular infant is approaching the danger zone. Neurological symptoms in a jaundiced infant require extreme vigilance, and, in most cases, immediate intervention. PMID:12516745

  18. The clinical application of UGT1A1 pharmacogenetic testing: Gene-environment interactions

    Directory of Open Access Journals (Sweden)

    Marques Sara

    2010-04-01

    Full Text Available Abstract Over the past decade, the number of pharmacogenetic tests has increased considerably, allowing for the development of our knowledge of their clinical application. The uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1 assay is an example of a pharmacogenetic test. Numerous variants have been found in UGT1A1, the main conjugating enzyme of bilirubin and drugs such as the anticancer drug irinotecan. Recently, the US Food and Drug Administration (FDA recommended testing for the presence of UGT1A1*28, an allele correlated with decreased transcriptional activity, to predict patients at risk of irinotecan toxicity. The administration of other drugs -- such as inhibitors of the UGT1A1 enzyme -- can clinically mimic the *28 phenotype, whereas inducers of UGT1A1 can increase the glucuronidation rate of the enzyme. The *28 polymorphism is not present in all ethnicities at a similar frequency, which suggests that it is important to study different populations to determine the clinical relevance of testing for UGT1A1*28 and to identify other clinically relevant UGT1A1 variants. Environmental factors such as lifestyle can also affect UGT1A1 activity. This review is a critical analysis of studies on drugs that can be affected by the presence of UGT1A1*28, the distribution of this polymorphism around the globe, distinct variants that may be clinically significant in African and Asian populations and how lifestyle can affect treatment outcomes that depend on UGT1A1 activity.

  19. BILIRUBIN AS AN INDIRECT MEASURE OF LABORATORY PERFORMANCE OF BILIRUBIN DETERMINATIONS

    Directory of Open Access Journals (Sweden)

    Suresh Babu

    2015-09-01

    Full Text Available OBJECTIVE : To correlate Total Serum Bilirubin (TSB values to the clinical course of hyperbilirubinemia in newborns as this can be an indirect method of quality assurance in the laboratory. METHODS : An observational study of bilirubin values from 100 randomly selected case records of newborn jaundice for a period of 6 months. TSB values were determined by diazo reaction on venous blood samples on a semi auto analyzer. MS excel sheet used for statistical analysis. RESULTS : Clinical course of hyperbilirubinemia in all subjects correlated well to the reported TSB values in first to last zones corresponding to 15 mg /dL on 3rd day to 5th day of age. Zones 3, 4 and 5 varied from 7th day of birth, as phototherapy and recovery altered visual assessment of jaundice. One patient was expired with kernicterus had very high TSB value. The median bilirubin values trend downfall which correlated clinically to recovery from jaundice and 33% rapid decline in TSB also indicated the intervention by phototherapy. CONCLUSIONS : Bilirubin is one parameter with higher inter laboratory variability since its discovery till today. Hence more quality methods are to be developed to minimize this bias in clinical interpretation of reported bilirubin levels. Our study is an intermediary quality measure useful for both clinicians and lab personnel. This study can be adopted for retrospective quality evaluation and can be adopted for other parameters as well.

  20. Hepatocyte cotransport of taurocholate and bilirubin glucuronides: Role of microtubules

    International Nuclear Information System (INIS)

    Modulation of bile pigment excretion by bile salts has been attributed to modification of canalicular membrane transport or a physical interaction in bile. Based on the observation that a microtubule-dependent pathway is involved in the hepatocellular transport of bile salts, the authors investigated the possibility that bilirubin glucuronides are associated with bile salts during intracellular transport. Experiments were conducted in intact rats (basal) or after overnight biliary diversion and intravenous reinfusion of taurocholate (depleted/reinfused). All rats were pretreated with intravenous low-dose colchicine or its inactive isomer lumicolchicine. Biliary excretion of radiolabeled bilirubin glucuronides derived from tracer [14C]bilirubin-[3H]bilirubin monoglucuronide (coinjected iv) was unchanged in basal rats but was consistently delayed in depleted/reinfused rats. This was accompanied by a significant shift toward bilirubin diglucuronide formation from both substrates. In basal Gunn rats, with deficient bilirubin glucuronidation, biliary excretion of intravenous [14C]bilirubin monoglucuronide-[3H]bilirubin diglucuronide was unaffected by colchicine but was retarded in depleted/reinfused Gunn rats. Colchicine had no effect on the rate of bilirubin glucuronidation in vitro in rat liver microsomes. They conclude that a portion of the bilirubin glucuronides generated endogenously in hepatocytes or taken up directly from plasma may be cotransported with bile salts to the bile canalicular membrane via a microtubule-dependent mechanism

  1. Rapid clearance of a structural isomer of bilirubin during phototherapy.

    OpenAIRE

    Ennever, J F; Costarino, A T; Polin, R A; Speck, W T

    1987-01-01

    During phototherapy for neonatal jaundice, bilirubin is converted into a variety of photoproducts. Determination of the relative importance of these photoproducts to the elimination of bilirubin requires knowledge of their rates of excretion. We have measured the rate at which the structural isomer of bilirubin, lumirubin, disappeared from the serum of nine jaundiced premature infants after the cessation of phototherapy. In all patients studied, the decline in serum lumirubin could be approxi...

  2. Bilirubin and its oxidation products damage brain white matter

    OpenAIRE

    Lakovic, Katarina; Ai, Jinglu; D'abbondanza, Josephine; Tariq, Asma; Sabri, Mohammed; Alarfaj, Abdullah K; Vasdev, Punarjot; Macdonald, Robert Loch

    2014-01-01

    Brain injury after intracerebral hemorrhage (ICH) occurs in cortex and white matter and may be mediated by blood breakdown products, including hemoglobin and heme. Effects of blood breakdown products, bilirubin and bilirubin oxidation products, have not been widely investigated in adult brain. Here, we first determined the effect of bilirubin and its oxidation products on the structure and function of white matter in vitro using brain slices. Subsequently, we determined whether these compound...

  3. Antioxidant mechanism of bilirubin: both HAT and SET are possible

    International Nuclear Information System (INIS)

    Bilirubin (BR) plays two extreme roles in physiology, one hand it is a toxic metabolite while at micromolar concentration it acts as antioxidant. It has been observed that hydroxyl, glutathiyl and Linoleic peroxyl radicals abstract hydrogen atom from bilirubin, whereas N3, Br2, CCl3OO, NO2 radicals react via single electron transfer action. Our study demonstrates that oxidation of bilirubin occurs via both hydrogen atom transfer and single electron transfer depending on the nature of the radical. (author)

  4. Bilirubin/Albumin Ratio for Predicting Acute Bilirubin-induced Neurologic Dysfunction

    Directory of Open Access Journals (Sweden)

    Gholamreza Esmaeeli Djavid

    2011-03-01

    Full Text Available Objective:The aim of this study was to evaluate the bilirubin albumin (B/A ratio in comparison with total serum bilirubin (TSB for predicting acute bilirubin-induced neurologic dysfunction (BIND. Methods:Fifty two term and near term neonates requiring phototherapy and exchange transfusion for severe hyperbilirubinemia in Childrens Medical Center, Tehran, Iran, during September 2007 to September 2008, were evaluated. Serum albumin and bilirubin were measured at admission. All neonates were evaluated for acute BIND based on clinical findings. Findings:Acute BIND developed in 5 (3.8% neonates. B/A ratio in patients with BIND was significantly higher than in patients without BIND (P<0.001. Receiver operation characteristics (ROC analysis identified a TSB cut off value of 25 mg/dL [area under the curve (AUC 0.945] with a sensitivity of 100% and specificity of 85%. Also, according to the ROC curve, B/A ratio cut off value for predicting acute BIND was 8 (bil mg/al g (AUC 0.957 with sensitivity of 100% and specificity of 94%. Conclusion:Based on our results, we suggest using B/A ratio in conjunction with TSB. This can improve the specificity and prevent unnecessary invasive therapy such as exchange transfusion in icteric neonates.

  5. Comparison of serum bilirubin estimation with transcutaneous bilirubinometry in neonates

    International Nuclear Information System (INIS)

    Objective: To assess usefulness of Minolta Air shield transcutaneous bilirubinometer by comparing bilirubin values obtained by transcutaneous jaundice meter with serum bilirubin estimation. Design: Analytical cross sectional study. Place and duration: NICU Military Hospital Rawalpindi Pakistan Jun 2002 to May 2005. Subjects and Methods: One hundred and fifty neonates admitted to NICU because of visible jaundice were included in the study. Serum was sent to laboratory for total bilirubin estimation. At the same time bilirubin was also checked by a Jaundice Meter. Data was tabulated and t-test applied to compare the two values. Results: One hundred and fifty paired estimations were performed. The transcutaneous bilirubin values ranged from 8.0 mg/dl to 20.4 mg/dl. While serum bilirubin by jaundice meter values ranged between 5.3 mg/dl and 26.0 mg/dl. A Scatter diagram was plotted. It showed a correlation coefficient of 0.78. Conclusion: Bilirubin values obtained by transcutaneous bilirubin meter were not significantly different from laboratory values thus proving the fact that transcutaneous bilirubinometer is a useful device to measure bilirubin. (author)

  6. Bilirubin and its oxidation products damage brain white matter.

    Science.gov (United States)

    Lakovic, Katarina; Ai, Jinglu; D'Abbondanza, Josephine; Tariq, Asma; Sabri, Mohammed; Alarfaj, Abdullah K; Vasdev, Punarjot; Macdonald, Robert Loch

    2014-11-01

    Brain injury after intracerebral hemorrhage (ICH) occurs in cortex and white matter and may be mediated by blood breakdown products, including hemoglobin and heme. Effects of blood breakdown products, bilirubin and bilirubin oxidation products, have not been widely investigated in adult brain. Here, we first determined the effect of bilirubin and its oxidation products on the structure and function of white matter in vitro using brain slices. Subsequently, we determined whether these compounds have an effect on the structure and function of white matter in vivo. In all, 0.5 mmol/L bilirubin treatment significantly damaged both the function and the structure of myelinated axons but not the unmyelinated axons in brain slices. Toxicity of bilirubin in vitro was prevented by dimethyl sulfoxide. Bilirubin oxidation products (BOXes) may be responsible for the toxicity of bilirubin. In in vivo experiments, unmyelinated axons were found more susceptible to damage from bilirubin injection. These results suggest that unmyelinated axons may have a major role in white-matter damage in vivo. Since bilirubin and BOXes appear in a delayed manner after ICH, preventing their toxic effects may be worth investigating therapeutically. Dimethyl sulfoxide or its structurally related derivatives may have a potential therapeutic value at antagonizing axonal damage after hemorrhagic stroke. PMID:25160671

  7. The effect of UGT1A1 promoter polymorphism in the development of hyperbilirubinemia and cholelithiasis in hemoglobinopathy patients.

    Directory of Open Access Journals (Sweden)

    Suad AlFadhli

    Full Text Available Present study was aimed to explore the effect of (TAn UGT1A1 gene promoter polymorphism on bilirubin metabolism, bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in Sickle-Cell Anemia (SCA and beta-Thalasemia major (bTH in Kuwaiti subjects compared to other population. This polymorphism was analyzed and correlated to total bilirubin and cholelithiasis in 270 age, gender, ethnically matched subjects (92 bTH, 116 SCA and 62 Controls using PCR, dHPLC, fragment analysis and direct sequencing. Four genotypes of UGT1A1 were detected in this study (TA6/6, TA6/7, TA6/8 and TA7/7. (TA6/8 was found only in four individuals; hence it was not included in the analysis. There was a statistically significant association of genotypes with serum total bilirubin levels in both bTH and SCA groups (p<0.001. Subjects with (TA7/7 had the highest total serum bilirubin level (178.7 ± 3.5 µmole/l. A significant association was observed between allele (TA7 and cholelithiasis development (p = 0.0001. The 40%, 67.5% and 100% of SCA with (TA6/6, (TA6/7 and (TA7/7 respectively developed cholelithiasis and were subsequently cholecystectomized. Our results confirm UGT1A1 (TA7 allele as one of the factors accounting for the hyperbilirubinemia and cholelithiasis observed in SCA and bTH.

  8. Cell damage by bilirubin and light

    International Nuclear Information System (INIS)

    Large doses of light are given to newborns during phototherapy for hyperbilirubinemia. Tissues containing concentrations of bilirubin almost in the mM range may be subjected to irradiation. Therefore it is of interest to study cellular effects of light and bilirubin on cells. In order to select the optimal wavelength, possible detrimental effects of light on cells must be taken into consideration among a number of other factors. In this study cellular effects of selected wavelengths of blue-green light are compared. It is not clear whether cullular damage occurs in vivo during phototherapy of newborns. Since a possibility exists that some adverse effects are caused by light, one should choose wavelengths where these effects are minimal without loosing therapeutic efficiency. Todays knowledge of the photochemical mechanisms of phototherapy, indicates that short waved light with wavelengths below 450 nm has a low therapeutic effect. The data in this paper indicate that the cellular damage is most severe at short wavelengths, and these should be reduced to a minimum in the spectra of phototherapy lamps. Further studies of possible side effects of phototherapy should be made. 64 refs., 34 figs., 1 tab

  9. Genetically elevated bilirubin and risk of ischaemic heart disease

    DEFF Research Database (Denmark)

    Stender, Stefan; Frikke-Schmidt, R; Nordestgaard, B G;

    2013-01-01

    Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a causal relationship remains unclear.......Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a causal relationship remains unclear....

  10. Low-normal free thyroxine confers decreased serum bilirubin in type 2 diabetes mellitus

    NARCIS (Netherlands)

    Deetman, Petronella E.; Kwakernaak, Arjan J.; Bakker, Stephan J. L.; Dullaart, Robin P. F.

    2013-01-01

    Background: Bilirubin may confer cardiovascular protection because of its strong antioxidative properties. Both thyroid dysfunction and the diabetic state affect bilirubin metabolism. Here we tested whether low-normal thyroid function affects serum bilirubin among euthyroid subjects with and without

  11. The inverse association of incident cardiovascular disease with plasma bilirubin is unaffected by adiponectin

    NARCIS (Netherlands)

    Dullaart, Robin P. F.; Boersema, Jeltje; Lefrandt, Joop D.; Wolffenbuttel, Bruce H. R.; Bakker, Stephan J. L.

    2014-01-01

    Objective: Bilirubin may protect against atherosclerotic cardiovascular disease (CVD). The heme oxygenase pathway is crucial for bilirubin generation, and is stimulated by adiponectin. We tested the relationship of plasma bilirubin with adiponectin, and determined whether the association of incident

  12. Transcutaneous Bilirubin Measurement in Preterm Neonates

    Directory of Open Access Journals (Sweden)

    Paymaneh Alizadeh Taheri

    2012-11-01

    Full Text Available Hyperbilirubinemia is a common problem during neonatal period especially in preterm neonates. Transcutaneous bilirubin measurement (TcB by special devices had been documented as an effective tool for predicting neonatal jaundice in full term neonate, but for preterm infants the present evidences are controversial. We carried out a prospective study in Shariati Hospital NICU. 126 paired TcB/total serum bilirubin (TSB measurements were obtained. TcB (on forehead and sternum were measured using JH2-1A device for every admitted preterm infant who clinically showed jaundice and TSB measurements was obtained within 30 min of TcB. 58 (46% were male and 68 (54% were female. The mean gestational age was 31 week and mean birth weight was 1728 ± 60 g. 30 percent of neonates were ill. The mean value obtained by TBS was 8.8 mg/dl and for frontal TcB was 8.2mg/dl and for sternal TcB was 7.4mg/dl. There were good correlation between TBS and TcB and the maximum correlation were seen in 33-37 weeks of gestation and birth weight more than 2500 g with forehead TcB measurement. Healthy preterm infants had significant correlation of TSB and TcB (r=0.56, P<0.001 and ill preterm neonate had r =0.82, P<0.001. The correlation between TBS and TcB with and without phototherapy was r=0.66, P=0.000 and r=0.69, P=0.000 respectively. Although TcB measurement may underestimate TBS but there is significant correlation between TcB and TBS in preterm cases even in ill neonate or who receiving phototherapy. This method can be used for determination of bilirbin level in preterm neonate and reduces the number of blood sampling.

  13. Trans-Cutaneous Bilirubinometery versus Serum Bilirubin in Neonatal Jaundice.

    Science.gov (United States)

    Mahram, Manoochehr; Oveisi, Sonia; Jaberi, Najmeh

    2015-12-01

    Hyperbilirubinemia is a common problem in neonates and causes serious complications. Thus, serial measurements of bilirubin should be done. This assessment is done through two methods of laboratory measurement in serum sample and transcutaneous bilirubinometer. This descriptive study compared transcutaneous bilirubin assessment and laboratory serum bilirubin. Bilirubin level was assessed among 256 neonates admitted to the Qods Children's Hospital in Qazvin- Iran, because of neonatal indirect jaundice, through two methods of transcutaneous bilirubinometery from two sites of forehead and sternum and laboratory measurement of bilirubin in serum. The cases were non-hemolytic icteric term neonates weighing 2500 gram or more and had not received phototherapy or other treatments. Neonates with hemolytic forms of jaundice, sepsis and suspicious to metabolic disorders were excluded. Assessments by means of KJ-8000 transcutaneous bilirubinometer from two sites of forehead and sternum and through laboratory measurement of serum bilirubin were registered and analyzed. The results of the current study showed that there was a correlation of 0.82 between serum bilirubin and transcutaneous forehead bilirubin assessment and for the used device sensitivity of 0.844; specificity of 0.842, Youden Index of 0.709 and Shortest of 0.042 for a cut-off of 12.4 in bilirubin of participants. Furthermore, Likelihood Ratio positive and negative (LR) were 5.665 and 0.164, respectively and diagnostic Odds Ratio (LR+/LR-) was 34.56. Transcutaneous bilirubinometery can be considered as a reliable tool to assess bilirubin for the screening of neonatal jaundice in term neonates. PMID:26749233

  14. Trans-Cutaneous Bilirubinometery versus Serum Bilirubin in Neonatal Jaundice

    Directory of Open Access Journals (Sweden)

    Manoochehr Mahram

    2015-12-01

    Full Text Available Hyperbilirubinemia is a common problem in neonates and causes serious complications. Thus, serial measurements of bilirubin should be done. This assessment is done through two methods of laboratory measurement in serum sample and transcutaneous bilirubinometer. This descriptive study compared transcutaneous bilirubin assessment and laboratory serum bilirubin. Bilirubin level was assessed among 256 neonates admitted to the Qods Children’s Hospital in Qazvin- Iran, because of neonatal indirect jaundice, through two methods of transcutaneous bilirubinometery from two sites of forehead and sternum and laboratory measurement of bilirubin in serum. The cases were non-hemolytic icteric term neonates weighing 2500 gram or more and had not received phototherapy or other treatments. Neonates with hemolytic forms of jaundice, sepsis and suspicious to metabolic disorders were excluded. Assessments by means of KJ-8000 transcutaneous bilirubinometer from two sites of forehead and sternum and through laboratory measurement of serum bilirubin were registered and analyzed. The results of the current study showed that there was a correlation of 0.82 between serum bilirubin and transcutaneous forehead bilirubin assessment and for the used device sensitivity of 0.844; specificity of 0.842, Youden Index of 0.709 and Shortest of 0.042 for a cut-off of 12.4 in bilirubin of participants. Furthermore, Likelihood Ratio positive and negative (LR were 5.665 and 0.164, respectively and diagnostic Odds Ratio (LR+/LR- was 34.56. Transcutaneous bilirubinometery can be considered as a reliable tool to assess bilirubin for the screening of neonatal jaundice in term neonates.

  15. [Does bilirubin interfere with capillary electrophoresis of serum proteins?].

    Science.gov (United States)

    Hellara, Ilhem; Fekih, Ons; Triki, Sonia; Elmay, Ahlem; Neffati, Fadoua; Najjar, Mohamed Fadhel

    2014-01-01

    Capillary electrophoresis of serum proteins is a fast, reliable and simple technique, but many interference exist. The objective of our work is to study the interference of bilirubin on this technique; 70 icteric sera were analysed on Capillarys ™ (Sebia). A second electrophoresis was performed on 40 samples after bilirubin photodegradation. The bilirubin and serum proteins were determinated respectively by Jendrassik and Grof and biuret methods on Konélab 20i ™ (Thermo Electron Corporation). We found abnormal spreading of the albumin fraction of the anode side wich constitute sometimes an isolated fraction in the traditional area of pre-albumin migration. This fraction varies from 2.0 ± 2.0% (0.0 to 7.3%) or 0.98 ± 1.53 g/L (0 to 5.3 g/L) and it seems to be related to the direct bilirubin since, following overloading sera with a solution of bilirubin, no further fraction was recovered. An average decrease of bilirubin after photodegradation of 58 ± 17% (26-89%) is followed by a decrease in the same order 64 ± 38% (10-100%) of the additional fraction. Acetate cellulose electrophoresis of the same samples showed no variation. The high bilirubin levels seem modify slightly the electrophoretic profile. However the impact of the interference on the interpretation of electrophoretic trace is negligible. PMID:24492101

  16. Atazanavir–bilirubin interaction: a pharmacokinetic–pharmacodynamic model

    Directory of Open Access Journals (Sweden)

    Lozano R

    2013-09-01

    Full Text Available Roberto Lozano,1 Nieves Domeque,2 Alberto-Fermin Apesteguia3 1Pharmacy Department, 2Psychiatry Department, Hospital Real Nuestra Señora de Gracia, 3Pharmacy Department, Hospital Clinico Universitario "Lozano Blesa", Zaragoza, Spain Purpose: The aim of this work was to analyze the atazanavir–bilirubin relationship, using a new mathematical approach to pharmacokinetic–pharmacodynamic models, for competitive drug interactions based on Michaelis–Menten equations. Patients and methods: Because atazanavir induces an increase of plasma bilirubin levels, in a concentration-dependent manner, we developed a mathematical model, based on increments of atazanavir and bilirubin concentrations at steady state, in HIV infected (HIV+ patients, and plotted the corresponding nomogram for detecting suboptimal atazanavir exposure. Results: By applying the obtained model, the results indicate that an absolute value or an increment of bilirubin at steady state below 3.8 µmol/L, are predictive of suboptimal atazanavir exposure and therapeutic failure. Conclusion: We have successfully implemented a new mathematical approach to pharmacokinetic–pharmacodynamic model for atazanavir–bilirubin interaction. As a result, we found that bilirubin plasma levels constitute a good marker of exposure to atazanavir and of viral suppression. Keywords: atazanavir, bilirubin, HIV/AIDS, pharmacodynamics, pharmacokinetics

  17. Relationship between serum bilirubin levels and optic neuritis

    Institute of Scientific and Technical Information of China (English)

    DENG Juan; LIANG Xue-mei; ZHANG Xiu-lan; LING Shi-qi; YANG Ting-ting; LI Min; PENG Fu-hua

    2013-01-01

    Background Bilirubin is the end product of heme catabolism and has strong antioxidant properties.Serum bilirubin levels are reported to be reduced in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO).The pathophysiology of optic neuritis (ON) resembles that of MS; however,the role of endogenous bilirubin in ON is unclear.The aim of this study is to measure serum bilirubin levels in patients with ON,and to investigate the correlation between ON and serum antioxidant status of bilirubin.Methods Serum levels of bilirubin were measured in 42 patients with ON,50 patients with multiple sclerosis (MS),48 patients with neuromyelitis optica (NMO) and 48 healthy control subjects.Results Serum total bilirubin (Tbil),direct bilirubin (Dbil) and indirect bilirubin (Ibil) levels in patients with ON were significantly lower than those in the healthy controls.However,no statistical significance was found between levels in the ON and MS,ON and NMO,and MS and NMO groups.In patients with ON,serum Tbil,Dbil,and Ibil levels were lower in those with recurrence or those with ON for a longer duration (>1 year).Moreover,Tbil,Dbil,and Ibil concentrations were lower in patients with papillitis than in those with retrobulbar type ON,but the differences were not statistically significant.Conclusions Low antioxidant status may exist in patients with ON.But serum levels of Tbil,Dbil,and Ibil did not correlate with clinical presentations,such as recurrence,duration of disease and subtypes of ON.Low antioxidant status already existed in MS or NMO patients before systemic symptoms appeared.

  18. Influence of bilirubin on surface tension properties of lung surfactant.

    OpenAIRE

    Amato, M; Schürch, S; Grunder, R; Bachofen, H.; Burri, P H

    1996-01-01

    AIM: To investigate the influence of bilirubin on the surface tension activity of a porcine derived (Curosurf) and synthetic (Exosurf) surfactant. METHODS: The captive bubble surfactometer at phospholipid doses of 0.5 mg/ml (low dose) and 1 mg/ml (high dose) in solutions of increasing bilirubin concentrations (0.25, 0.5, and 1.0 mg/ml) was used. RESULTS: Curosurf (without bilirubin) showed a higher surface f1p4ion activity than Exosurf, as shown by area compression of 30 (SD 0.6)% compared wi...

  19. Clinical significance of the UGT1A1*28 allele detection in HIV-infected patients

    Directory of Open Access Journals (Sweden)

    Veronika Kanestri

    2014-11-01

    Full Text Available Introduction: The UGT1A1*28 (rs8175347 polymorphism is associated with hyperbilirubinemia. The presence of 6 TA-repeats in the UGT1A1 gene promoter region corresponds to normal UGT1TA1 activity. A detection of 7 TA-repeats in hetero- or homozygous individuals [(TA6/(TA7 and (TA7/(TA7] is associated with lower UGT1TA1 activity, which may eventually result in the development of Gilbert syndrome and/or modified individual response to drugs metabolized by this enzyme. ATV contributes to the decreased levels of UGT1A1, which may lead to elevations of indirect bilirubin, jaundice and even to therapy discontinuation. We evaluated the prevalence of the UGT1A1*28 among HIV-infected patients and the dependence of the frequency and severity of AE during ATV treatment on individual genetic characteristics. Materials and Methods: 47 HIV-infected patients was screen for UGT1A1 genotype and the presence of UGT1A1*28. All patients received ATV in the HAART regimen for 48 weeks. Changes in the total, direct and indirect bilirubin, ALT, AST, GGT and jaundice were evaluated. Statistical analysis was performed using Microsoft Office Excel for Windows XP Professional 2007 and Biostat. Results: All patients were followed up in the AIDS Center (males 72.3%, median age 33 years, median CD4+ count-282 cells/µl (19.5%. HBV/HCV was in 36.2% patients. Ten patients had risk factors that could affect bilirubin turnover (chronic cholecystitis, biliary dyskinesia, etc.. Genotype (TA6/(TA6 was found in 42.6% patients, (TA6/(TA7-42.6% and (TA7/(TA7-14.9%. Overall prevalence of UGT1A1*28 was 57.4%, and homozygous allele frequency was 14.9%. G3/4 of indirect bilirubin were detected in 36.2% patients [(TA6/(TA6 in 10–20%, (TA6/(TA7-25-40%, (TA7/(TA7-72-86%], and significant jaundice in 10.6% [80% with (TA7/(TA7]. The OR for hyperbilirubinemia>40 µmol/L in patients with heterozygous UGT1A1*28 was increased 3 times over patients without this allele (OR 3.07, 95% CI 1.54–4.6 and

  20. Determinants of bilirubin neurotoxicity by an in vitro molecular approach

    OpenAIRE

    Coda Zabetta, Carlos Daniel

    2012-01-01

    Unconjugated Bilirubin (UCB) is the final product of the heme catabolism. The high serum UCB concentrations in the first days of life of the newborns, due to immature mechanisms for hepatic uptake, conjugation and biliary secretion, is called physiological neonatal jaundice. This common condition is generally a benign and transient phenomenon, but in some cases the hyperbilirubinemia can progress to bilirubin encephalopaties ranging from minimally neurological injury to severe and permanent n...

  1. Relationship between bilirubin free radical and formation of pigment gallstone

    Institute of Scientific and Technical Information of China (English)

    Xiang-Tao Liu; Jian Hu

    2002-01-01

    In this paper, we summarize the main progresses made inour group in the field of the mechanism of pigment gallstoneformation. It was found that after treetment with freeradicals, bilirubin (BR) was changed into free radical itself,and a semiquinone free radical and a superoxide free radicalbound with metal were recognized, which was detected byESR (electron spin resonance). By the meana of NMR(nuclear magnetic resonance) and IR (Infra-red spectra), itwas postulated that bilirubin polymerized through thereaction between the vinyl group and the hydroxyl groupunder the attack of free radicals. It was also found thatbilirubin free radical were liable to calcify in a kinetic study.Because of its chemical properties, bilirubin free radical wasshown to be cytotoxic to hepetocyte, which wasdemonstrated based on the following facts: induction ofphospholipid peroxidation (LPO), leakage of lactatedehydrogenase (LDH) and decrease of glutathione. As tothe mechanism of bilirubin-induced cytotoxicity, it waspostulated that the main target of bilirubin free radical wasthe cell membrane, including phospholipid and membranebound proteins, especially spectrin, a content ofcytoskeleton. Based on the results mentioned above, it wasdeduced that bilirubin free radical is the key factor thatinitiates and promotes the formation of pigment gallstone,which is consistent with other researches in recent years.

  2. Study on Removal of Bilirubin with Magnetic Affinity Separation Technique

    Institute of Scientific and Technical Information of China (English)

    张凤宝; 王淑兰; 徐辉; 张国亮

    2003-01-01

    An affinity adsorbent, Cibacron Blue 3GA immobilized magnetic polyvinyl alcohol (PVA) microspheres was used for bilirubin removal taking the advantage of easy separation of magnetic sorbent from the biosystem.Fe3 O4 superparamagnetic particles was synthesized with hydrothermal reaction of ferrous chloride (FeC12) and ferric chloride (FeCl3). Such magnetic particles are then encapsulated in biocompatible PVA to form magnetic polymer microspheres sized from 2 to 15 nm with hydroxyl groups on its surface. Cibacron Blue 3GA, a dye-ligand, was covalently coupled with the polyvinyl alcohol through the nucleophilic reaction between the chloride of its triazine ring and the hydroxyl groups of PVA molecules under alkaline condition. The affinity adsorbent carried 21.1μmol Cibacron Blue 3GA per gram magnetic polymer microspheres was used to remove unconjugated and conjugated bilirubin from the solution which was composed of bilirubin or bilirubin and protein. After the adsorption, the adsorbent loaded with bilirubin was removed easily in the magnetic field.

  3. Mitochondrial targeting of bilirubin regulatory enzymes: An adaptive response to oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Muhsain, Siti Nur Fadzilah, E-mail: sitinurfadzilah077@ppinang.uitm.edu.my [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Faculty of Pharmacy, University Teknologi Mara (Malaysia); Lang, Matti A., E-mail: m.lang@uq.edu.au [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Abu-Bakar, A' edah, E-mail: a.abubakar@uq.edu.au [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia)

    2015-01-01

    The intracellular level of bilirubin (BR), an endogenous antioxidant that is cytotoxic at high concentrations, is tightly controlled within the optimal therapeutic range. We have recently described a concerted intracellular BR regulation by two microsomal enzymes: heme oxygenase 1 (HMOX1), essential for BR production and cytochrome P450 2A5 (CYP2A5), a BR oxidase. Herein, we describe targeting of these enzymes to hepatic mitochondria during oxidative stress. The kinetics of microsomal and mitochondrial BR oxidation were compared. Treatment of DBA/2J mice with 200 mg pyrazole/kg/day for 3 days increased hepatic intracellular protein carbonyl content and induced nucleo-translocation of Nrf2. HMOX1 and CYP2A5 proteins and activities were elevated in microsomes and mitoplasts but not the UGT1A1, a catalyst of BR glucuronidation. A CYP2A5 antibody inhibited 75% of microsomal BR oxidation. The inhibition was absent in control mitoplasts but elevated to 50% after treatment. An adrenodoxin reductase antibody did not inhibit microsomal BR oxidation but inhibited 50% of mitochondrial BR oxidation. Ascorbic acid inhibited 5% and 22% of the reaction in control and treated microsomes, respectively. In control mitoplasts the inhibition was 100%, which was reduced to 50% after treatment. Bilirubin affinity to mitochondrial and microsomal CYP2A5 enzyme is equally high. Lastly, the treatment neither released cytochrome c into cytoplasm nor dissipated membrane potential, indicating the absence of mitochondrial membrane damage. Collectively, the observations suggest that BR regulatory enzymes are recruited to mitochondria during oxidative stress and BR oxidation by mitochondrial CYP2A5 is supported by mitochondrial mono-oxygenase system. The induced recruitment potentially confers membrane protection. - Highlights: • Pyrazole induces oxidative stress in the mouse liver. • Pyrazole-induced oxidative stress induces mitochondrial targeting of key bilirubin regulatory enzymes, HMOX1

  4. Evidence for differences in regioselective and stereoselective glucuronidation of silybin diastereomers from milk thistle (Silybum marianum) by human UDP-glucuronosyltransferases

    Czech Academy of Sciences Publication Activity Database

    Jančová, P.; Šiller, M.; Anzenbacherová, E.; Křen, Vladimír; Anzenbacher, P.; Šimánek, V.

    2011-01-01

    Roč. 41, č. 9 (2011), s. 743-751. ISSN 0049-8254 Institutional research plan: CEZ:AV0Z50200510 Keywords : Silybin * conjugation * metabolism Subject RIV: CE - Biochemistry Impact factor: 1.791, year: 2011

  5. Identification of Flavone Glucuronide Isomers by Metal Complexation and Tandem Mass Spectrometry: Regioselectivity of UDP-Glucuronosyltransferase Isozymes in the Biotransformation of Flavones

    Science.gov (United States)

    Robotham, Scott A.; Brodbelt, Jennifer S.

    2013-01-01

    Flavone Glucuronide isomers of five flavones (chrysin, apigenin, luteolin, baicalein, and scutellarein) were differentiated by collision induced dissociation (CID) of [Co(II) (flavone-H) (4,7-diphenyl-1,10-phenanthroline)2]+ complexes. The complexes were generated via post-column addition of a metal/ligand solution after separation of the glucuronide products generated upon incubation of each flavone with an array of UDP-glucuronosyl-transferase (UGT) isozymes. Elucidation of the glucuronide isomers allowed a systematic investigation of the regioselectivity of twelve human UDP-glucuronosyl-transferase (UGT) isozymes, including eight UGT1A and four UGT2B isozymes. Glucuronidation of the 7-OH position was the preferred site for all the flavones except for luteolin, which possessed adjacent hydroxyl groups on the B ring. For all flavones and UGT isozymes, glucuronidation of the 5-OH position was never observed. As confirmed by the metal complexation/MS/MS strategy, glucuronidation of the 6-OH position only occurred for baicalein and scutellarein when incubated with three of the UGT isozymes. PMID:23362992

  6. In vitro interaction of a novel neutrophil growth factor with human liver microsomal cytochromes P450 and the contribution of UDP-glucuronosyltransferases to its metabolism

    Czech Academy of Sciences Publication Activity Database

    Siller, M.; Anzenbacher, P.; Anzenbacherová, E.; Doležal, Karel; Strnad, Miroslav

    2011-01-01

    Roč. 41, č. 11 (2011), s. 934-944. ISSN 0049-8254 R&D Projects: GA ČR GA301/08/1649 Institutional research plan: CEZ:AV0Z50380511 Keywords : DRUG-DRUG INTERACTIONS * SUBSTRATE-SPECIFICITY * R-ROSCOVITINE * GLUCURONIDATION * CELLS Subject RIV: EF - Botanics Impact factor: 1.791, year: 2011

  7. The different metabolism of morusin in various species and its potent inhibition against UDP-glucuronosyltransferase (UGT) and cytochrome p450 (CYP450) enzymes.

    Science.gov (United States)

    Shi, Xianbao; Yang, Shuman; Zhang, Gang; Song, Yonggui; Su, Dan; Liu, Yali; Guo, Feng; Shan, Lina; Cai, Jiqun

    2016-05-01

    1. The aim of this study was to investigate the inhibitory effect of morusin on Glucuronosyltransferase (UGT) isoforms and cytochrome P450 enzymes (CYP450s). We also investigated the metabolism of morusin in human, rat, dog, monkey, and minipig liver microsomes. 2. 100 μM of morusin exhibited strong inhibition on all UGTs and CYP450s. The half inhibition concentration (IC50) values for CYP3A4, CYP1A2, CYP2C9, CYP2E1, UGT1A6, UGT1A7, and UGT1A8 were 2.13, 1.27, 3.18, 9.28, 4.23, 0.98, and 3.00 μM, and the inhibition kinetic parameters (Ki) were 1.34, 1.16, 2.98, 6.23, 4.09, 0.62, and 2.11 μM, respectively. 3. Metabolism of morusin exhibited significant species differences. The quantities of M1 from minipig, monkey, dog, and rat were 7.8, 11.9, 2.0, and 6.3-fold of human levels. The Km values in HLMs, RLMs, MLMs, DLMs, and PLMs were 7.84, 22.77, 14.32, 9.13, and 22.83 μM, and Vmax for these species were 0.09, 1.23, 1.43, 0.15, and 0.75 nmol/min/mg, respectively. CLint (intrinsic clearance) values (Vmax/Km) for morusin obeyed the following order: monkey > rat > minipig > dog > human. CLH (hepatic clearance) values for humans, dogs, and rats were calculated to be 8.28, 17.38, and 35.12 mL/min/kg body weight, respectively. 4. This study provided vital information to understand the inhibitory potential and metabolic behavior of morusin among various species. PMID:26372370

  8. Anti-Genotoxic Potential of Bilirubin In Vivo

    DEFF Research Database (Denmark)

    Wallner, Marlies; Antl, Nadja; Rittmannsberger, Barbara;

    2013-01-01

    The bile pigment bilirubin is a known antioxidant and is associated with protection from cancer and cardiovascular disease (CVD) when present in too strong concentrations. Unconjugated bilirubin (UCB) might also possess anti-genotoxic potential by preventing oxidative damage to DNA. Moderately...... (age- and sex-matched) were allocated into Gilbert syndrome (UCB ≥17.1 μmol/L; n = 38) or control groups (UCB < 17.1 μmol/L; n = 38). In addition, 40 Gunn rats were used to support the results of the human trial. Single-cell gel electrophoresis (SCGE) assay measuring standard conditions (strand breaks...

  9. Disruption of thyroid hormone homeostasis in Ugt1a-deficient Gunn rats by microsomal enzyme inducers is not due to enhanced thyroxine glucuronidation☆

    OpenAIRE

    Richardson, Terrilyn A.; Klaassen, Curtis D.

    2010-01-01

    Microsomal enzyme inducers (MEI) that increase UDP-glucuronosyltransferases (UGTs) are thought to increase glucuronidation of thyroxine (T4), thus reducing serum T4, and subsequently increasing thyroid stimulating hormone (TSH). Ugt1a1 and Ugt1a6 mediate T4 glucuronidation. Therefore, this experiment determined the involvement of Ugt1a enzymes in increased T4 glucuronidation, decreased serum T4, and increased TSH after MEI treatment. Male Wistar and Ugt1a-deficient Wistar (Gunn) rats were fed...

  10. Effect of pH and temperature on the binding of bilirubin to human erythrocyte membranes

    Indian Academy of Sciences (India)

    H Rashid; Mohammad K Ali; S Tayyab

    2000-06-01

    Effect of pH and temperature on the binding of bilirubin to human erythrocyte membranes was studied by incubating the membranes at different pH and temperatures and determining the bound bilirubin. At all pH values, the amount of membrane-bound bilirubin increased with the increase in bilirubin-to-albumin molar ratios (B/As), being highest at lower pH values in all cases. Further, linear increase in bound bilirubin with the increase in bilirubin concentration in the incubate was observed at a constant B/A and at all pH values. However, the slope value increased with the decrease in pH suggesting more bilirubin binding to membranes at lower pH values. Increase in bilirubin binding at lower pH can be explained on the basis of increased free bilirubin concentration as well as more conversion of bilirubin dianion to monoanion. Temperature dependence of bilirubin binding to membranes was observed within the temperature range of 7°–60°C, showing minimum binding at 27°C and 37°C which increased on either side. Increase in bilirubin binding at temperatures lower than 20°C and higher than 40°C can be ascribed to the change in membrane topography as well as bilirubin-albumin interaction.

  11. Interaction of bilirubin with Ag and Au ions: green synthesis of bilirubin-stabilized nanoparticles

    International Nuclear Information System (INIS)

    We report a simple green chemistry to synthesize and stabilize monodispersed silver and gold nanoparticles sols by reducing aqueous solution of the respective metal salts in the presence of bilirubin (BR). No additional capping agent was used in the process of stabilization of the nanoparticles. As a completely new finding, we have observed that BR known to be toxic at higher concentration in one hand and conversely an antioxidant at physiological concentration reduces these metal ions to form the respective metal nanoparticles. Moreover, BR and its oxidized products also serve as capping agents to the nanoparticles. The particles were characterized by transmission electron microscopy. BR and its oxidized products capped nanoparticles are stable for months. The UV–Vis absorption spectra of the silver sol show the plasmon peak of symmetric spherical particles which was further reflected in the TEM images. The sizes of the silver particles were about 5 nm. These silver particles showed reasonably high antibacterial activity in Gram negative wild type E. coli. In the case of interaction of BR with gold ions, we could obtain cubic gold nanoparticles of average sizes 20–25 nm. Possible modes of anchorage of BR and/its oxidized products to silver nanoparticles were demonstrated by surface-enhanced resonance Raman spectroscopy (SERS) that in turn demonstrated the feasibility of using these nanoparticles as SERS substrates.

  12. Interaction of bilirubin with Ag and Au ions: green synthesis of bilirubin-stabilized nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Shukla, Shashi P. [Bhabha Atomic Research Centre, Radiation and Photochemistry Division (India); Roy, Mainak [Bhabha Atomic Research Centre, Chemistry Division (India); Mukherjee, Poulomi [Bhabha Atomic Research Centre, Nuclear Agriculture and Biotechnology Division (India); Tyagi, A. K. [Bhabha Atomic Research Centre, Chemistry Division (India); Mukherjee, Tulsi [Bhabha Atomic Research Centre, Chemistry Group (India); Adhikari, Soumyakanti, E-mail: asoumya@barc.gov.in [Bhabha Atomic Research Centre, Radiation and Photochemistry Division (India)

    2012-07-15

    We report a simple green chemistry to synthesize and stabilize monodispersed silver and gold nanoparticles sols by reducing aqueous solution of the respective metal salts in the presence of bilirubin (BR). No additional capping agent was used in the process of stabilization of the nanoparticles. As a completely new finding, we have observed that BR known to be toxic at higher concentration in one hand and conversely an antioxidant at physiological concentration reduces these metal ions to form the respective metal nanoparticles. Moreover, BR and its oxidized products also serve as capping agents to the nanoparticles. The particles were characterized by transmission electron microscopy. BR and its oxidized products capped nanoparticles are stable for months. The UV-Vis absorption spectra of the silver sol show the plasmon peak of symmetric spherical particles which was further reflected in the TEM images. The sizes of the silver particles were about 5 nm. These silver particles showed reasonably high antibacterial activity in Gram negative wild type E. coli. In the case of interaction of BR with gold ions, we could obtain cubic gold nanoparticles of average sizes 20-25 nm. Possible modes of anchorage of BR and/its oxidized products to silver nanoparticles were demonstrated by surface-enhanced resonance Raman spectroscopy (SERS) that in turn demonstrated the feasibility of using these nanoparticles as SERS substrates.

  13. Serum bilirubin kinetics in intermittent phototherapy of physiological jaundice.

    OpenAIRE

    Lau, S. P.; Fung, K P

    1984-01-01

    Thirty four term babies with physiological jaundice were subjected to continuous phototherapy and to two regimens of intermittent phototherapy. The difference in serum bilirubin kinetics between the three groups of treated babies was insignificant; a schedule of one in four hours of irradiation achieved the same treatment effect as continuous phototherapy.

  14. Biphasic Effect of Rifampicin on Bilirubin- A Case Report.

    Science.gov (United States)

    Gopi, Manigandan; Seshadri, Mandalam Subramanian

    2016-04-01

    Drug induced hepatitis is a major problem which a physician encounters in his clinical practice. In view of increasing incidence of tuberculosis in our country a large number of infected individuals are started on Antituberculous (ATT) drugs and rifampicin is invariably part of the regimen. One of the major adverse effects of ATT drugs is drug- induced hepatitis which is characterized by elevation of liver enzymes and bilirubin. Hepatotoxicity is usually idiosyncratic or dose-dependent. Rifampicin causes transient elevation of transaminases in 10-20 percent of individuals and this does not warrant dose adjustments of the drug. Rarely rifampicin can lead to severe hepatitis with hyperbilirubinaemia and marked elevations of SGOT and SGPT and in some patients this can be fatal. The exact mechanism of Rifampicin induced hepatotoxicity is not known but it is postulated to be due to idiosyncratic reaction to rifampicin metabolites which may be directly toxic or induce an immunologically mediated liver injury. Rarely rifampicin may cause hyperbilirubinaemia without enzyme elevation. Here we report a patient with bilateral pulmonary tuberculosis who developed transient severe indirect hyperbilirubinaemia on rifampicin. On review of relevant literature we find that rifampicin can have a biphasic effect on bilirubin, an initial increase in indirect bilirubin and later normalization of bilirubin. We have reported this case because of its rarity in clinical practice. PMID:27190870

  15. The pharmacological features of bilirubin: the question of the century.

    Science.gov (United States)

    Zahir, Farhana; Rabbani, Gulam; Khan, Rizwan Hasan; Rizvi, Shamim J; Jamal, Mohammad Sarwar; Abuzenadah, Adel M

    2015-09-01

    This review looks at the toxicity and metabolism of bilirubin in terms of its pharmacological potential. Its role has gained importance as more research has revealed the functional significance and interrelationship between the gasotransmitters nitric oxide and carbon monoxide. The biological actions of bilirubin have mostly been characterized in the high micromolar range where toxic effects occur. However, it could also prove to be an important cytoprotector for brain tissue, which is inherently less equipped for antioxidant defense. Plasma bilirubin levels negatively correlate to a number of disease states. Higher levels of bilirubin that are still within the normal range provide a protective effect to the body. The effects on various disorders could be tested using controlled pharmacological upregulation of the molecule with animal models. At nanomolar concentrations, considerable benefits have been obtained when the molecule was delivered pharmacologically under in vitro or in vivo test conditions, particularly in neurodegenerative disorders and after tissue or organ transplantation. The induction of heme oxygenase-1 (HMOX-1) via the activation of nuclear factor erythroid 2-related factor or the use of bile pigments in the harvesting of diseased tissue are novel applications, and like every new therapy, should be used with caution. HMOX-1 is tissue specific, and in exceptional states, such as schizophrenia and specific types of renal disorder, the same therapy may have disastrous effects. PMID:26208389

  16. Clinical Significance of Serum Bilirubin Detection of Patient with Coronary Heart Disease

    Institute of Scientific and Technical Information of China (English)

    TAO Li; LUO Rui; ZHUANG Diankui

    2004-01-01

    Objective To explore the relation between serum bilirubin and coronary heart disease.Methods Compare the level of serum bilirubin among patients with coronary heart disease, patients with other disease and normal persons. Results The level of serum bilirubin of patients with coronary heart disease is higher than that of normal persons. Conclusion The reduction of density of serum bilirubin is one of the independent risk factors of coronary heart disease.

  17. Bilirubin Neurotoxicity in Preterm Infants: Risk and Prevention

    OpenAIRE

    Bhutani, Vinod K.; Wong, Ronald J

    2013-01-01

    Hemolytic conditions in preterm neonates, including Rhesus (Rh) disease, can lead to mortality and long-term impairments due to bilirubin neurotoxicity. Universal access to Rh immunoprophylaxis, coordinated perinatal-neonatal care, and effective phototherapy has virtually eliminated the risk of kernicterus in many countries. In the absence of jaundice due to isoimmunization and without access to phototherapy or exchange transfusion (in 1955), kernicterus was reported at 10.1%, 5.5%, and 1.2% ...

  18. Bilirubin: an endogenous molecule with antiviral activity in vitro.

    Directory of Open Access Journals (Sweden)

    CesareMancuso

    2012-03-01

    Full Text Available Bilirubin-IX-alpha (BR is the final product of heme metabolism through the heme oxygenase/biliverdin reductase (HO/BVR system. Previous papers reported on the microbicidal effects of the HO by-products biliverdin-IX-alpha, carbon monoxide and iron, through either direct or indirect mechanisms. In this paper the evidence of a virucidal effect of BR against human herpes simplex virus type 1 (HSV-1 and the enterovirus EV71 was provided. Bilirubin-IX-alpha, at concentrations 1-10 µM, close to those found in blood and tissues, significantly reduced HSV-1 and EV71 replication in Hep-2 and Vero cell lines, respectively. Bilirubin-IX-alpha inhibited viral infection of Hep-2 and Vero cells when given 2 hours before, concomitantly and 2 hours after viral infection. Furthermore, BR retained its antiviral activity even complexed with a saturating concentration of human serum-albumin. Moreover, 10 µM BR increased the formation of nitric oxide and the phosphorylation of JNK in Vero and Hep-2 cell lines, respectively, thus implying a role of these two pathways in the mechanism of antiviral activity of the bile pigment. In conclusion, these results support the antiviral effect of BR against HSV-1 and enterovirus in vitro, and put the basis for further basic and clinical studies to understand the real role of BR as an endogenous antiviral molecule.

  19. Multistimuli-Responsive Bilirubin Nanoparticles for Anticancer Therapy.

    Science.gov (United States)

    Lee, Yonghyun; Lee, Soyoung; Lee, Dong Yun; Yu, Byeongjun; Miao, Wenjun; Jon, Sangyong

    2016-08-26

    Although stimuli-responsive materials hold potential for use as drug-delivery carriers for treating cancers, their clinical translation has been limited. Ideally, materials used for the purpose should be biocompatible and nontoxic, provide "on-demand" drug release in response to internal or external stimuli, allow large-scale manufacturing, and exhibit intrinsic anticancer efficacy. We present multistimuli-responsive nanoparticles formed from bilirubin, a potent endogenous antioxidant that possesses intrinsic anticancer and anti-inflammatory activity. Exposure of the bilirubin nanoparticles (BRNPs) to either reactive oxygen species (ROS) or external laser light causes rapid disruption of the BRNP nanostructure as a result of a switch in bilirubin solubility, thereby releasing encapsulated drugs. In a xenograft tumor model, BRNPs loaded with the anticancer drug doxorubicin (DOX@BRNPs), when combined with laser irradiation of 650 nm, significantly inhibited tumor growth. This study suggests that BRNPs may be used as a drug-delivery carrier as well as a companion medicine for effectively treating cancers. PMID:27485478

  20. Ambivalent property of bilirubin in human bile juice

    Directory of Open Access Journals (Sweden)

    Anna Blázovics, Péter Sípos, Ferenc Örsi,* Mervat Abdel Rahman

    2005-03-01

    Full Text Available Gallstones are formed as a result of many metabolic disorders e.g. chronic haemolytic anaemia, diabetes mellitus, ileal diseases, short bowel syndrome, gluten sensitive enteropathy, elevated serum lipids or Crohn's disease. The relationship between gallstone disease and free radical reactions is not known exactly even today. Free radicals are involved in many clinical conditions e.g. in hyperlipidemia and in fatty liver. Oxygen free radicals are produced and accumulated while the function of mitochondrial and microsomal electron transport or in peroxisomes and the activated arachidonic acid cascade. Spontaneous lipid peroxidation and oxygen free radical products of respiratory burst of Kupffer cells can be added to peroxide pool of liver tissue. Tissues, cells and subcellular particles exhibit different specific defence activities in pathological processes, which involve free radicals. The activity of microsomal P450 enzyme system and the microsomal structure are changed during pathological free radical attack and the cholesterol/bile acid ratio in bile juice is also altered. At the same time bilirubin metabolism can also be modified. Bile samples of 88 cholecystectomysed patients in both sexes (male: 29, female: 59 were examined. HPLC analysis (HP1090 liquid chromatograph with diode array detector was used for the detection of free bilirubin and bilirubin derivates. HP5890 gas chromatograph and flame ionization detector was used for fatty acid analysis. The induced chemiluminescence intensity was also determined in bile juice with (Berthold Lumat 9501 luminometer. As results show, the occurrence of C18:1 9, C18:2 6, C20:4 6 fatty acids were in high percentage in gallbladder bile in every case of randomly chosen 17 cholecystectomysed patients in both sexes suffered from cholecystitis chronica with gallstone. Lipid peroxidation products (diene conjugates and malondialdehyde were detected in all cases of bile as well. Mathematical statistical

  1. Bilirubin binding with liver cystatin induced structural and functional changes.

    Science.gov (United States)

    Mustafa, Mir Faisal; Bano, Bilqees

    2014-05-01

    Cysteine proteinases and their inhibitors play a significant role in the proteolytic environment of the cells. Inhibitors of cysteine proteinases regulate the activity of these enzymes helping in checking the degdration activity of cathepsins. The bilirubin secreated by liver cells can bind to cystatin present in the liver resulting in its functional inactivation, which may further lead to the increase in cathepsins level causing liver cirrhosis. In case of some pathophysiological conditions excess bilirubin gets accumulated e.g. in presence of Fasciola hepatica (liver fluke) in mammals and humans, leading to liver cirrhosis and possibly jaundice or normal blockade of bile duct causing increased level of bilirubin in blood. Protease-cystatin imbalance causes disease progression. In the present study, Bilirubin (BR) and liver cystatin interaction was studied to explore the cystatin inactivation and structural alteration. The binding interaction was studied by UV-absorption, FT-IR and fluorescence spectroscopy. The quenching of protein fluorescence confirmed the binding of BR with buffalo liver cystatin (BLC). Stern-Volmer analysis of BR-BLC system indicates the presence of static component in the quenching mechanism and the number of binding sites to be close to 1. The fluorescence data proved that the fluorescence quenching of liver cystatin by BR was the result of BR-cystatin complex formation. FTIR analysis of BR-Cystatin complex revealed change in the secondary structure due to perturbation in the microenvironment further confirmed by the decreased caseinolytic activity of BLC against papain. Fluorescence measurements also revealed quenching of fluorescence and shift in peak at different time intervals and at varying pH values. Photo-illumination of BR-cystatin complex causes change in the surrounding environment of liver cystatin as indicated by red-shift. The binding constant for BR-BLC complex was found to be 9.279 × 10(4) M(-1). The cystatin binding with

  2. AB161. High resolution melting analysis of buccal DNA revealed a significant association between UGT1A1 c.211G>A and neonatal hyperbilirubinemia development in Malay population

    Science.gov (United States)

    Cheung, Tian Pei; Van Rostenberghe, Hans; Ismail, Rosliza; Nawawi, Noor Namirah; Abdullah, Nurul Amierah; Ramli, Noraida; Ibrahim, Nor Rosidah; Hj Abd Majid, Noorizan; Mohd Yusoff, Narazah; Nishio, Hisahide; Yusoff, Surini

    2015-01-01

    Background Severe neonatal hyperbilirubinemia or neonatal jaundice (NNJ) characterised by an elevated total serum bilirubin (TSB) level may result in kernicterus or even death. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is the key enzyme which conjugates bilirubin with glucuronic acid for the subsequent bilirubin excretion. Conversely, constitutive androstane receptor (CAR), encoded by nuclear receptor subfamily 1, group I, member 3 (NR1I3) gene, regulates bilirubin excretion by activating the components of the bilirubin clearance pathway. Thus, genetic variants in UGT1A1 and NR1I3 genes may modulate bilirubin excretion and lead to NNJ. This study aimed to determine the association between UGT1A1 and NR1I3 genetic variants and NNJ development in Malay population by genotyping the DNA isolated from buccal swabs. The accuracy and reliability of the genotyping results produced by buccal DNA was also compared with that of the whole blood DNA. Methods Buccal swabs were collected from 232 hyperbilirubinemia and 232 non-hyperbilirubinemia newborns admitted to and/or born in Hospital Universiti Sains Malaysia (HUSM). Hyperbilirubinemia subjects were those with TSB levels ≥250 µmol/L within the first week after birth while non-hyperbilirubinemia subjects were newborns without significant hyperbilirubinemia. The UGT1A1 (c.211G>A) and NR1I3 [MPJ6_1I3008 (G>A), IVS8+116T>G and 540A>G] variants were genotyped by using high resolution melting (HRM) analysis. Binary logistic regression was used to assess the association between variant genotypes and risk of NNJ. Whole blood samples were also collected from 60 subjects and genotyped to compare the HRM genotyping results with that of the buccal swabs. Results When compared with wild-type genotype, both heterozygous and homozygous variant genotypes of MPJ6_1I3008 (G>A), IVS8+116T>G and 540A>G were not significantly associated with NNJ. However, the heterozygous genotype (GA) of c.211G>A was found to increase the

  3. Depurative capacity of molecular adsorbent recycling system (MARS): A focus on bilirubin removal.

    Science.gov (United States)

    Gong, D; Cruz, D; Ronco, C

    2008-10-01

    The molecular adsorbent recycling system (MARS) is now widely used in the treatment of patients with hepatic failure (HF). A great deal of interest has been directed toward its effect on clinical outcome, whereas its depurative capacity also needs attention. Bilirubin, a tightly albumin-bound toxin accumulating in patients with HF, is regarded as a surrogate to evaluate the depurative capacity of albumin-bound toxins by blood purification modalities. The removal of bilirubin by MARS is difficult to predict, because both the clearance of bilirubin and the reduction ratio of bilirubin after a single session differ between patients and sessions. A reduction of depurative capacity over the course of a treatment is observed. Furthermore, the later sessions are likely less efficient than previous ones. It cannot be taken for granted that the reduction of depurative capacity is due to the saturation and reduced efficiency of the adsorbent columns used in MARS. The answer lies in the property of bilirubin/albumin binding. The removal of bilirubin by MARS is a diffusion process, dependent on the free bilirubin concentration. Bilirubin binds to albumin in 3 ways with different affinity. High-affinity binding bilirubin is difficult to dissociate from albumin and is accompanied by a smaller free fraction, which means it is also difficult for MARS to remove. The factors affecting the free fraction of bilirubin will impact on bilirubin removal by MARS. Among them, the molar ratio of bilirubin to albumin is the most important one. Other factors include the interaction of other agents with bilirubin/albumin binding, the albumin concentration, plasma ion strength, and pH. PMID:19009505

  4. An hour-specific transcutaneous bilirubin nomogram for Mongolian neonates

    OpenAIRE

    Akahira-Azuma, Moe; Yonemoto, Naohiro; Mori, Rintaro; Hosokawa, Shinichi; Matsushita, Takeji; Sukhbat, Khulan; Nansal, Gerelmaa; Bavuusuren, Bayasgalantai; Shonkhuuz, Enkhtur

    2015-01-01

    Transcutaneous bilirubin (TcB) nomograms have been developed for different populations. However, the TcB level, rate of rise and peak varies among countries and ethnicities. The aim of this study was to establish an hour-specific TcB nomogram for healthy term and late preterm Mongolian neonates during the first 144 h after birth. A total of 5084 TcB measurements from 1297 healthy neonates (gestational age ≥35 weeks, birth weight ≥2000 g) were obtained from October 2012 to October 2013. All me...

  5. "The effect of fluid supplementation on serum bilirubin level during phototerapy in term infants "

    OpenAIRE

    Torkaman M; Afsharpeyman SH; Khalili Matinzadeh Z; Amirsalary S; Kavehmanesh Z; Hashemi S.A.

    2007-01-01

    Background: Jaundice is a common and benign problem in neonatal period. Several therapeutic procedures for decreasing of serum bilirubin level has been recommended. phototherapy is most common them. Our goal Form this study is the evaluation of serum therapy effects in decreasing of serum bilirubin concentration in icteric infants that are treated with phototherapy. Methods: This is a prospective clinical trial in Najmeih Hospital in 2002. In this study 80 term icteric infants with bilirubin ...

  6. Dexmedetomidine Attenuates Bilirubin-Induced Lung Alveolar Epithelial Cell Death In Vitro and In Vivo*

    OpenAIRE

    Cui, Jian; Zhao, Hailin; Yi, Bin; Zeng, Jing; Lu, Kaizhi; Ma, Daqing

    2015-01-01

    Objective: To investigate bilirubin-induced lung alveolar epithelial cell injury together with the protection afforded by dexmedetomidine. Design: Prospective, randomized, controlled study. Setting: Research laboratory. Subjects: Sprague Dawley rats. Interventions: Alveolar epithelial A549 cell lines were cultured and received bilirubin (from 0 to 160 μM) to explore the protective pathway of dexmedetomidine on bilirubin-induced alveolar epithelial cell injury assessed by immunochemistry and f...

  7. In vitro displacement of bilirubin by antibiotics and 2-hydroxybenzoylglycine in newborns.

    OpenAIRE

    Wadsworth, S J; Suh, B

    1988-01-01

    Hyperbilirubinemia is frequently observed in neonates, and serious neurological complications such as kernicterus can be precipitated when the concentration of unconjugated bilirubin is abnormally increased. The administration of drugs which bind to albumin and compete with bilirubin can increase the possibility of such a complication. To test the bilirubin-displacing activity of pharmacological agents that are used with newborns, 52 antimicrobial agents were investigated in vitro. A glycine ...

  8. Unconjugated bilirubin mediates heme oxygenase-1-induced vascular benefits in diabetic mice.

    Science.gov (United States)

    Liu, Jian; Wang, Li; Tian, Xiao Yu; Liu, Limei; Wong, Wing Tak; Zhang, Yang; Han, Quan-Bin; Ho, Hing-Man; Wang, Nanping; Wong, Siu Ling; Chen, Zhen-Yu; Yu, Jun; Ng, Chi-Fai; Yao, Xiaoqiang; Huang, Yu

    2015-05-01

    Heme oxygenase-1 (HO-1) exerts vasoprotective effects. Such benefit in diabetic vasculopathy, however, remains unclear. We hypothesize that bilirubin mediates HO-1-induced vascular benefits in diabetes. Diabetic db/db mice were treated with hemin (HO-1 inducer) for 2 weeks, and aortas were isolated for functional and molecular assays. Nitric oxide (NO) production was measured in cultured endothelial cells. Hemin treatment augmented endothelium-dependent relaxations (EDRs) and elevated Akt and endothelial NO synthase (eNOS) phosphorylation in db/db mouse aortas, which were reversed by the HO-1 inhibitor SnMP or HO-1 silencing virus. Hemin treatment increased serum bilirubin, and ex vivo bilirubin treatment improved relaxations in diabetic mouse aortas, which was reversed by the Akt inhibitor. Biliverdin reductase silencing virus attenuated the effect of hemin. Chronic bilirubin treatment improved EDRs in db/db mouse aortas. Hemin and bilirubin reversed high glucose-induced reductions in Akt and eNOS phosphorylation and NO production. The effect of hemin but not bilirubin was inhibited by biliverdin reductase silencing virus. Furthermore, bilirubin augmented EDRs in renal arteries from diabetic patients. In summary, HO-1-induced restoration of endothelial function in diabetic mice is most likely mediated by bilirubin, which preserves NO bioavailability through the Akt/eNOS/NO cascade, suggesting bilirubin as a potential therapeutic target for clinical intervention of diabetic vasculopathy. PMID:25475440

  9. 21 CFR 862.1115 - Urinary bilirubin and its conjugates (nonquantitative) test system.

    Science.gov (United States)

    2010-04-01

    ... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1115 Urinary bilirubin and its conjugates (nonquantitative)...

  10. 21 CFR 862.1113 - Bilirubin (total and unbound) in the neonate test system.

    Science.gov (United States)

    2010-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1113 Bilirubin (total and unbound) in the neonate test system....

  11. Translation elongation factor-1A1 (eEF1A1 localizes to the spine by domain III

    Directory of Open Access Journals (Sweden)

    Sun-Jung Cho

    2012-04-01

    Full Text Available In vertebrates, there are two variants of eukaryotic peptideelongation factor 1A (eEF1A; formerly eEF-1α, eEF1A1 andeEF1A2, which have three well-conserved domains (DI, DII,and DIII. In neurons, eEF1A1 is the embryonic type, which isexpressed during embryonic development as well as the firsttwo postnatal weeks. In the present study, EGFP-tagged eEF1A1truncates were expressed in cortical neurons isolated from ratembryo (E18-19. Live cell images of transfected neurons showedthat DIII-containing EGFP-fusion proteins (EGFP-DIII, -DII-III,-DI-III formed clusters that were confined within somatodendriticdomains, while DIII-missing ones (EGFP-DI, -DII, -DI-II andcontrol EGFP were homogeneously dispersed throughout theneuron including axons. In dendrites, EGFP-DIII was targeted tothe heads of spine- and filopodia-like protrusions, where it wascolocalized with SynGAPα, a postsynaptic marker. Our dataindicate that DIII of eEF1A1 mediates formation of clusters andlocalization to spines. [BMB reports 2012; 45(4: 227-232

  12. Mutations in COL1A1 Gene Change Dentin Nanostructure.

    Science.gov (United States)

    Duan, Xiaohong; Liu, Zhenxia; Gan, Yunna; Xia, Dan; Li, Qiang; Li, Yanling; Yang, Jiaji; Gao, Shan; Dong, Mingdong

    2016-04-01

    Although many studies have attempted to associate specific gene mutations with dentin phenotypic severity, it remains unknown how the mutations in COL1A1 gene influence the mechanical behavior of dentin collagen and matrix. Here, we reported one osteogenesis imperfecta (OI) pedigree caused by two new inserting mutations in exon 5 of COL1A1 (NM_000088.3:c.440_441insT;c.441_442insA), which resulted in the unstable expression of COL1A1 mRNA and half quantity of procollagen production. We investigated the morphological and mechanical features of proband's dentin using atomic force microscope (AFM), scanning electron microscope, and transmission electron microscope. Increased D-periodic spacing, variably enlarged collagen fibrils coating with fewer minerals were found in the mutated collagen. AFM analysis demonstrated rougher dentin surface and sparsely decreased Young's modulus in proband's dentin. We believe that our findings provide new insights into the genetic-/nano- mechanisms of dentin diseases, and may well explain OI dentin features with reduced mechanical strength and a lower crosslinked density. Anat Rec, 299:511-519, 2016. © 2015 Wiley Periodicals, Inc. PMID:26694865

  13. Association of bilirubin and protein thiols in relation to copper and ceruloplasmin in hyperbilirubinemic patients

    Institute of Scientific and Technical Information of China (English)

    Mungli Prakash; Jeevan K Shetty; Roshan D'Souza; Suhasa Upadhya; Vijay Kumar

    2009-01-01

    Objective:Bilirubin is a double edged sword in biological system,acting as a toxic molecule and cytoprotecrant.Unconjugated bilirubin is proved to show antioxidant activity in vitro and in vivo.In the current work we tried to know the relationship between both conjugated and unconjugated bilirubin with copper and protein thiols in patients with hyperbilirnbinemia.Methods:Study was conducted on 56 hyperbilirubinemic cases and 56 healthy controls.Serum copper,ceruloplasmin,protein thiols,total bilirubin,conjugated and unconjugated bilirubin,unconjugated bilimbin/albumin ratio,total protein,albumin,AST,ALT and ALP were estimated.Results:There was significant increase in serum copper,total bilirubin,conjugated and unconjugated bilimbin.uriconjugated bilirubin/albumin ratio,AST,ALT,and ALP,and decrease in serum ceruloplasmin,protein thiols,total protein,and albumin in hyperbilimbinemic cases when compared to healthy controls.Conjugated bilimbin correlated positively with liver enzymes AST and ALP,and negatively with protein thials,total protein and albumin.Unconjugated bilirubin correlated positively with ALT.Protein thiols correlated negatively with copper and positively with ceruloplasmin,and also correlated negativelv with liver enzymes like AST,ALT and ALP,and positively with total protein and albumin.Conclusion:Combination of elevated levels of trace elements like copper and availability of reducing agent like bilimbin may prove deleterious by generating free radicals.

  14. Protein-Support Interactions for Rationally Designed Bilirubin Oxidase Based Cathode: A Computational Study.

    Science.gov (United States)

    Matanovic, Ivana; Babanova, Sofia; Chavez, Madelaine Seow; Atanassov, Plamen

    2016-04-21

    An example of biocathode based on bilirubin oxidase (BOx) was used to demonstrate how density functional theory can be combined with docking simulations in order to study the interface interactions between the enzyme and specifically designed electrode surface. The electrode surface was modified through the adsorption of bilirubin, the natural substrate for BOx, and the prepared electrode was electrochemically characterized using potentiostatic measurements. The experimentally determined current densities showed that the presence of bilirubin led to significant improvement of the cathode operation. On the basis of the computationally calculated binding energies of bilirubin to the graphene support and BOx and the analysis of the positioning of bilirubin relative to the support and T1 Cu atom of the enzyme, we hypothesize that the bilirubin serves as a geometric and electronic extension of the support. The computational results further confirm that the modification of the electrode surface with bilirubin provides an optimal orientation of BOx toward the support but also show that bilirubin facilitates the interfacial electron transfer by decreasing the distance between the electrode surface and the T1 Cu atom. PMID:27015361

  15. Metabolism of bilirubin by human cytochrome P450 2A6

    International Nuclear Information System (INIS)

    The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic “Bilirubin Oxidase” (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14–22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated Ki of 2.23 μM. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301, 315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human “Bilirubin Oxidase” where bilirubin is potentially a substrate and a regulator of the enzyme. -- Highlights: ► Human CYP2A6 interacts with bilirubin with a high affinity. ► Bilirubin docking to the CYP2A6 active site is more stable than biliverdin docking. ► Recombinant CYP2A6 microsomes metabolised bilirubin to biliverdin. ► Bilirubin increased the hepatic CYP2A6

  16. Metabolism of bilirubin by human cytochrome P450 2A6

    Energy Technology Data Exchange (ETDEWEB)

    Abu-Bakar, A' edah, E-mail: a.abubakar@uq.edu.au [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Arthur, Dionne M. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Cooperative Research Centre for Contamination Assessment and Remediation of the Environment, Adelaide (Australia); Wikman, Anna S. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Department of Pharmaceutical Biosciences, Uppsala University, SE-75123 Uppsala (Sweden); Rahnasto, Minna; Juvonen, Risto O.; Vepsäläinen, Jouko; Raunio, Hannu [School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio (Finland); Ng, Jack C. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Cooperative Research Centre for Contamination Assessment and Remediation of the Environment, Adelaide (Australia); Lang, Matti A. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia)

    2012-05-15

    The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic “Bilirubin Oxidase” (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14–22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K{sub i} of 2.23 μM. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301, 315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human “Bilirubin Oxidase” where bilirubin is potentially a substrate and a regulator of the enzyme. -- Highlights: ► Human CYP2A6 interacts with bilirubin with a high affinity. ► Bilirubin docking to the CYP2A6 active site is more stable than biliverdin docking. ► Recombinant CYP2A6 microsomes metabolised bilirubin to biliverdin. ► Bilirubin increased the hepatic

  17. Hepatic bilirubin UDP-glucuronyltransferase in patients with sickle cell anemia.

    Science.gov (United States)

    Maddrey, W C; Cukier, J O; Maglalang, A C; Boitnott, J K; Odell, G B

    1978-02-01

    In sickle cell anemia the shortened survival of red blood cells presents the liver with an augmented load of bilirubin for hepatic clearance. To determine the effects of this excessive bilirubin load on the microsomal conjugating enzyme, hepatic bilirubin UDP-glucuronyltransferase, levels of this enzyme were measured in liver biopsies from patients with sickle cell anemia and several comparison groups. UDP-glucuronyltransferase activity in 14 patients with sickle cell anemia was 2-fold greater (P less than 0.005) than in 14 nonjaundiced comparison patients without liver disease. The elevated UDP-glucuronyltransferase activity in sickle cell anemia was similar to that found in 10 patients who chronically ingested drugs (barbiturates or estrogens) known to increase UDP-glucuronyltransferase activity. These observations suggest enhanced conjugation of bilirubin in patients with sickle cell anemia may result from substrate (bilirubin) induction of UDP-glycuronyltransferase. PMID:413760

  18. Bilirubin enhances neuronal excitability by increasing glutamatergic transmission in the rat lateral superior olive.

    Science.gov (United States)

    Li, Chun-Yan; Shi, Hai-Bo; Song, Ning-Ying; Yin, Shan-Kai

    2011-06-18

    Hyperbilirubinemia is one of the most common clinical phenomena observed in human newborns. To achieve effective therapeutic treatment, numerous studies have been done to determine the molecular mechanisms of bilirubin-induced neuronal excitotoxicity. However, there is no conclusive evidence for the involvement of glutamatergic synaptic transmission in bilirubin-induced neuronal hyperexcitation and excitotoxicity. In the present study, using gramicidin-perforated patch-clamp techniques, spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from lateral superior olive (LSO) neurons isolated from postnatal 11-14-day-old (P11-14) rats. The application of 3 μM bilirubin increased the frequency, but not the amplitude, of sEPSCs. The action of bilirubin was tetrodotoxin (TTX)-insensitive, as bilirubin also increased the frequency, but not the amplitude, of mEPSCs. The amplitudes of GABA-activated (I(GABA)) and glutamate-activated (I(glu)) currents were not affected by bilirubin. Under current-clamp conditions, no spontaneous action potentials were observed in control solution. However, the application of 3 μM bilirubin for 4-6 min evoked a considerable rate of action-potential firing. The evoked firing was partially occluded by D,L-2-amino-5-phosphonovaleric acid (APV), an NMDA receptor antagonist, but completely inhibited by a combination of APV and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX), an AMPA receptor antagonist. These results indicate that bilirubin facilitates presynaptic glutamate release, enhances glutamatergic synaptic transmission by activating postsynaptic AMPA and NMDA receptors, and leads to neuronal hyperexcitation. This study provides a better understanding of the mechanism of bilirubin-induced excitotoxicity and determines for the first time that both AMPA and NMDA receptors are likely involved in the excitotoxicity produced by bilirubin. PMID:21440030

  19. Low dose of oleanolic acid protects against lithocholic acid-induced cholestasis in mice: potential involvement of nuclear factor-E2-related factor 2-mediated upregulation of multidrug resistance-associated proteins.

    Science.gov (United States)

    Chen, Pan; Zeng, Hang; Wang, Yongtao; Fan, Xiaomei; Xu, Chenshu; Deng, Rongrong; Zhou, Xunian; Bi, Huichang; Huang, Min

    2014-05-01

    Oleanolic acid (OA) is a natural triterpenoid and has been demonstrated to protect against varieties of hepatotoxicants. Recently, however, OA at high doses was reported to produce apparent cholestasis in mice. In this study, we characterized the protective effect of OA at low doses against lithocholic acid (LCA)-induced cholestasis in mice and explored further mechanisms. OA cotreatment (5, 10, and 20 mg/kg, i.p.) significantly improved mouse survival rate, attenuated liver necrosis, and decreased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase; more importantly, serum total bile acids and bilirubin, as well as hepatic total bile acids were also remarkably reduced. Gene and protein expression analysis showed that hepatic expression of multidrug resistance-associated protein 2 (Mrp2), Mrp3, and Mrp4 was significantly increased by OA cotreatment, whereas other bile acid metabolism- and transport-related genes, including Na+/taurocholate cotransporter, organic anion transporter 1b2, bile salt export pump, multidrug resistance protein 3, Cyp3a11, Cyp2b10, Sulfotransferase 2a1 (Sult2a1), and UDP-glucuronosyltransferase 1a1 (Ugt1a1), were only slightly changed. OA also caused increased nuclear factor-E2-related factor (Nrf2) mRNA expression and nuclear protein accumulation, whereas nuclear receptors farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor were not significantly influenced by OA. Luciferase (Luc) assays performed in HepG2 cells illustrated that OA was a strong Nrf2 agonist with moderate PXR and weak FXR agonism. Finally, in mouse primary cultured hepatocytes, OA dose- and time-dependently induced expression of Mrp2, Mrp3, and Mrp4; however, this upregulation was abrogated when Nrf2 was silenced. In conclusion, OA produces a protective effect against LCA-induced hepatotoxicity and cholestasis, possibly due to Nrf2-mediated upregulation of Mrp2, Mrp3, and Mrp4. PMID:24510383

  20. Analgesic Response to Intravenous Ketamine Is Linked to a Circulating microRNA Signature in Female Patients With Complex Regional Pain Syndrome.

    Science.gov (United States)

    Douglas, Sabrina R; Shenoda, Botros B; Qureshi, Rehman A; Sacan, Ahmet; Alexander, Guillermo M; Perreault, Marielle; Barrett, James E; Aradillas-Lopez, Enrique; Schwartzman, Robert J; Ajit, Seena K

    2015-09-01

    Although ketamine is beneficial in treating complex regional pain syndrome (CRPS), a subset of patients respond poorly to therapy. We investigated treatment-induced microRNA (miRNA) changes and their predictive validity in determining treatment outcome by assessing miRNA changes in whole blood from patients with CRPS. Blood samples from female patients were collected before and after 5 days of intravenous ketamine administration. Seven patients were responders and 6 were poor responders. Differential miRNA expression was observed in whole blood before and after treatment. In addition, 33 miRNAs differed between responders and poor responders before therapy, suggesting the predictive utility of miRNAs as biomarkers. Investigation of the mechanistic significance of hsa-miR-548d-5p downregulation in poor responders showed that this miRNA can downregulate UDP-glucuronosyltransferase UGT1A1 mRNA. Poor responders had a higher conjugated/unconjugated bilirubin ratio, indicating increased UGT1A1 activity. We propose that lower pretreatment levels of miR-548d-5p may result in higher UDP-GT activity, leading to higher levels of inactive glucuronide conjugates, thereby minimizing the therapeutic efficacy of ketamine in poor responders. Differences in miRNA signatures can provide molecular insights distinguishing responders from poor responders. Extending this approach to other treatment and outcome assessments might permit stratification of patients for maximal therapeutic outcome. Perspective: This study suggests the usefulness of circulating miRNAs as potential biomarkers. Assessing miRNA signatures before and after treatment demonstrated miRNA alterations from therapy; differences in miRNA signature in responders and poor responders before therapy indicate prognostic value. Mechanistic studies on altered miRNAs can provide new insights into disease. PMID:26072390

  1. Unilobar versus bilobar biliary drainage: effect on quality of life and bilirubin level reduction

    Directory of Open Access Journals (Sweden)

    Shivanand Gamanagatti

    2016-01-01

    Conclusion: Percutaneous biliary drainage provides good palliation of malignant obstructive jaundice. Partial-liver drainage achieved results as good as those after complete liver drainage with significant improvements in QOL and reduction of the bilirubin level.

  2. Neonatal bilirubin management as an implementation example of interdisciplinary continuum of care tools

    OpenAIRE

    Thornton, Sidney N.; Thompson, Bryce S.; Millar, Jean A.; Eggert, Larry D.; Wilcox, Adam B

    2007-01-01

    Management of newborn bilirubin spans the inpatient and outpatient continuum of care. Intermountain Healthcare has developed and implemented a web-based tool for managing bilirubin that follows newborn patients across care settings and providers with a consistent plan of care. The underlying model for the tool is derived from published guidelines. The model divides the time-sensitive data into risk zones and associates each zone with the appropriate order set for follow-up care. The tool inte...

  3. Studies on The Adsorption Capacity for Bilirubin of The Adsorbent Chitosan-β-Cyclodextrin

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The adsorbent crosslinked chitosan-β-cyclodextrin (β-CD) was prepared by the reaction of glutaraldehyde with chitosan and β-cyclodextrin. This type of adsorbent has high adsorption capacity for unconjugated bilirubin. The adsorption capacity was related to the β-CD content of the adsorbent; phosphate buffer concentration; temperature; pH value; ionic strength and the adsorbent beads. The results indicated that the chitosan-β-CD was a good adsorbent for unconjugated bilirubin with high capacity.

  4. The origins and kinetics of bilirubin in dogs with hepatobiliary and haemolytic diseases.

    Science.gov (United States)

    Rothuizen, J; van den Brom, W E; Fevery, J

    1992-05-01

    In 35 dogs with spontaneous hepatobiliary liver disease the kinetics and the sources of bilirubin were quantified. The disorders were extrahepatic bile duct obstruction (n = 4), fulminant hepatitis (n = 2), (sub)acute hepatitis (n = 5), chronic active hepatitis (CAH) with cirrhosis (n = 6), hepatic lymphosarcoma (n = 5), centrizonal necrosis secondary to haemolytic anaemia (n = 6) and other (n = 2). The plasma disappearance of [3H]bilirubin was analyzed with a two-compartment model in all dogs. The ratio early labeled/late labeled bilirubin was determined by measuring the incorporation of [14C]glycine into erythrocyte haem and faecal stercobilin. By introducing this relation in the model analysis the bilirubin production rates from erythrocyte destruction (PE), ineffective erythropoiesis (PI) and hepatic haemoprotein (PL) could be quantified. Total bilirubin turnover was increased in both primary haemolytic disease and most cases of hepatobiliary disease. Erythrocyte survival was reduced in all cases but one. The bilirubin clearance was impaired to 30-50% of the normal value in most cases of hepatobiliary disease and also in primary haemolysis. In dogs with fulminant hepatitis, and cirrhosis with or without CAH, the clearance rates were reduced to values below 15% of normal. In these dogs both an impaired clearance and an increased production were important determinants of hyperbilirubinaemia. In other cases plasma bilirubin was primarily determined by increased production. These clearances and production rates were similar in haemolysis and in many cases of primary hepatobiliary disease. The hepatic haemoprotein turnover was quite variable in all subgroups, ranging from 1-74% of the total bilirubin turnover.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1506635

  5. Relationship of serum bilirubin concentration to kidney function and 24-hour urine protein in Korean adults

    OpenAIRE

    Jung Yeon Soon; Shin Ho Sik; Rim Hark

    2011-01-01

    Abstract Background The relationships among serum bilirubin concentration, kidney function and proteinuria have yet to be fully elucidated, nor have these relationships been investigated in Korean adults. Method We retrospectively reviewed the medical records of Korean adults who were evaluated at Kosin University Gospel Hospital (Busan, Republic of Korea) during a five-year period from January 2005 to December 2009. We evaluated the relationships among serum bilirubin concentration, estimate...

  6. "The effect of fluid supplementation on serum bilirubin level during phototerapy in term infants "

    Directory of Open Access Journals (Sweden)

    Torkaman M

    2007-04-01

    Full Text Available Background: Jaundice is a common and benign problem in neonatal period. Several therapeutic procedures for decreasing of serum bilirubin level has been recommended. phototherapy is most common them. Our goal Form this study is the evaluation of serum therapy effects in decreasing of serum bilirubin concentration in icteric infants that are treated with phototherapy. Methods: This is a prospective clinical trial in Najmeih Hospital in 2002. In this study 80 term icteric infants with bilirubin level greater than 17 mg/dl were randomized in two groups, both groups underwent phototherapy and in the case group intravenous fluid supplementation was added. There were no significant differences in the mean gestational age, birth weight, hemoglobin, and also in total serum bilirubin level at admission in the two groups. Results: There were no significant differences in the mean rate of of serum bilirubin level decline during first 24 and 48 hours of hospitalization and also the time of bilirubin decreasing to less than 15 mg/dl and the length of hospitalization in two groups. Conclution: Our study showed intravenous fluid supplementation could be limited to special cases of neonatal icter such as moderate to severe dehydration.

  7. The evaluation of the effect of different anesthetic techniques on neonatal bilirubin levels

    Directory of Open Access Journals (Sweden)

    Fatma Eskicioğlu

    2014-01-01

    Full Text Available Objective: The aim of the present study was to determine whether different anesthetic techniques applied for vaginal delivery and cesarean section affect neonatal bilirubin levels in the first 24 hours of life .Materials and Methods: A total of 511 neonates delivered by vaginal route or cesarean section were included in the study. The neonates were classified according to method of delivery and anesthetic agents as group A (cesarean section / general anesthesia with sevoflurane, group B (cesarean section / spinal anesthesia with bupivacaine hydrochlorur , group C (vaginal delivery with episiotomy / local anesthesia with prilocaine hydrochloride and group D (vaginal delivery/ no anesthesia . The levels of neonatal serum bilirubin in the groups were compared.Results: There was no difference between group A and group B when compared in terms of neonatal bilirubin levels (p = 0.98. Depending on the use of prilocaine hydrochloride as local anesthetic agent in the vaginal delivery, there was no significant difference between the groups C and D ,who had vaginal delivery, in terms of the neonatal bilirubin levels (p = 0.99. The serum levels of bilirubin in cesarean section groups were significantly higher than those of the vaginal delivery groups (p < 0.001.Conclusion: Prilocaine hydrochloride used for episiotomy is not effective on neonatal hyperbilirubinemia. However, sevoflurane and bupivacaine hydrochloride used in cesarean section seem to be increasing bilirubin levels.

  8. Stopped-flow studies of spectral changes in bilirubin-human serum albumin following an alkaline pH jump and following binding of bilirubin

    DEFF Research Database (Denmark)

    Honoré, B

    1987-01-01

    changes were analyzed according to a scheme of consecutive unimolecular reactions. Spectral monitoring of a pH jump from 11.3 to 11.8 reveals that the bilirubin-albumin complex changes its structure in several steps. The UV absorption spectra show that 3.8 tyrosine residues ionize in the first step, 2...

  9. Development of a System Model for Non-Invasive Quantification of Bilirubin in Jaundice Patients

    Science.gov (United States)

    Alla, Suresh K.

    Neonatal jaundice is a medical condition which occurs in newborns as a result of an imbalance between the production and elimination of bilirubin. Excess bilirubin in the blood stream diffuses into the surrounding tissue leading to a yellowing of the skin. An optical system integrated with a signal processing system is used as a platform to noninvasively quantify bilirubin concentration through the measurement of diffuse skin reflectance. Initial studies have lead to the generation of a clinical analytical model for neonatal jaundice which generates spectral reflectance data for jaundiced skin with varying levels of bilirubin concentration in the tissue. The spectral database built using the clinical analytical model is then used as a test database to validate the signal processing system in real time. This evaluation forms the basis for understanding the translation of this research to human trials. The clinical analytical model and signal processing system have been successful validated on three spectral databases. First spectral database is constructed using a porcine model as a surrogate for neonatal skin tissue. Samples of pig skin were soaked in bilirubin solutions of varying concentrations to simulate jaundice skin conditions. The resulting skins samples were analyzed with our skin reflectance systems producing bilirubin concentration values that show a high correlation (R2 = 0.94) to concentration of the bilirubin solution that each porcine tissue sample is soaked in. The second spectral database is the spectral measurements collected on human volunteers to quantify the different chromophores and other physical properties of the tissue such a Hematocrit, Hemoglobin etc. The third spectral database is the spectral data collected at different time periods from the moment a bruise is induced.

  10. Serum total bilirubin levels and coronary heart disease--Causal association or epiphenomenon?

    Science.gov (United States)

    Kunutsor, Setor K

    2015-12-01

    Observational epidemiological evidence supports a linear inverse and independent association between serum total bilirubin levels and coronary heart disease (CHD) risk, but whether this association is causal remains to be ascertained. A Mendelian randomization approach was employed to test whether serum total bilirubin is causally linked to CHD. The genetic variant rs6742078--well known to specifically modify levels of serum total bilirubin and accounting for up to 20% of the variance in circulating serum total bilirubin levels--was used as an instrumental variable. In pooled analysis of estimates reported from published genome-wide association studies, every copy of the T allele of rs6742078 was associated with 0.42 standard deviation (SD) higher levels of serum total bilirubin (95% confidence interval, 0.40 to 0.43). Based on combined data from the Coronary Artery Disease Genome wide Replication and Meta-analyses and the Coronary Artery Disease (C4D) Genetics Consortium involving a total of 36,763 CHD cases and 76,997 controls, the odds ratio for CHD per copy of the T allele was 1.01 (95% confidence interval, 0.99 to 1.04). The odds ratio of CHD for a 1 SD genetically elevated serum total bilirubin level was 1.03 (95% confidence interval, 0.98 to 1.09). The current findings casts doubt on a strong causal association of serum total bilirubin levels with CHD. The inverse associations demonstrated in observational studies may be driven by biases such as unmeasured confounding and/or reverse causation. However, further research in large-scale consortia is needed. PMID:26408227

  11. Predictors of the change in bilirubin levels over twelve weeks of treatment with atazanavir

    LENUS (Irish Health Repository)

    Cotter, Aoife G

    2013-05-16

    AbstractObjectiveTo determine the factors associated with change in bilirubin concentration 12 weeks after the initiation of an atazanavir (ATV)-containing antiretroviral regimen.MethodsWe performed a retrospective case note review of all patients prescribed ATV between January 2004 and October 2007 in a cohort of HIV infected subjects. Data collected included baseline demographics, hepatitis B and C serology, current antiretroviral therapy, baseline and week 12 routine bloods. The primary endpoint was the change in bilirubin concentration at 12 weeks after start of ATV. Multvariable linear regression was performed to assess the relationships between the change in bilirubin and variables of interest. Results: Eighty-three ATV-treated patients were included in the analysis of whom 46 (60.5%) were hepatitis C antibody positive. The median (interquartile range) change in bilirubin by week 12 was 16 (4, 22) umol\\/L; only 1 patient developed grade 4 hyperbilirubinaemia at week 12. After controlling for baseline bilirubin levels, HCV seropositivity and baseline ALP were associated with a smaller change in bilirubin over the 12 weeks with a trend towards lower increases in those receiving tenofovir. Sensitivity analyses reported similar associations with methadone use and injection drug use, when these variables replaced HCV sero-positivity in the model. Conclusion: Patients with hepatitis C co-infection experience smaller changes in bilirubin upon exposure to ATV. Although the underlying mechanism for this association remains unclear, these data support the safe use of this drug in this patient setting. Further research into the clinical predictors of ATV-related hyperbilirubinaemia is warranted.

  12. Bilirubin modulated cytokines, growth factors and angiogenesis to improve cutaneous wound healing process in diabetic rats.

    Science.gov (United States)

    Ram, Mahendra; Singh, Vishakha; Kumawat, Sanjay; Kant, Vinay; Tandan, Surendra Kumar; Kumar, Dinesh

    2016-01-01

    Bilirubin has shown cutaneous wound healing potential in some preliminary studies. Here we hypothesize that bilirubin facilitates wound healing in diabetic rats by modulating important healing factors/candidates and antioxidant parameters in a time-dependent manner. Diabetes was induced in male Wistar rats by streptozotocin. In all diabetic rats wounds were created under pentobarbitone anesthesia. All the rats were divided into two groups, of which one (control) was treated with ointment base and other with bilirubin ointment (0.3%). Wound closer measurement and tissue collection were done on days 3, 7, 14 and 19 post-wounding. The relative expressions of hypoxia inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 alpha (SDF-1α), transforming growth factor- beta1 (TGF-β1()), tumor necrosis factor-α (TNF-α) and interlukin-10 (IL-10) mRNA and proteins and the mRNA of interlukin-1 beta (IL-1β) and matrix metalloprteinase-9 (MMP-9) were determined in the wound tissues. CD-31 staining and collagen content were evaluated by immunohistochemistry and picrosirius red staining, respectively. Histopathological changes were assessed by H&E staining. The per cent wound closer was significantly higher from day 7 onwards in bilirubin-treated rats. HIF-1α, VEGF, SDF-1α, TGF-β1, IL-10 mRNA and protein levels were significantly higher on days 3, 7 and 14 in bilirubin-treated rats. The mRNA expression and protein level of TNF-α and the mRNA of IL-1β and MMP-9 were progressively and markedly reduced in bilirubin-treated rats. The collagen deposition and formation of blood vessels were greater in bilirubin-treated rats. Bilirubin markedly facilitated cutaneous wound healing in diabetic rats by modulating growth factors, cytokines, neovasculogenesis and collagen contents to the wound site. Topical application of bilirubin ointment might be of great use in cutaneous wound healing in diabetic patients. PMID:26679676

  13. Physiological antioxidative network of the bilirubin system in aging and age-related diseases

    Directory of Open Access Journals (Sweden)

    Sung Young eKim

    2012-03-01

    Full Text Available Oxidative stress is detrimental to life processes and is particularly responsible for aging and age-related diseases. Thus, most organisms are well equipped with a spectrum of biological defense mechanisms against oxidative stress. The major efficient antioxidative mechanism is the glutathione system, operating a redox cycling mechanism for glutathione utilization, which consists of glutathione and its peroxidase and reductase. However, this system is mainly effective for hydrophilic oxidants, while lipophilic oxidants require another scavenging system. Since many age-related pathological conditions are related to lipid peroxidation, especially in association with the aging process, the physiological role of the scavenging system for lipophilic oxidants should be considered. In this regard, the biliverdin to bilirubin conversion pathway, via biliverdin reductase, is suggested to be another major protective mechanism that scavenges lipophilic oxidants because of the lipophilic nature of bilirubin. The efficiency of this bilirubin system might be potentiated by operation of the intertwined bicyclic systems of the suggested redox metabolic cycle of biliverdin and bilirubin and the transcriptional control cycle of biliverdin reductase and heme oxygenase-1. In order to combat oxidative stress, both anti-oxidative systems, against hydrophilic and lipophilic oxidants, respectively, are required to work cooperatively. In this regard, the roles of the bilirubin system in aging and age-related diseases are reassessed in this review, and their interacting networks are evaluated.

  14. STUDY TO PREDICT NEWBORN AT RISK OF DEVELOPING NEONATAL HYPERBILIRUBINAEMIA BY MEASURING CORD BLOOD BILIRUBIN

    Directory of Open Access Journals (Sweden)

    Uthaya

    2016-04-01

    Full Text Available BACKGROUND NNH is a common problem in neonates during 1st week of life. Early discharge of healthy-term newborn is a common practice and NNH is a cause for readmission in most babies. Our aim was to predict the risk of NNH using cord bilirubin values. METHODS Around 150 intramurally delivered healthy term neonates were prospectively enrolled. Cord bilirubin and serum bilirubin at or after 72 hours were estimated. RESULTS AND DISCUSSION Using statistical analysis SPSS 19.0.2 program for windows, significant hyperbilirubinaemia was found in 14% of the neonates. Using cord bilirubin >2 mg/dL, significant hyperbilirubinaemia can be predicted with sensitivity of 90.4%, specificity of 75.1%, PPV of 37.2%, NPV of 97.9% and a p value of <0.05. CONCLUSION A high NPV in our study suggests that healthy term babies with cord bilirubin <2 mg/dL can be discharged early with assurance to parents.

  15. Pro-healing effects of bilirubin in open excision wound model in rats.

    Science.gov (United States)

    Ahanger, Azad A; Leo, Marie D; Gopal, Anu; Kant, Vinay; Tandan, Surendra K; Kumar, Dinesh

    2016-06-01

    Bilirubin, a by-product of heme degradation, has an important role in cellular protection. Therefore, we speculated that bilirubin could be of potential therapeutic value in wound healing. To validate the hypothesis, we used a full-thickness cutaneous wound model in rats. Bilirubin (30 mg/kg) was administered intraperitoneally every day for 9 days. The surface area of the wound was measured on days 0, 2, 4, 7 and 10 after the creation of the wound. The granulation tissue was collected on day 10 post-wounding for analysing various parameters of wound healing. Bilirubin treatment accelerated wound contraction and increased hydroxyproline and glucosamine contents. mRNA expression of pro-inflammatory factors such as intercellular cell adhesion molecule-1 (ICAM-1) and tumour necrosis factor-α (TNF-α) were down-regulated and that of anti-inflammatory cytokine interleukin-10 (IL-10) was up-regulated. The findings suggest that bilirubin could be a new agent for enhancing cutaneous wound healing. PMID:24947136

  16. Comparison of transcutaneous and total serum bilirubin measurement in Turkish newborns.

    Science.gov (United States)

    Şimşek, Fatih Mehmet; Narter, Fatma; Ergüven, Müferet

    2014-01-01

    Severe neonatal hyperbilirubinemia can be prevented by screening for neonatal jaundice. Transcutaneous bilirubin (TcB) measurement is a noninvasive method for screening neonates. The aim of this study was to examine the correlation between TcB measurement (using the JM-103 bilirubinometer) and total serum bilirubin (TSB) measurement. To our knowledge, this is the first study evaluating the usefulness of the JM-103 bilirubinometer in Turkish neonates. Two hundred and fifty healthy infants in our well-baby nurseries and follow-up clinic with a gestational age of ≥36 weeks who were ≤15 days old were enrolled in this study. TcB measurements were taken usinng the JM-103; almost simultaneously, TSB was checked using a spectrophotometric method. The mean±SD TSB level was 11.2±4.6 mg/dl (range, 0.9-27.0 mg/dl); 17.2% of cases had TSB>15 mg/dl. There was good correlation between transcutaneous bilirubin and total serum bilirubin measurements (Pearson's correlation coefficient 0.87 for TcB from the forehead, 0.88 for TcB from the sternum; pjaundiced infants that require a serum bilirubin check and may reduce the need for TSB measurements. PMID:26388591

  17. Bilirubin Levels and Thrombus Burden in Patients With ST-Segment Elevation Myocardial Infarction.

    Science.gov (United States)

    Hamur, Hikmet; Duman, Hakan; Bakirci, Eftal Murat; Kucuksu, Zafer; Demirelli, Selami; Kalkan, Kamuran; Degirmenci, Husnu

    2016-07-01

    We investigated whether serum bilirubin level (a marker of heme oxygenase activity) is a predictor of thrombus burden in patients with acute myocardial infarction. Patients (n = 229; male 72.9%; mean age 63 ± 13.4 years) who were admitted with ST-segment elevation myocardial infarction (STEMI) were enrolled. Patients were divided into 2 groups. Group 1 was defined as low thrombus burden and group 2 was defined as high thrombus burden. Patients with high thrombus burden had higher total bilirubin levels (14.4 [4.3-22.9] vs 7.7 [2.4-20.3] µmol/L, P ≤ .001), (0.84 [0.25-1.34] vs 0.45 [0.14-1.19] mg/dL P ≤ .001) and direct bilirubin levels (3.1 [2.1-8.4] vs 1.7 [0.5-6.5] µmol/L, P ≤ .001), (0.18 [0.03-0.49] vs 0.10 [0.03-0.38] mg/dL, P ≤ .001). At multivariate analysis, total bilirubin (odds ratio: 1.05, 95% confidence interval: 1.03-1.08, P ≤ .001) was the independent predictor of high thrombus burden. In conclusion, total bilirubin level is independently associated with high thrombus burden in patients with STEMI. PMID:26339042

  18. Low expression of aldehyde deyhdrogenase 1A1 (ALDH1A1) is a prognostic marker for poor survival in pancreatic cancer

    International Nuclear Information System (INIS)

    Aldehyde deyhdrogenase 1 (ALDH1) has been characterised as a cancer stem cell marker in different types of tumours. Additionally, it plays a pivotal role in gene regulation and endows tumour cells with augmented chemoresistance. Recently, ALDH1A1 has been described as a prognostic marker in a pancreatic cancer tissue microarray. The aim of this study was to reevaluate the expression of ALDH1A1 as a prognostic marker on whole-mount tissue sections. Real-time-quantitative-PCR (qRT-PCR) and Western blotting were used to evaluate the expression profile of ALDH1A1 in seven pancreatic cancer cell lines and one non-malignant pancreatic cell line. Immunostaining against ALDH1A1 and Ki-67 was performed on paraffin-embedded samples from 97 patients with pancreatic cancer. The immunohistochemical results were correlated to histopathological and clinical data. qRT-PCR and Western blotting revealed a different expression pattern of ALDH1A1 in different malignant and non-malignant pancreatic cell lines. Immunohistochemical analysis demonstrated that ALDH1A1 was confined to the cellular cytoplasm and occurred in 72 cases (74%), whereas it was negative in 25 cases (26%). High expression of ALDH1A1 was significantly correlated to an increased proliferation rate (Spearman correlation, p = 0.01). Univariate and multivariate analyses showed that decreased expression of ALDH1A1 is an independent adverse prognostic factor for overall survival. Immunonhistochemical analysis on whole-mount tissue slides revealed that ALDH1A1 is more abundantly expressed in pancreatic cancer than initially reported by a tissue microarray analysis. Moreover, high expression of ALDH1A1 correlated significantly with the proliferation of tumour cells. Intriguingly, this study is the first which identifies low expression of ALDH1A1 as an independent adverse prognostic marker for overall survival in pancreatic cancer

  19. Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sangsoo Daniel; Antenos, Monica [Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada); Squires, E. James [Department of Animal and Poultry Sciences, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada); Kirby, Gordon M., E-mail: gkirby@uoguelph.ca [Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada)

    2013-07-15

    Bilirubin (BR) has recently been identified as the first endogenous substrate for cytochrome P450 2A5 (CYP2A5) and it has been suggested that CYP2A5 plays a major role in BR clearance as an alternative mechanism to BR conjugation by uridine-diphosphate glucuronyltransferase 1A1. This study investigated the mechanisms of Cyp2a5 gene regulation by BR and the cytoprotective role of CYP2A5 in BR hepatotoxicity. BR induced CYP2A5 expression at the mRNA and protein levels in a dose-dependent manner in primary mouse hepatocytes. BR treatment also caused nuclear translocation of Nuclear factor-E2 p45-related factor 2 (Nrf2) in hepatocytes. In reporter assays, BR treatment of primary hepatocytes transfected with a Cyp2a5 promoter-luciferase reporter construct resulted in a 2-fold induction of Cyp2a5 reporter activity. Furthermore, cotransfection of the hepatocytes with a Nrf2 expression vector without BR treatment resulted in an increase in Cyp2a5 reporter activity of approximately 2-fold and BR treatment of Nrf2 cotransfectants further increased reporter activity by 4-fold. In addition, site-directed mutation of the ARE in the reporter construct completely abolished both the BR- and Nrf2-mediated increases in reporter activity. The cytoprotective role of CYP2A5 against BR-mediated apoptosis was also examined in Hepa 1–6 cells that lack endogenous CYP2A5. Transient overexpression of CYP2A5 partially blocked BR-induced caspase-3 cleavage in Hepa 1–6 cells. Furthermore, in vitro degradation of BR was increased by microsomes from Hepa 1–6 cells overexpressing CYP2A5 compared to control cells transfected with an empty vector. Collectively, these results suggest that Nrf2-mediated CYP2A5 transactivation in response to BR may provide an additional mechanism for adaptive cytoprotection against BR hepatotoxicity. - Highlights: • The mechanism of Cyp2a5 gene regulation by BR was investigated. • The cytoprotective role of CYP2A5 in BR hepatotoxicity was determined. • BR

  20. Bilirubin Encephalopathy in a Domestic Shorthair Cat With Increased Osmotic Fragility and Cholangiohepatitis.

    Science.gov (United States)

    Contreras, E T; Giger, U; Malmberg, J L; Quimby, J M; Schaffer, P A

    2016-05-01

    A 7-month-old female domestic shorthair cat was diagnosed with chronic regenerative hemolytic anemia characterized by increased osmotic fragility of unknown etiology. At 13 months of age, the cat was evaluated for acute collapse. The cat was icteric with severe hyperbilirubinemia but no hematocrit changes. Severe obtundation and lateral recumbency progressed to tetraparesis and loss of proprioception in all 4 limbs, and a cerebellar or brainstem lesion was suspected. Postmortem examination revealed suppurative cholangiohepatitis and acute neuronal necrosis in the nuclei of the brainstem and cerebellum, consistent with bilirubin encephalopathy. This is the first known occurrence of cholangiohepatitis and bilirubin encephalopathy in an adult cat with chronic hemolytic anemia. Although rare, bilirubin encephalopathy should be considered a possible sequela to hyperbilirubinemia in adult patients. It remains unknown whether increased osmotic fragility was related to the cholangiohepatopathy. PMID:26354310

  1. Persistent high serum bilirubin level after percutaneous transhepatic biliary drainage: analysis of 32 cases

    Energy Technology Data Exchange (ETDEWEB)

    Choo, In Wook; Choi, Byung Ihn; Park, Jae Hyung; Han, Man Chung; Kim, Chu Wan [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1986-12-15

    The aim of percutaneous transhepatic biliary drainage (PTBD) is to decrease serum bilirubin level and promote liver function in patient with biliary tract disease, especially obstruction by malignant disease. But some patients showed persistent high serum bilirubin level or higher than pre-PTBD level. Percutaneous transhepatic biliary drainage was performed in 341 patients of obstructive jaundice for 5 years form July, 1981 to July, 1986 at department of radiology, Seoul National University Hospital. Follow up check of the serum bilirubin level was possible in 188 patients. Among them the authors analysed 32 patients who showed persistent high serum bilirubin level after PTBD. The results were as follows: 1. The male to female ratio was 3.4:1 and the age ranged from 33 to 75. 2. The causes of obstructive jaundice included 30 malignant diseases and 2 benign diseases. Malignant disease were 16 cases of bile duct carcinoma, 7 cases of pancreatic cancer and 7 cases of metastasis from stomach, colon and uterine cervix. Benign disease were 1 case of common hepatic duct stone and 1 case of intrahepatic duct stones. 3. The most common level of obstruction was trifurcation in 17 cases. 4. The most common indication of PTBD was palliative drainage of obstruction secondary to malignant tumor in 28 cases. 5. Change of serum bilirubin level ratio (post-PTBD level/pre-PTBD level) was 1.28, 1.22, 1.38, 1.51 in serial period of 1-3 days, 4-6 days, 1-2 week 2-3 week after PTBD. 6. Causes of persistent high serum bilirubin level after PTBD were 12 cases of partial drainage of intrahepatic bile, 13 cases of hepatic dysfunction including 9 cases of metastatic nodule, 2 cases of biliary cirrhosis, 2 cases of multiple liver abscess, and 7 cases of poor function of catheter including 4 cases of hemobilia, 1 case of multiple intrahepatic stones, pyobilia and intrahepatic Clonorchis sinensis.

  2. Persistent high serum bilirubin level after percutaneous transhepatic biliary drainage: analysis of 32 cases

    International Nuclear Information System (INIS)

    The aim of percutaneous transhepatic biliary drainage (PTBD) is to decrease serum bilirubin level and promote liver function in patient with biliary tract disease, especially obstruction by malignant disease. But some patients showed persistent high serum bilirubin level or higher than pre-PTBD level. Percutaneous transhepatic biliary drainage was performed in 341 patients of obstructive jaundice for 5 years form July, 1981 to July, 1986 at department of radiology, Seoul National University Hospital. Follow up check of the serum bilirubin level was possible in 188 patients. Among them the authors analysed 32 patients who showed persistent high serum bilirubin level after PTBD. The results were as follows: 1. The male to female ratio was 3.4:1 and the age ranged from 33 to 75. 2. The causes of obstructive jaundice included 30 malignant diseases and 2 benign diseases. Malignant disease were 16 cases of bile duct carcinoma, 7 cases of pancreatic cancer and 7 cases of metastasis from stomach, colon and uterine cervix. Benign disease were 1 case of common hepatic duct stone and 1 case of intrahepatic duct stones. 3. The most common level of obstruction was trifurcation in 17 cases. 4. The most common indication of PTBD was palliative drainage of obstruction secondary to malignant tumor in 28 cases. 5. Change of serum bilirubin level ratio (post-PTBD level/pre-PTBD level) was 1.28, 1.22, 1.38, 1.51 in serial period of 1-3 days, 4-6 days, 1-2 week 2-3 week after PTBD. 6. Causes of persistent high serum bilirubin level after PTBD were 12 cases of partial drainage of intrahepatic bile, 13 cases of hepatic dysfunction including 9 cases of metastatic nodule, 2 cases of biliary cirrhosis, 2 cases of multiple liver abscess, and 7 cases of poor function of catheter including 4 cases of hemobilia, 1 case of multiple intrahepatic stones, pyobilia and intrahepatic Clonorchis sinensis.

  3. Multiple secretoglobin 1A1 genes are differentially expressed in horses

    Directory of Open Access Journals (Sweden)

    Côté Olivier

    2012-12-01

    Full Text Available Abstract Background Secretoglobin 1A1 (SCGB 1A1, also called Clara cell secretory protein, is the most abundantly secreted protein of the airway. The SCGB1A1 gene has been characterized in mammals as a single copy in the genome. However, analysis of the equine genome suggested that horses might have multiple SCGB1A1 gene copies. Non-ciliated lung epithelial cells produce SCGB 1A1 during inhalation of noxious substances to counter airway inflammation. Airway fluid and lung tissue of horses with recurrent airway obstruction (RAO, a chronic inflammatory lung disease affecting mature horses similar to environmentally induced asthma of humans, have reduced total SCGB 1A1 concentration. Herein, we investigated whether horses have distinct expressed SCGB1A1 genes; whether the transcripts are differentially expressed in tissues and in inflammatory lung disease; and whether there is cell specific protein expression in tissues. Results We identified three SCGB1A1 gene copies on equine chromosome 12, contained within a 512-kilobase region. Bioinformatic analysis showed that SCGB1A1 genes differ from each other by 8 to 10 nucleotides, and that they code for different proteins. Transcripts were detected for SCGB1A1 and SCGB1A1A, but not for SCGB1A1P. The SCGB1A1P gene had most inter-individual variability and contained a non-sense mutation in many animals, suggesting that SCGB1A1P has evolved into a pseudogene. Analysis of SCGB1A1 and SCGB1A1A sequences by endpoint-limiting dilution PCR identified a consistent difference affecting 3 bp within exon 2, which served as a gene-specific “signature”. Assessment of gene- and organ-specific expression by semiquantitative RT-PCR of 33 tissues showed strong expression of SCGB1A1 and SCGB1A1A in lung, uterus, Fallopian tube and mammary gland, which correlated with detection of SCGB 1A1 protein by immunohistochemistry. Significantly altered expression of the ratio of SCGB1A1A to SCGB1A1 was detected in RAO

  4. Transport and metabolism at blood-brain interfaces and in neural cells: relevance to bilirubin-induced encephalopathy

    Directory of Open Access Journals (Sweden)

    Silvia eGazzin

    2012-05-01

    Full Text Available Bilirubin, the end-product of heme catabolism, circulates in non pathological plasma mostly as a protein-bound species. When bilirubin concentration builds up, the free fraction of the molecule increases. Unbound bilirubin then diffuses across blood-brain interfaces into the brain, where it accumulates and exerts neurotoxic effects. In this classical view of bilirubin neurotoxicity, blood-brain interfaces act merely as structural barriers impeding the penetration of the pigment-bound carrier protein, and neural cells are considered as passive targets of its toxicity. Yet, the role of blood-brain interfaces in the occurrence of bilirubin encephalopathy appears more complex than being simple barriers to the diffusion of bilirubin, and neural cells such as astrocytes and neurons can play an active role in controlling the balance between the neuroprotective and neurotoxic effects of bilirubin. This article reviews the emerging in vivo and in vitro data showing that transport and metabolic detoxification mechanisms at the blood-brain and blood-CSF barriers may modulate bilirubin flux across both cellular interfaces, and that these protective functions can be affected in chronic hyperbilirubinemia. Then the in vivo and in vitro arguments in favor of the physiological antioxidant function of intracerebral bilirubin are presented, as well as with the potential role of transporters such as ABCC-1 and metabolizing enzymes such as cytochromes P-450 in setting the cerebral cell- and structure-specific toxicity of bilirubin following hyperbilirubinemia. The relevance of these data to the pathophysiology of bilirubin-induced neurological diseases is discussed.

  5. Association between bilirubin and risk of Non-Alcoholic Fatty Liver Disease based on a prospective cohort study

    Science.gov (United States)

    Tian, Jianbo; Zhong, Rong; Liu, Cheng; Tang, Yuhan; Gong, Jing; Chang, Jiang; Lou, Jiao; Ke, Juntao; Li, Jiaoyuan; Zhang, Yi; Yang, Yang; Zhu, Ying; Gong, Yajie; Xu, Yanyan; Liu, Peiyi; Yu, Xiao; Xiao, Lin; Du, Min; Yang, Ling; Yuan, Jing; Wang, Youjie; Chen, Weihong; Wei, Sheng; Liang, Yuan; Zhang, Xiaomin; He, Meian; Wu, Tangchun; Yao, Ping; Miao, Xiaoping

    2016-01-01

    The study aimed to assess the association between total, direct, and indirect bilirubin and nonalcoholic fatty live disease (NAFLD) risk given its high prevalence and serious clinical prognosis. Among 27,009 subjects who participated in a healthy screening program from the Dongfeng-Tongji cohort study in 2008, 8189 eligible subjects (aged 35–86 years; males, 43.95%) were ultimately enrolled. The incidence rates of NAFLD in 2013 were compared with respect to baseline bilirubin levels among subjects free of NAFLD, and the effect sizes were estimated by logistic regression analysis. During 5 years follow-up, we observed 1956 cases of newly developed NAFLD with the overall incidence of 23.88%. Direct bilirubin was presented to inversely associate with NAFLD risk. Compared with quartile 1 of direct bilirubin, the multivariable-adjusted ORs (95% CIs) for NAFLD of quartile 2 to 4 were 1.104 (0.867–1.187), 0.843 (0.719–0.989), and 0.768 (0.652–0.905), respectively, P for trend 0.002). Similarly, inverse effects of direct bilirubin on NAFLD incidence were also observed when stratified by sex and BMI. However, no significant associations were found between total, and indirect bilirubin and NAFLD risk. Direct bilirubin reduced NAFLD risk independent of possible confounders among middle-aged and elderly Chinese population, probably based on the endogenous antioxidation of bilirubin. PMID:27484402

  6. Association between bilirubin and risk of Non-Alcoholic Fatty Liver Disease based on a prospective cohort study.

    Science.gov (United States)

    Tian, Jianbo; Zhong, Rong; Liu, Cheng; Tang, Yuhan; Gong, Jing; Chang, Jiang; Lou, Jiao; Ke, Juntao; Li, Jiaoyuan; Zhang, Yi; Yang, Yang; Zhu, Ying; Gong, Yajie; Xu, Yanyan; Liu, Peiyi; Yu, Xiao; Xiao, Lin; Du, Min; Yang, Ling; Yuan, Jing; Wang, Youjie; Chen, Weihong; Wei, Sheng; Liang, Yuan; Zhang, Xiaomin; He, Meian; Wu, Tangchun; Yao, Ping; Miao, Xiaoping

    2016-01-01

    The study aimed to assess the association between total, direct, and indirect bilirubin and nonalcoholic fatty live disease (NAFLD) risk given its high prevalence and serious clinical prognosis. Among 27,009 subjects who participated in a healthy screening program from the Dongfeng-Tongji cohort study in 2008, 8189 eligible subjects (aged 35-86 years; males, 43.95%) were ultimately enrolled. The incidence rates of NAFLD in 2013 were compared with respect to baseline bilirubin levels among subjects free of NAFLD, and the effect sizes were estimated by logistic regression analysis. During 5 years follow-up, we observed 1956 cases of newly developed NAFLD with the overall incidence of 23.88%. Direct bilirubin was presented to inversely associate with NAFLD risk. Compared with quartile 1 of direct bilirubin, the multivariable-adjusted ORs (95% CIs) for NAFLD of quartile 2 to 4 were 1.104 (0.867-1.187), 0.843 (0.719-0.989), and 0.768 (0.652-0.905), respectively, P for trend 0.002). Similarly, inverse effects of direct bilirubin on NAFLD incidence were also observed when stratified by sex and BMI. However, no significant associations were found between total, and indirect bilirubin and NAFLD risk. Direct bilirubin reduced NAFLD risk independent of possible confounders among middle-aged and elderly Chinese population, probably based on the endogenous antioxidation of bilirubin. PMID:27484402

  7. Physiological and pharmacological functions of OATP1A/1B transporters

    OpenAIRE

    Steeg, E.

    2010-01-01

    Organic Anion Transporting Polypeptide (OATP; mouse Oatp) transporters of the 1A/1B subfamilies are uptake transporters that mediate the cellular uptake of a wide range of endogenous and xenobiotic compounds. Since OATP1A/1B transporters are expressed in pharmacological important organs, like liver, kidney and small intestine, it has been hypothesized that OATP1A/1B transporters play an important role in drug disposition and elimination. By generating and utilizing novel Oatp1a/1b cluster kno...

  8. Evaluation of the Predictive Value of Umbilical Cord Serum Bilirubin Level for the Development of Subsequent Hyperbilirubinemia in Term and Late-Preterm Neonates

    Directory of Open Access Journals (Sweden)

    Fariba Hemmati

    2016-03-01

    Conclusion: Based on the findings, UCS bilirubin level could not predict subsequent hyperbilirubinemia. Therefore, the best predictive marker for neonatal jaundice is the assessment of clinical risk factors and predischarge bilirubin level.

  9. Identification of bilirubin reduction products formed by Clostridium perfringens isolated from human neonatal fecal flora

    Czech Academy of Sciences Publication Activity Database

    Vítek, L.; Majer, F.; Muchová, L.; Zelenka, J.; Jirásková, A.; Branny, Pavel; Malina, J.; Ubik, Karel

    2006-01-01

    Roč. 833, - (2006), s. 149-157. ISSN 1570-0232 R&D Projects: GA ČR GA310/02/1436 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40550506 Keywords : bilirubin * bacterial reduction * intestinal microflora Subject RIV: EE - Microbiology, Virology Impact factor: 2.647, year: 2006

  10. Profile of Minocycline Neuroprotection in Bilirubin-Induced Auditory System Dysfunction

    OpenAIRE

    Rice, Ann C.; Chiou, Victoria; Zuckoff, Sarah B; Shapiro, Steven M

    2010-01-01

    Excessive hyperbilirubinemia in human neonates can cause permanent dysfunction of the auditory system, as assessed with brainstem auditory evoked potentials (BAEPs). Jaundiced Gunn rat pups (jjs) exhibit similar BAEP abnormalities as hyperbilirubinemic neonates. Sulfadimethoxine (sulfa) administration to jjs, which displaces bilirubin from serum albumin into tissues including brain, exacerbates acute toxicity. Minocycline administered prior to sulfa in jjs protects against BAEP abnormalities....

  11. 21 CFR 862.1110 - Bilirubin (total or direct) test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Bilirubin (total or direct) test system. 862.1110 Section 862.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  12. Preparation and adsorption property of aminated cross linking microbeads of GMA/EGDMA for bilirubin

    Indian Academy of Sciences (India)

    Zhiping Chen; Baojiao Gao; Xiaofeng Yang

    2009-11-01

    Cross linking microbeads with a controllable diameter were synthesized by suspension copolymerization of the monomer glycidyl methacrylate (GMA) and the cross linking agent ethylene glycol dimethylacrylate (EGDMA). By the ring-opening reaction of the epoxy groups, the microbeads GMA/EGDMA were modified with different aminating agents and resulting in the aminated microbeads. The morphology of the microbeads was characterized by SEM. The adsorption property of aminated microbeads for bilirubin was investigated, and the effects of various factors, such as the chemical structures of the aminating agents, pH values of the medium and the presence of bovine serum albumin in the adsorption medium, on the adsorption property were examined. The experimental results show that the aminated microbeads have strong adsorption ability for bilirubin, and the isotherm adsorption behaviour is fitted to Freundlich equation satisfactorily. The adsorption ability of the aminated microbeads modified with hexanediamine is stronger than that of others, and the longer the molecule of multi-ethylene multiamine, the weaker the adsorption ability for bilirubin. The pH value of the medium affects the adsorption ability greatly, as pH = 6, the adsorption ability is strongest. In the presence of BSA, the microbeads still have a higher adsorption capacity towards bilirubin.

  13. Surface modifying of microporous PTFE capillary for bilirubin removing from human plasma and its blood compatibility

    Energy Technology Data Exchange (ETDEWEB)

    Jin Gu [Department of Chemistry, University of Science and Technology of China, HeFei, 230026 (China)], E-mail: Gjin@ustc.edu.cn; Yao Qizhi; Zhang Shanzi [Department of Chemistry, University of Science and Technology of China, HeFei, 230026 (China); Zhang Lei [Department of Chemistry, University of Science and Technology of China, HeFei, 230026 (China); AnHui Entry Exit Inspection and Quarantine Bureau, HeFei, 230001 (China)

    2008-12-01

    In this study, human serum albumin (HSA) was covalently immobilized onto the inner surface of microporous poly(tetrafluoroethylene) (MPTFE) capillaries for direct bilirubin removal from human plasma. To obtain active binding sites for HSA, the MPTFE capillaries were chemically functionalized by using a coating of poly(vinyl alcohol) (PVA)-glycidyl methacrylate (GMA) copolymers. Characterization of grafted MPTFE capillaries was verified by XPS, Fourier transform infrared spectroscopy (FT-IR), scanning electronic microscopy (SEM). Non-specific adsorption on the PVA-GMA coated capillary remains low (< 0.38 mg bilirubin/g), and higher affinity adsorption capacity, of up to 73.6 mg bilirubin/g polymer was obtained after HSA is immobilized. Blood compatibility of the grafted MPTFE capillary was evaluated by SEM and platelet rich plasma (PRP) contacting experiments. The experimental data on blood compatibility indicated that PVA-coated and PVA-GMA-HSA coated PTFE capillary showed a sharp suppress on platelets adhesion. The proposed method has the potential of serving in bilirubin removal in clinical application.

  14. Prognostic value of serum total bilirubin in patients with acute coronary syndrome after percutaneous coronary intervention

    Institute of Scientific and Technical Information of China (English)

    孙同文

    2013-01-01

    Objective To investigate the predictive value of serum total bilirubin (STB) level in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) .Methods A total of 1273 consecutive patients treated with PCI in cardiology department,First Affiliated Hospital of Zhengzhou University from June

  15. A novel predictor of infarct-related artery patency before percutaneous intervention and in-hospital outcomes for ST-segment elevation myocardial infarction patients: serum bilirubin level

    OpenAIRE

    Acet, Halit; Ertş, Faruk; Akıl, Mehmet Ata; Polat, Nihat; Aydın, Mesut; Akyüz, Abdurrahman; Ayçiçek, Hilal; Alan, Sait

    2014-01-01

    Introduction Previous studies have reported a relationship between serum bilirubin levels and coronary artery disease (CAD). However, data are rare up to now regarding the relation of bilirubin levels with infarct-related artery (IRA) patency in the setting of ST-segment elevation myocardial infarction (STEMI). Moreover, previous studies reported that increased bilirubin was related to impaired post-intervention coronary flow. To our knowledge, the association between serum total bilirubin (T...

  16. [Quantifying intestino-esophageal reflux with a fiberoptic bilirubin detection probe].

    Science.gov (United States)

    Stein, H J; Kraemer, S J; Feussner, H; Siewert, J R

    1994-05-01

    Currently available methods to assess reflux of duodenal contents into the esophagus are cumbersome, unphysiologic, and inaccurate. The role of intestino-esophageal reflux has therefore been controversial. We assessed intestino-esophageal reflux using a new system which allows prolonged intraesophageal measurement of bilirubin, the major pigment of bile. Measurements were made with a newly developed fiber-optic sensor electrode connected to a portable data processing unit (BILITEC 2000, Synectics Medical Inc., Sweden). Light absorption was measured at the absorption peak of bilirubin and a reference point. Studies were performed in 9 subjects without esophagitis, 9 subjects with esophagitis and primary reflux disease and 7 subjects with erosive esophagitis after a total or subtotal gastrectomy. The fiberoptic electrode was placed 5 cm above the lower esophageal sphincter. In vitro studies showed linear correlations between absorbance measurements obtained with the BILITEC-unit and known bilirubin and bile acid concentrations, respectively (p < 0.01). Compared to both other groups, light absorption was markedly increased in the subjects who had esophagitis after a total or subtotal gastrectomy (p < 0.05) indicating severe biliary reflux. An increase in bilirubin absorption occurred particularly during the post-prandial and supine periodes (p < 0.01). A Roux-en-Y biliary diversion procedure completely abolished bile reflux in 2 of these patients. These data indicate that ambulatory 24-hour fiberoptic measurement of bilirubin in the esophagus is feasible and allows quantitation of intestino-esophageal reflux. Intestino-esophageal reflux occurs particularly during the postprandial period and the early morning hours in patients who had a previous subtotal or total gastrectomy. PMID:8073796

  17. Assessment of duodenogastric reflux by combined continuous intragastric pH and bilirubin monitoring

    Institute of Scientific and Technical Information of China (English)

    Fei Dai; Jun Gong; Ru Zhang; Jin-Yan Luo; You-Ling Zhu; Xue-Qin Wang

    2002-01-01

    AIM: To assess the diagnostic value of a combination of continuous intragastric pH and bilirubin monitoring in the detection of duodenogastric reflux (DGR), and the effects of diet on the bilirubin absorbance.METHODS: 30 healthy volunteers were divided into twogroups: standard diet group (Group 1) 18 cases, free diet group (Group 2) 12 cases. Each subjects were subjected to simultaneous 24 hour intragastric pH and spectrophotometric bilirubin concentration monitoring (Bilitec 2000).RESULTS: There was no difference of preprandial phasebilirubin absorbance between two groups. The absorbanceof postprandial phase was significantly increased in group 2than group 1. There was no difference between preprandialphase and postprandial phase absorbance in group 1.Postprandial phase absorbance was significantly higher ingroup 2. In a comparison of bile reflux with intragastric pHduring night time, there were 4 types of reflux:Simultaneous increase in absorbance and pH in only 19.6%, increase in bilirubin with unchanged pH 33. 3 %, pHincrease with unchanged absorbance 36. 3 %, and bothunchanged in 10. 8 %. Linear regression analysis showed nocorrelation between percertage total time of pH < 4 aridpercentage total time of absortance > 0. 14, r=0.068, P<0.05.CONCLUSION: Because of the dietary effect, highabsorbance fluids or foods should be avoided in detection.Intrsgastric pH and bilirubin monitoring separately predictthe presence of duodenal (and/or pancreatic) reflux and bilereflux. They can not substitute for each other. The detectionof DGR is improved if the two parameters are combinedsimultanoously.

  18. Protein expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 in young patients with oral squamous cell carcinoma.

    Science.gov (United States)

    Kaminagakura, E; Caris, A; Coutinho-Camillo, C; Soares, F A; Takahama-Júnior, A; Kowalski, L P

    2016-06-01

    The purpose of this study was to evaluate the expression of the enzymes involved in the biotransformation of tobacco and alcohol. A study group of 41 young patients (≤40 years old) with oral squamous cell carcinoma (OSCC) was compared to 59 control subjects (≥50 years old) with tumours of similar clinical stages and topographies. The immunohistochemical expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 was evaluated using the tissue microarray technique. There was a predominance of males, smokers, and alcohol drinkers in both groups. Most tumours were located in the tongue (43.9% vs. 50.8%), were well-differentiated (63.4% vs. 56.6%), and were in clinical stages III or IV (80.5% vs. 78.0%). No difference was observed in the expression of CYP1A1, ALDH1A1, or ALDH2 between the two groups. CYP1A1 and ALDH2 protein expression had no influence on the prognosis. The immunoexpression of CYP1B1 was significantly higher in the control group than in the young group (Pexpression improved relapse-free survival in young patients. These results suggest a lower risk of recurrence with increased metabolism of carcinogens by CYP1B1. Further studies involving other genes and proteins are necessary to complement the results of this research. PMID:26944893

  19. Reversibility of Intersystem Crossing in the {a}1A1(000) and {a}1A1(010) States of Methylene, CH_2

    Science.gov (United States)

    Le, Anh T.; Sears, Trevor; Hall, Gregory

    2015-06-01

    The lowest energy singlet ( {a}1A1) and triplet ( {X}3B1) electronic states of methylene, CH_2, are only separated by 3150 wn, but differ greatly in chemical reactivity. Overall methylene reaction rates and chemical behavior are therefore strongly dependent on collisionally-mediated singlet-triplet interconversion. Collisions with inert partners tend to depopulate the excited singlet state and populate vibrationally excited triplet levels in CH_2. This process is generally considered as irreversible for large molecules, however, this is not the case for small molecules such as CH_2. An investigation of the decay kinetics of CH_2 in the presence of argon and various amounts of oxygen has been carried out using transient frequency modulation (FM) absorption spectroscopy, to monitor ortho and para rotational levels in both the {a}1A1(000) and {a}1A1(010) states. In the {a}1A1(000) state, all observed rotational levels follow double exponential decay kinetics, a direct consequence of reversible intersystem crossing. The relative amplitude of the slower decay component is an indicator of how quickly the reverse crossing from excited triplet levels becomes significant during the reaction and relaxation of singlet methylene. The para rotational levels show more obvious signs of reversibility than ortho rotational levels. Adding oxygen enhances the visibility of reversibility for both ortho and para levels. However, in the {a}1A1(010) state where the FM signal is 5-10 times smaller than the {a}1A1(000) state, there is no evidence of double exponential decay kinetics. Acknowledgments: Work at Brookhaven National Laboratory was carried out under Contract No. DE-AC02-98CH10886 and DE-SC0012704 with the U.S. Department of Energy and supported by its Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences.

  20. Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A5

    International Nuclear Information System (INIS)

    We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic “BR oxidase”. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301, 315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible “BR oxidase” where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced. -- Highlights: ► CYP2A5 metabolizes bilirubin to biliverdin and dipyrroles. ► Bilirubin increased the hepatic CYP2A5 protein and activity levels. ► Bilirubin does not change the hepatic CYP2A5 mRNA levels. ► Co-treatment with a protein synthesis inhibitor

  1. Interaction of bilirubin and indocyanine green with the binding and conjugation of sulfobromophthalein by rat liver cytosol proteins.

    Science.gov (United States)

    Davis, D R; Yeary, R A

    1980-02-01

    The interaction of bilirubin and indocyanine green with sulfobromophthalein (BSP) binding and conjugation by rat liver cytosol proteins was studied. BSP bound to cytosol proteins X, ligandin and Z and the BSP-glutathione conjugate were isolated by sephadex gel chromatography. Neither bilirubin nor indocyanine green affected the binding of BSP to ligandin and Z protein. However, indocyanine green did significantly reduce BSP conjugation in both in vitro and in vivo experiments. Diethyl maleate significantly reduced liver glutathione levels and BSP conjugation. It is suggested that indocyanine gree competitively binds at the ligandin catalytic site whereas the primary binding site for bilirubin is probably a noncatalytic site. PMID:7367753

  2. Fully Oriented Bilirubin Oxidase on Porphyrin-Functionalized Carbon Nanotube Electrodes for Electrocatalytic Oxygen Reduction.

    Science.gov (United States)

    Lalaoui, Noémie; Le Goff, Alan; Holzinger, Michael; Cosnier, Serge

    2015-11-16

    The efficient immobilization and orientation of bilirubin oxidase from Myrothecium verrucaria on multi-walled carbon nanotube electrodes by using π-stacked porphyrins as a direct electron-transfer promoter is reported. By comparing the use of different types of porphyrin, the rational effect of the porphyrin structure on both the immobilization and orientation of the enzyme is demonstrated. The best performances were obtained for protoporphyrin IX, which is the natural precursor of bilirubin. These electrodes exhibit full orientation of the enzyme, as confirmed by the observable non-catalytic redox system corresponding to the T1 copper center associated with pure Nernstian electrocatalytic behavior with high catalytic currents of almost 5 mA cm(-2) at neutral pH. PMID:26449635

  3. THE ROLE OF DIETARY PROPOLIS ON ALBUMINS AND BILIRUBIN CONTENT IN CHICKENS

    Directory of Open Access Journals (Sweden)

    Marcela Capcarová

    2013-12-01

    Full Text Available The present study was designed to determinate the effect of propolis as a feed additive on the serum bilirubin and albumin content of female and male chickens. Broiler chickens hybrid Hubbard JV (n=500 were divided into five groups in each gender (control – C and four experimental groups E1 – E4. Experimental chickens received a propolis extract in feed mixture in various doses (E1 – 150 mg/kg; E2 – 450 mg/kg; E3 – 600 mg/kg; E4 – 800 mg/kg. The group that received feed without propolis addition served as the control. Contents of albumin and bilirubin were determined with spectrophotometer. Supplementation of the diet with propolis in the dose of 600 mg/kg significantly (P<0.05 increased albumin content in male chickens. Propolis addition to diets may be a source for antioxidant capacity in human and animals.

  4. Epigenetic Modulation of Collagen 1A1: Therapeutic Implications in Fibrosis and Endometriosis.

    Science.gov (United States)

    Zheng, Ye; Khan, Zaraq; Zanfagnin, Valentina; Correa, Luiz F; Delaney, Abigail A; Daftary, Gaurang S

    2016-04-01

    Progressive fibrosis is recalcitrant to conventional therapy and commonly complicates chronic diseases and surgical healing. We evaluate here a novel mechanism that regulates scar-tissue collagen (COL1A1/Col1a1) expression and characterizes its translational relevance as a targeted therapy for fibrosis in an endometriosis disease model. Endometriosis is caused by displacement and implantation of uterine endometrium onto abdominal organs and spreads with progressive scarring. Transcription factor KLF11 is specifically diminished in endometriosis lesions. Loss of KLF11-mediated repression of COL1A1/Col1a1 expression resulted in increased fibrosis. To determine the biological significance of COL1A1/Col1a1 expression on fibrosis, we modulated its expression. In human endometrial-stromal fibroblasts, KLF11 recruited SIN3A/HDAC (histone deacetylase), resulting in COL1A1-promoter deacetylation and repression. This role of KLF11 was pharmacologically replicated by a histone acetyl transferase inhibitor (garcinol). In contrast, opposite effects were obtained with a HDAC inhibitor (suberoyl anilide hydroxamic acid), confirming regulatory specificity for these reciprocally active epigenetic mechanisms. Fibrosis was concordantly reversed in Klf11(-/-)animals by histone acetyl transferase inhibitor and in wild-type animals by HDAC inhibitor treatments. Aberrant lesional COL1A1 regulation is significant because fibrosis depended on lesion rather than host genotype. This is the first report demonstrating feasibility for targeted pharmacological reversal of fibrosis, an intractable phenotype of diverse chronic diseases. PMID:26935598

  5. Cytochrome P450 1A1 genetic polymorphisms as cancer biomarkers

    Directory of Open Access Journals (Sweden)

    A Bag

    2015-01-01

    Full Text Available Phase I metabolic enzyme CYP1A1 plays an important role in xenobiotics metabolism and has been extensively studied as a cancer risk biomarker. CYP1A1 is polymorphic and its four variants, e.g., CYP1A1* 2 A, CYP1A1* 2C, CYP1A1* 3 and CYP1A1* 4 with trivial names m1, m2, m3, and m4 respectively, are most commonly studied for cancer link. Gene- gene interaction studies combining polymorphisms of this enzyme with those of phase II detoxifying enzymes, especially glutathione S- transferases (GSTs revealed greater risk for cancer susceptibility. Variants of CYP1A1 have also been found to be associated with chemotherapeutic adverse- effects. Results of these studies, however, remained largely contradictory mainly because of lack of statistical power due to involvement of small sample size. Strongly powered experimental designs involving gene- gene, gene- environment interactions are required in order to validate CYP1A1 as reliable cancer- biomarker.

  6. THE ASSOCIATION BETWEEN G6PD DEFICIENCY AND TOTAL SERUM BILIRUBIN LEVEL IN ICTERIC NEONATES

    OpenAIRE

    S. Behjati-Ardakani; A. Nikkhah M. Sedaghat

    2007-01-01

    "nGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most important disease of the hexose monophosphate pathway. Deficiency of this enzym can lead to hemolysis of red blood cells. Our aim was to study the prevalence of G6PD deficiency in relation to neonatal jaundice. We studied 456 clinically icteric neonates Laboratory investigations included determination of direct and indirect serum bilirubin concentrations, blood group typing, direct coomb's test, hemoglobin, blood smea...

  7. Bilirubin oxidase based enzymatic air-breathing cathode: Operation under pristine and contaminated conditions

    OpenAIRE

    Santoro, Carlo; Babanova, Sofia; Erable, Benjamin; Schuler, Andrew; Atanassov, Plamen

    2016-01-01

    The performance of bilirubin oxidase (BOx) based air breathing cathode was constantly monitored over 45 days. The effect of electrolyte composition on the cathode oxygen reduction reaction (ORR) output was investigated. Particularly, deactivation of the electrocatalytic activity of the enzyme in phosphate buffer saline (PBS) solution and in activated sludge (AS) was evaluated. The greatest drop in current density was observed during the first 3 days of constant operation with a decrease of ~6...

  8. Effect of Intravenous Fluid Supplementation on Serum Bilirubin Level in Jaundiced Healthy Neonates during Conventional Phototherapy

    OpenAIRE

    R.Iranpour; R Nohekhan; I Haghshenas

    2004-01-01

    Background: Adequate hydration and good urine output improve the efficacy of phototherapy. The aim of this study was to evaluate the effect of intravenous fluid supplementation on decrease of serum bilirubin levels in jaundiced healthy term infants during conventional phototherapy. Methods: Sixty healthy breast-fed neonates with non-hemolytic hyperbilirubinemia were assigned randomly to receive either breast milk exclusively (non-supplemented group; n=30) or intravenous fluid in addition to b...

  9. The Effect of Clofibrate on Decreasing Serum Bilirubin in Healthy Term Neonates under Home Phototherapy

    OpenAIRE

    Simin Sharafi; Zhaleh Mortazavi; Reza Sharafi; Reza Moradi Parashkouh

    2010-01-01

    Objective: this study was designed to determine the effect of clofibrate on neonatal uncomplicated jaundice treated with home phototherapy. Methods:This clinical trial study was performed on 60 newborns with jaundice that received home phototherapy. Inclusion criteria were body weight between 2500 to 4000 gr, breastfed, total serum bilirubin (TSB) between 14 to 20 mg/dl, aged over 72 hours. The neonates were randomly divided into two groups. All received home phototherapy. Group i received a ...

  10. Bilirubin influence on oxidative lung damage and surfactant surface tension properties

    OpenAIRE

    Dani C.; Martelli E.; Tronchin M.; Buonocore G.; Longini M.; Di Filippo A; Giossi M.; Rubaltelli F.F.

    2004-01-01

    To study the hypothesis that hyperbilirubinemia might reduce in vivo oxidative lung damage while also diminishing lung surfactant surface tension properties during acute lung injury, we performed a randomized study in a rabbit model of acute lung injury. Twenty rabbits were randomized to receive bilirubin or saline intravenously. Acute lung injury was induced by lung lavages with saline. Lung tissue oxidation was evaluated by measuring total hydroperoxide (TH), advanced oxidation protein prod...

  11. Bilirubin and heme as growth inhibitors of chicken embryos in ovo.

    Science.gov (United States)

    Vassilopoulou-Sellin, R; Foster, P; Oyedeji, C O

    1990-06-01

    The increased morbidity during pregnancies complicated by hematologic or liver disease has generally been attributed to the metabolic abnormalities of the illness itself. Because tetrapyrrole concentrations are elevated in these conditions, we introduced bilirubin or heme (prepared as 10 mM solutions) into the air sac of fertilized chicken eggs to study their effect on the growth of normal chicken embryos. In 9-d eggs, the injection of 0.06 mL heme resulted in significant embryo growth inhibition as indicated by overall wt (91 +/- 3% versus control), tibia length (84 +/- 2%), tibia wt (81 +/- 3%), femur length (88 +/- 1%), and femur wt (78 +/- 3%); doses greater than 0.10 mL resulted in substantial fetal losses. The injection of 0.06 mL bilirubin into the same-age eggs also resulted in less than normal tibia length (87 +/- 2% versus control), tibia wt (75 +/- 4%), femur length (91 +/- 2%), and femur wt (81 +/- 3%); larger doses resulted in more pronounced growth inhibition, but fetal losses were less common than with heme. Older chick embryos (12-d) appeared more resistant to the effects of bilirubin: 0.15 mL bilirubin inhibited only tibia and femur wt; larger doses were required to significantly suppress the other growth parameters. The same-age chicken embryos, however, remained exquisitely sensitive to heme; 0.05 mL resulted in less than normal whole embryo wt (88 +/- 2% versus control), tibia length (80 +/- 1%), tibia wt (76 +/- 1%), femur length (78 +/- 1%), and femur wt (77 +/- 1%).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2356106

  12. Low solubility of unconjugated bilirubin in dimethylsulfoxide – water systems: implications for pKa determinations

    Directory of Open Access Journals (Sweden)

    Ostrow J Donald

    2002-06-01

    Full Text Available Abstract Background Aqueous pKa values of unconjugated bilirubin are important determinants of its solubility and transport. Published pKa data on an analog, mesobilirubin-XIIIα, studied by 13C-NMR in buffered solutions containing 27 and 64 vol% (C2H32SO because of low aqueous solubility of mesobilirubin, were extrapolated to obtain pKa values in water of 4.2 and 4.9. Previous chloroform-water partition data on bilirubin diacid led to higher estimates of its pKa, 8.12 and 8.44, and its aqueous solubility. A thermodynamic analysis, using this solubility and a published solubility in DMSO, suggested that the systems used to measure 13C-NMR shifts were highly supersaturated. This expectation was assessed by measuring the residual concentrations of bilirubin in the supernatants of comparable DMSO-buffer systems, after mild centrifugation to remove microprecipitates. Results Extensive sedimentation was observed from numerous systems, many of which appeared optically clear. The very low supernatant concentrations at the lowest pH values (4.1-5.9 were compatible with the above thermodynamic analysis. Extensive sedimentation and low supernatant concentrations occurred also at pH as high as 7.2. Conclusions The present study strongly supports the validity of the aqueous solubility of bilirubin diacid derived from partition data, and, therefore, the corresponding high pKa values. Many of the mesobilirubin systems in the 13C-NMR studies were probably supersaturated, contained microsuspensions, and were not true solutions. This, and previously documented errors in pH determinations that caused serious errors in pKa values of the many soluble reference acids and mesobilirubin, raise doubts regarding the low pKa estimates for mesobilirubin from the 13C-NMR studies.

  13. Unilobar Versus Bilobar Biliary Drainage: Effect on Quality of Life and Bilirubin Level Reduction

    OpenAIRE

    Shivanand Gamanagatti; Tejbir Singh; Raju Sharma; Srivastava, Deep N; Nihar Ranjan Dash; Pramod Kumar Garg

    2016-01-01

    Background: Percutaneous biliary drainage is an accepted palliative treatment for malignant biliary obstruction. Purpose: To assess the effect on quality of life (QOL) and bilirubin level reduction in patients with inoperable malignant biliary obstruction treated by unilobar or bilobar percutaneous transhepatic biliary drainage (PTBD). Materials and Methods: Over a period of 2 years, 49 patients (age range, 22–75 years) of inoperable malignant biliary obstruction were treated by PTBD. T...

  14. Organic anion transporting polypeptide 1a1 null mice are sensitive to cholestatic liver injury.

    Science.gov (United States)

    Zhang, Youcai; Csanaky, Iván L; Cheng, Xingguo; Lehman-McKeeman, Lois D; Klaassen, Curtis D

    2012-06-01

    Organic anion transporting polypeptide 1a1 (Oatp1a1) is predominantly expressed in livers of mice and is thought to transport bile acids (BAs) from blood into liver. Because Oatp1a1 expression is markedly decreased in mice after bile duct ligation (BDL). We hypothesized that Oatp1a1-null mice would be protected against liver injury during BDL-induced cholestasis due largely to reduced hepatic uptake of BAs. To evaluate this hypothesis, BDL surgeries were performed in both male wild-type (WT) and Oatp1a1-null mice. At 24 h after BDL, Oatp1a1-null mice showed higher serum alanine aminotransferase levels and more severe liver injury than WT mice, and all Oatp1a1-null mice died within 4 days after BDL, whereas all WT mice survived. At 24 h after BDL, surprisingly Oatp1a1-null mice had higher total BA concentrations in livers than WT mice, suggesting that loss of Oatp1a1 did not prevent BA accumulation in the liver. In addition, secondary BAs dramatically increased in serum of Oatp1a1-null BDL mice but not in WT BDL mice. Oatp1a1-null BDL mice had similar basolateral BA uptake (Na(+)-taurocholate cotransporting polypeptide and Oatp1b2) and BA-efflux (multidrug resistance-associated protein [Mrp]-3, Mrp4, and organic solute transporter α/β) transporters, as well as BA-synthetic enzyme (Cyp7a1) in livers as WT BDL mice. Hepatic expression of small heterodimer partner Cyp3a11, Cyp4a14, and Nqo1, which are target genes of farnesoid X receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and NF-E2-related factor 2, respectively, were increased in WT BDL mice but not in Oatp1a1-null BDL mice. These results demonstrate that loss of Oatp1a1 function exacerbates cholestatic liver injury in mice and suggest that Oatp1a1 plays a unique role in liver adaptive responses to obstructive cholestasis. PMID:22461449

  15. Effect of Intravenous Fluid Supplementation on Serum Bilirubin Level in Jaundiced Healthy Neonates during Conventional Phototherapy

    Directory of Open Access Journals (Sweden)

    R Iranpour

    2004-08-01

    Full Text Available Background: Adequate hydration and good urine output improve the efficacy of phototherapy. The aim of this study was to evaluate the effect of intravenous fluid supplementation on decrease of serum bilirubin levels in jaundiced healthy term infants during conventional phototherapy. Methods: Sixty healthy breast-fed neonates with non-hemolytic hyperbilirubinemia were assigned randomly to receive either breast milk exclusively (non-supplemented group; n=30 or intravenous fluid in addition to breast milk (supplemented group; n=30 during conventional phototherapy. Results: The mean total serum bilirubin (TSB levels at the time of enrollment and within 84 hours after phototherapy were not statistically different between two groups. Similarly, the mean rate of decrease in TSB levels during the first 12 h of phototherapy were 0.13±0.06 and 0.10 ± 0.1 mg/dL/h in supplemented and non supplemented groups , respectively (P=0.13. Duration of phototherapy required in supplemented and non-supplemented groups was 58 ± 13.02 and 63.20 ± 13.71 hours, respectively (P=0.13. Conclusion: These data show that administration of extra intravenous fluid in jaundiced healthy, term, breastfed neonates have no beneficial effect on the rate of serum bilirubin reduction during conventional phototherapy. Keywords: Hyperbilirubinemia, Phototherapy, Neonates, Fluid Supplementation, Dehydration.

  16. Ternary complexes of albumin-Mn(II)-bilirubin and Electron Spin Resonance studies of gallstones

    CERN Document Server

    Chikvaidze, E N; Kirikashvili, I N; Mamniashvili, G I

    2009-01-01

    The stability of albumin-bilirubin complex was investigated depending on pH of solution. It was shown that the stability of complex increases in presence of Mn(II) ions. It was also investigated the paramagnetic composition of gallstones by the electron spin resonance (ESR) method. It turned out that all investigated gallstones contain a free bilirubin radical-the stable product of its radical oxidation. Accordingly the paramagnetic composition gallstones could be divided on three main types: cholesterol, brown pigment and black pigment stones. ESR spectra of cholesterol stones is singlet with g=2.003 and splitting between components 1.0 mT. At the same time the brown gallstones, besides aforementioned signal contain the ESR spectrum which is characteristics for Mn(II) ion complexes with inorganic compounds and, finally, in the black pigment stones it was found out Fe(III) and Cu(II) complexes with organic compounds and a singlet of bilirubin free radical. It is supposed that crystallization centers of gallst...

  17. Harman induces CYP1A1 enzyme through an aryl hydrocarbon receptor mechanism

    International Nuclear Information System (INIS)

    Harman is a common compound in several foods, plants and beverages. Numerous studies have demonstrated its mutagenic, co-mutagenic and carcinogenic effects; however, the exact mechanism has not been fully identified. Aryl hydrocarbon receptor (AhR) is a transcription factor regulating the expression of the carcinogen-activating enzyme; cytochrome P450 1A1 (CYP1A1). In the present study, we examined the ability of harman to induce AhR-mediated signal transduction in human and rat hepatoma cells; HepG2 and H4IIE cells. Our results showed that harman significantly induced CYP1A1 mRNA in a time- and concentration-dependent manner. Similarly, harman significantly induced CYP1A1 at protein and activity levels in a concentration-dependent manner. Moreover, the AhR antagonist, resveratrol, inhibited the increase in CYP1A1 activity by harman. The RNA polymerase inhibitor, actinomycin D, completely abolished the CYP1A1 mRNA induction by harman, indicating a transcriptional activation. The role of AhR in CYP1A1 induction by harman was confirmed by using siRNA specific for human AhR. The ability of harman to induce CYP1A1 was strongly correlated with its ability to stimulate AhR-dependent luciferase activity and electrophoretic mobility shift assay. At post-transcriptional and post-translational levels, harman did not affect the stability of CYP1A1 at the mRNA and the protein levels, excluding other mechanisms participating in the obtained effects. We concluded that harman can directly induce CYP1A1 gene expression in an AhR-dependent manner and may represent a novel mechanism by which harman promotes mutagenicity, co-mutagenicity and carcinogenicity.

  18. Fluorescence Excitation Spectrum of Bilirubin in Blood: A Model for the Action Spectrum for Phototherapy of Neonatal Jaundice†

    OpenAIRE

    Lamola, Angelo A.; Russo, Marie

    2013-01-01

    A recent report (Lamola et al. 2013 Pediatric Research, 74, 54–60) presents a semi-empirical model for facile calculation of an action spectrum for bilirubin photochemistry in vivo using the most current knowledge of the optics of neonatal skin. The calculations indicate that competition for phototherapy light by hemoglobin in the skin is the predominant factor that defines the spectrum of light absorbed by bilirubin. If the latter is correct, a valid physical analog of the calculated spectru...

  19. Serum bilirubin value predicts hospital admission in carbon monoxide-poisoned patients. Active player or simple bystander?

    Directory of Open Access Journals (Sweden)

    Gianfranco Cervellin

    2015-09-01

    Full Text Available OBJECTIVES: Although carbon monoxide poisoning is a major medical emergency, the armamentarium of recognized prognostic biomarkers displays unsatisfactory diagnostic performance for predicting cumulative endpoints. METHODS: We performed a retrospective and observational study to identify all patients admitted for carbon monoxide poisoning during a 2-year period. Complete demographical and clinical information, along with the laboratory data regarding arterial carboxyhemoglobin, hemoglobin, blood lactate and total serum bilirubin, was retrieved. RESULTS: The study population consisted of 38 poisoned patients (23 females and 15 males; mean age 39±21 years. Compared with discharged subjects, hospitalized patients displayed significantly higher values for blood lactate and total serum bilirubin, whereas arterial carboxyhemoglobin and hemoglobin did not differ. In a univariate analysis, hospitalization was significantly associated with blood lactate and total serum bilirubin, but not with age, sex, hemoglobin or carboxyhemoglobin. The diagnostic performance obtained after combining the blood lactate and total serum bilirubin results (area under the curve, 0.90; 95% CI, 0.81-0.99; p<0.001 was better than that obtained for either parameter alone. CONCLUSION: Although it remains unclear whether total serum bilirubin acts as an active player or a bystander, we conclude that the systematic assessment of bilirubin may, alongside lactate levels, provide useful information for clinical decision making regarding carbon monoxide poisoning.

  20. Downregulation of Col1a1 induces differentiation in mouse spermatogonia

    Institute of Scientific and Technical Information of China (English)

    Sun-Hong Chen; Ding Li; Chen Xu

    2012-01-01

    Col1a1 (one of the subunit of collagen type Ⅰ) is a collagen,which belongs to a family of extracellular matrix (ECM) proteins that play an important role in cellular proliferation and differentiation.However,the role of Col1a1 in spermatogenesis,especially in the control of proliferation and differentiation of spermatogonial stem cells (SSCs),remains unknown.In this study,we explored effects of downregulation of Col1a1 on differentiation and proliferation of mouse spermatogonia.Loss-of-function study revealed that Oct4 and Plzf,markers of SSC self-renewal,were significantly decreased,whereas the expression of c-kit and haprin,hallmarks of SSC differentiation,was enhanced after Col1a1 knockdown.Cell cycle analyses indicated that two-thirds of spermatogonia were arrested in S phase after Col1a1 knockdown.In vivo experiments,DNA injection and electroporation of the testes showed that spermatogonia self-renewal ability was impaired remarkably with the loss-of-function of Col1a1.Our data suggest that silencing of Col1a1 can suppress spermatogonia self-renewal and promote spermatogonia differentiation.

  1. Elongation factor-1A1 is a novel substrate of the protein phosphatase 1-TIMAP complex.

    Science.gov (United States)

    Boratkó, Anita; Péter, Margit; Thalwieser, Zsófia; Kovács, Előd; Csortos, Csilla

    2015-12-01

    TIMAP (TGF-β inhibited membrane associated protein) is a protein phosphatase 1 (PP1) regulatory subunit highly abundant in endothelial cells and it is involved in the maintenance of pulmonary endothelial barrier function. It localizes mainly in the plasma membrane, but it is also present in the nuclei and cytoplasm. Direct interaction of TIMAP with the eukaryotic elongation factor 1 A1 (eEF1A1) is shown by pull-down, LC-MS/MS, Far-Western and immunoprecipitations. In connection with the so called moonlighting functions of the elongation factor, eEF1A is thought to establish protein-protein interactions through a transcription-dependent nuclear export motif, TD-NEM, and to aid nuclear export of TD-NEM containing proteins. We found that a TD-NEM-like motif of TIMAP has a critical role in its specific binding to eEF1A1. However, eEF1A1 is not or not exclusively responsible for the nuclear export of TIMAP. On the contrary, TIMAP seems to regulate membrane localization of eEF1A1 as the elongation factor co-localized with TIMAP in the plasma membrane fraction of control endothelial cells, but it has disappeared from the membrane in TIMAP depleted cells. It is demonstrated that membrane localization of eEF1A1 depends on the phosphorylation state of its Thr residue(s); and ROCK phosphorylated eEF1A1 is a novel substrate for TIMAP-PP1 underlining the complex regulatory role of TIMAP in the endothelium. The elongation factor seems to be involved in the regulation of endothelial cell attachment and spreading as silencing of eEF1A1 positively affected these processes which were monitored by transendothelial resistance measurements. PMID:26497934

  2. Differential cell type-specific transcriptional regulation of the CYP1A1 gene

    OpenAIRE

    Adamska, Magdalena

    2005-01-01

    Cytochrome P450 1A1 (CYP1A1) monooxygenase plays an important role in the metabolism of environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) and halogenated polycyclic aromatic hydrocarbons (HAHs). Oxidation of these compounds converts them to the metabolites that subsequently can be conjugated to hydrophilic endogenous entities e.g. glutathione. Derivates generated in this way are water soluble and can be excreted in bile or urine, which is a defense mechanism. Besides de...

  3. ON THE DIOPHANTINE EQUATION (an - 1)((a + 1)n - 1) =x2%关于Diophantine方程(an-1)((a+1)n-1)=x2

    Institute of Scientific and Technical Information of China (English)

    梁明

    2012-01-01

    In this article, the positive integer solution (n, x) of the exponential diophantine equation (αn - 1)((α + l)n-1) = x2 is discussed. Using elementary number theory methods, we prove that, if a = 2 or 3(mod 4), then the equation has no integer solution.%本文研究了指数Diophantine方程(an-1)((a+1)n-1)=x2的正整数解(n,x),其中a是大于1的正整数.运用初等数论方法证明了:当a≡2或3(mod 4)时,该方程无解.

  4. Utility of bilirubins and bile acids as endogenous biomarkers for the inhibition of hepatic transporters.

    Science.gov (United States)

    Watanabe, Tomoko; Miyake, Manami; Shimizu, Toshinobu; Kamezawa, Miho; Masutomi, Naoya; Shimura, Takesada; Ohashi, Rikiya

    2015-04-01

    It is useful to identify endogenous substrates for the evaluation of drug-drug interactions via transporters. In this study, we investigated the utility of bilirubins, substrates of OATPs and MRP2, and bile acids and substrates of NTCP and BSEP, as biomarkers for the inhibition of transporters. In rats administered 20 and 80 mg/kg rifampicin, the plasma levels of bilirubin glucuronides were elevated, gradually decreased, and almost returned to the baseline level at 24 hours after administration without an elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This result indicates the transient inhibition of rOatps and/or rMrp2. Although the correlation between free plasma concentrations and IC50 values of rOatps depended on the substrates used in the in vitro studies, the inhibition of rOatps by rifampicin was confirmed in the in vivo study using valsartan as a substrate of rOatps. In rats administered 10 and 30 mg/kg cyclosporin A, the plasma levels of bile acids were elevated and persisted for up to 24 hours after administration without an elevation of ALT and AST. This result indicates the continuous inhibition of rNtcp and/or rBsep, although there were differences between the free plasma or liver concentrations and IC50 values of rNtcp or rBsep, respectively. This study suggests that the monitoring of bilirubins and bile acids in plasma is useful in evaluating the inhibitory potential of their corresponding transporters. PMID:25581390

  5. Inverse association between serum bilirubin levels and arterial stiffness in Korean women with type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Eun Sook Kim

    Full Text Available BACKGROUND: Considerable evidence suggests that bilirubin is a potent physiologic antioxidant that may provide important protection against cardiovascular disease (CVD and inflammation. We investigated the relationship between serum total bilirubin (TB levels and arterial stiffness, measured by the brachial-ankle pulse wave velocity (baPWV, in patients with type 2 diabetes. METHODS: We conducted a cross-sectional analysis of 1,711 subjects with type 2 diabetes (807 men and 904 women; mean age, 57.1 years. The subjects were stratified based on gender-specific tertiles of TB values, and a high baPWV was defined as greater than 1,745 cm/s ( >75th percentile. RESULTS: The serum TB concentration was negatively correlated with the duration of diabetes, HbA1c, the 10-year Framingham risk score, and baPWV and was positively correlated with high-density lipoprotein cholesterol and the eGFR in both genders. Inverse association between TB categories and unadjusted prevalence of high PWV was only observed in women. After adjusting for confounding factors, the TB levels were inversely associated with a greater risk of a high baPWV, both as a continuous variable [a 1-SD difference; odds ratio (OR, 0.70; 95% confidence interval (CI, 0.54-0.90; P = 0.005] and when categorized in tertiles (the highest vs. the lowest tertile; OR, 0.49; 95% CI, 0.28-0.85; P = 0.011 in women but not in men. The relationship remained significant even after adjusting for retinopathy and nephropathy. CONCLUSIONS: Low TB levels were significantly associated with arterial stiffness in Korean women with type 2 diabetes. Our data suggested that bilirubin may protect against macrovascular disease in diabetic women.

  6. Total bilirubin in nasogastric aspirates: A potential new indicator of postoperative gastrointestinal recovery

    OpenAIRE

    Go Miyano; Hiroki Nakamura; Toshiaki Takahashi; Lane, Geoffrey J.; Atsuyuki Yamataka

    2013-01-01

    Background: The aim of our study was to investigate if total bilirubin (T-bil), amylase (Amy), and sodium (Na) in nasogastric (NG) aspirates can reflect gastrointestinal motility reliably. Materials and Methods: NG aspirates from all laparotomies lasting more than 150 min in children less than 12 months old were studied for 3 months. Color of aspirates and intensity of bowel sounds were graded every 3 h by nursing staff and aspirate samples for measuring T-bil, Amy, and Na were collected inde...

  7. Design and synthesis of resveratrol-salicylate hybrid derivatives as CYP1A1 inhibitors.

    Science.gov (United States)

    Aldawsari, Fahad S; Elshenawy, Osama H; El Gendy, Mohamed A M; Aguayo-Ortiz, Rodrigo; Baksh, Shairaz; El-Kadi, Ayman O S; Velázquez-Martínez, Carlos A

    2015-12-01

    Resveratrol and aspirin are known to exert potential chemopreventive effects through modulation of numerous targets. Considering that the CYP450 system is responsible for the activation of environmental procarcinogens, the aim of this study was to design a new class of hybrid resveratrol-aspirin derivatives possessing the stilbene and the salicylate scaffolds. Using HepG2 cells, we evaluated (a) the inhibition of TCDD-mediated induction of CYP1A1 exerted by resveratrol-aspirin derivatives using the EROD assay, and (b) CYP1A1 mRNA in vitro. We observed significant inhibition (84%) of CYP1A1 activity and a substantial decrease in CYP1A1 mRNA with compound 3, compared to control. Resveratrol did not exert inhibition under the same experimental conditions. This inhibitory profile was supported by docking studies using the crystal structure of human CYP1A1. The potential effect exerted by compound 3 (the most active), provide preliminary evidence supporting the design of hybrid molecules combining the chemical features of resveratrol and aspirin. PMID:25407017

  8. Inhibition of human and rat CYP1A1 enzyme by grapefruit juice compounds.

    Science.gov (United States)

    Santes-Palacios, Rebeca; Romo-Mancillas, Antonio; Camacho-Carranza, Rafael; Espinosa-Aguirre, Jesús Javier

    2016-09-01

    Cytochrome P4501A1 is involved in the metabolism of carcinogenic polycyclic aromatic hydrocarbons; therefore, its inhibition interferes with the carcinogenesis process induced by these compounds in rats. The human and rat CYP1A1 differ by 21% in amino acid sequence, including the active site of the enzyme; this difference may be an important factor when results obtained using animal models are interpolated to humans. Based on its previously reported CYP inhibitory properties, we studied the effects of two molecules contained within grapefruit juice, naringenin and 6',7'-dihydroxybergamottin, on human and rat CYP1A1 activity. For this purpose, the kinetics of inhibition as well as computational simulations were used. Naringenin and 6',7'-dihydroxybergamottin were found to be competitive inhibitors of human and rat CYP1A1. Additionally, naringenin exerted a mixed type inhibition effect on rat CYP1A1. Computational docking showed that inhibitors might block the oxidation of 7-ethoxyresorufin by binding to the CYP1A1 active site. Our results demonstrate the differences in CYP inhibitory mechanisms for the same molecule when CYP from different species are considered. PMID:27444380

  9. The molecular basis for the broad substrate specificity of human sulfotransferase 1A1.

    Directory of Open Access Journals (Sweden)

    Ilana Berger

    Full Text Available Cytosolic sulfotransferases (SULTs are mammalian enzymes that detoxify a wide variety of chemicals through the addition of a sulfate group. Despite extensive research, the molecular basis for the broad specificity of SULTs is still not understood. Here, structural, protein engineering and kinetic approaches were employed to obtain deep understanding of the molecular basis for the broad specificity, catalytic activity and substrate inhibition of SULT1A1. We have determined five new structures of SULT1A1 in complex with different acceptors, and utilized a directed evolution approach to generate SULT1A1 mutants with enhanced thermostability and increased catalytic activity. We found that active site plasticity enables binding of different acceptors and identified dramatic structural changes in the SULT1A1 active site leading to the binding of a second acceptor molecule in a conserved yet non-productive manner. Our combined approach highlights the dominant role of SULT1A1 structural flexibility in controlling the specificity and activity of this enzyme.

  10. Evaluation of 99mTc-Mercaptoacetyltriglycine-Biocytin as a new hepatobiliary imaging agent in mice coinjected with bilirubin

    International Nuclear Information System (INIS)

    We evaluated 99mTc-labeled mercaptoacetyltriglycine (99mTc-MAG3)-biocytin as a hepatobiliary imaging agent in the absence and presence of bilirubin in mice. We then compared its pharmacokinetic parameters; peak liver/heart activity ratio (rmax) and half clearance time (HCT) with those of 99mTc-labeled diisopropyl-iminodiacetic acid (99mTc-disofenin). Balb/c mice were injected intravenously with hepatobiliary agent (99mTc-MAG3-biocytin or 99mTc-disofenin) alone or in combination with bilirubin at two doses (7 and 14 mg/kg) dissolved in 5% human serum albumin. Images were acquired every 15 s for 30 min with a gamma-camera equipped with a pinhole collimator. Dynamic images showed rapid hepatic uptake of 99mTc-MAG3-biocytin, with rapid clearance from the blood and rapid excretion via the biliary system. Its hepatic uptake was not affected by bilirubin coinjection, whereas 99mTc-disofenin coinjected with bilirubin showed a higher blood background than 99mTc-disofenin alone. These qualitative findings were reflected in pharmacokinetic parameters, rmax and HCT. The rmax was obtained from plots of time versus liver/heart activity ratios obtained in equal-area regions of interest over the heart and liver. The HCT was calculated from the hepatic clearance curve from plots of time versus liver activity. 99mTc-MAG3-biocytin without bilirubin coinjection showed an rmax of 8.9±1.3 and an HCT of 399±36 s. These values did not change even when 14 mg/kg of bilirubin were coinjected. By contrast, the parameters for 99mTc-disofenin with bilirubin were significantly (pmax was decreased from 7.9±2.5 to 1.4±0.2 and HCT was increased from 292±32 s to 782±133 s. 99mTc-MAG3-biocytin hepatobiliary scintigraphy in mice is not affected by bilirubin coinjection, and this hepatobiliary agent appears to offer promise for estimating hepatic function in patients with high bilirubin levels

  11. Association of CYP1A1 and GSTM1 Polymorphisms With Oral Cancer Susceptibility

    OpenAIRE

    Liu, Haitao; Jia, Jinlin; Mao, Xuemei; Lin, Zhiyong

    2015-01-01

    Abstract Our meta-analysis was aimed to evaluate the association of CYP1A1 and glutathione-S-transferase M1 (GSTM1) polymorphisms with oral cancer susceptibility. The related articles were searched in PubMed, Embase, and CNKI databases. Fifty eligible studies were included in our meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the relationship of CYP1A1 (rs4646903 and rs1048943) and GSTM1 polymorphisms with oral cancer risk. A random-effects model or...

  12. The predictive value of first day bilirubin levels for early discharged newborns.

    Directory of Open Access Journals (Sweden)

    MUSTAFA TOLGA ÜNSÜR

    2015-09-01

    Full Text Available Objective: Early discharge of newborns is essential because of social, economic an medical reasons in our area, but it increases readmission rates especially for hyperbilirubinemia. Hence, predicting the high risk neonates for subsequent hyperbilirubinemia is required. This study was designed to investigate which level of total serum bilirubin (TSB at the first day could be used to predict hyperbilirubinemia .Methods: The venous blood samples obtained from 300 newborns at post-partum 24±6 hours for blood group, direct coomb’s, TSB and direct bilirubin level (DBL. These newborns were followed up during 5- day and TSB and DBLwere detected in 90 newborns with jaundice again according to Kramer dermal zones at 120±6 hours of age.Results: In 23.3% of 90 newborns phototherapy was needed. The cut off value of TSB at the first day to define newborns at high risk for subsequent hyperbilirubinemia was 6.50 mg/dl with positive predictive value 19.75%, negative predictive value 97.72%. At that point sensitivity was 76.19%, specificity was 76.70%.Conclusion: The cut-off point of 6.5 mg/dl of TSB at the first day might be used to predict subsequent hyperbilirubinemia risk at healthy, full-term early discharged newborns as the test is economic and available in all healthcare units.

  13. Impact of Rhesus disease on the global problem of bilirubin-induced neurologic dysfunction.

    Science.gov (United States)

    Zipursky, Alvin; Bhutani, Vinod K

    2015-02-01

    Clinical experience with Rhesus (Rh) disease and its post-icteric sequelae is limited among high-income countries because of nearly over four decades of effective prevention care. We hypothesized that Rh disease is prevalent in other regions of the world because it is likely that protection is limited or non-existent. Following a worldwide study, it has been concluded that Rh hemolytic disease is a significant public health problem resulting in stillbirths and neonatal deaths, and is a major cause of severe hyperbilirubinemia with its sequelae, kernicterus and bilirubin-induced neurologic dysfunction. Knowing that effective Rh-disease prophylaxis depends on maternal blood-type screening, healthcare afforded to the high-risk mothers needs to be free of bottlenecks and coupled with unfettered access to effective Rh-immunoglobulin. Future studies that match the universal identification of Rh-negative status of women and targeted use of immunoprophylaxis to prevent childhood bilirubin neurotoxicity are within reach, based on vast prior experiences. PMID:25582277

  14. Bilirubin oxidase bound to multi-walled carbon nanotube-modified gold

    International Nuclear Information System (INIS)

    We report on direct electron transfer (DET) reactions of bilirubin oxidase at multi-walled carbon nanotube-(MWCNT) modified gold electrodes. MWCNTs are very suitable for protein immobilisation and provide surface groups that can be used for the stable fixation on electrodes. They can also effectively replace the natural substrate of BOD - bilirubin, the electron donor for oxygen reduction. The bioelectrocatalytic oxygen reduction was recorded using linear sweep voltammetry (LSV) with BOD covalently linked to the nanotubes. The start potential of the bioelectrocatalytic oxygen reduction at pH 7 and a scan rate of 10 mV/s was determined to be 485 ± 10 mV vs. Ag/AgCl, 1 M KCl (720 mV vs. SHE). Current densities up to 500 μA/cm2 were detected in an air-saturated buffer at room temperature (25 ± 5 deg. C). Experiments with a rotating disk electrode (RDE) indicate a diffusion controlled electrode reaction. A ks value in the range of 80-100 s-1 could be estimated. The DET could also be observed directly by the redox conversion of a copper centre of BOD under anaerobic conditions. A peak pair with a formal potential of 680 ± 10 mV vs. SHE was found. The T1 site is probably addressed by the electrode as indicated by several experimental studies

  15. Effects of aluminum chloride on serum proteins, bilirubin, and hepatic trace elements in chickens.

    Science.gov (United States)

    Wang, Ben; Zhu, Yanzhu; Zhang, Hongling; Liu, Liming; Li, Guojiang; Song, Yongli; Li, Yanfei

    2016-09-01

    The aim of this study was to reveal the effects of aluminum chloride (AlCl3) on the hepatic metabolism function and trace elements' distribution. Two hundred healthy male chickens (1 day old) were intraperitoneally administered with AlCl3 (0, 18.31, 27.47, and 36.62 mg kg(-1) day(-1) of Al(3+)) consecutively for 3 days. Then the chickens were allowed to rest for 1 day. The cycle lasted four days. The cycle was repeated 15 times (60 days). The contents of serum total protein (TP), albumin (ALB), total bilirubin (TBI), direct bilirubin (DBI), hepatic aluminum (Al), copper (Cu), iron (Fe), and zinc (Zn) were examined. The results showed that the contents of serum TP and ALB and hepatic Fe and Zn decreased and the contents of serum TBI and DBI and hepatic Al and Cu increased in the chickens with AlCl3 This indicates that chronic administration of AlCl3 impairs the hepatic metabolism function and disorders the hepatic trace elements' distribution. PMID:25896954

  16. Spontaneous evolution in bilirubin levels predicts liver-related mortality in patients with alcoholic hepatitis.

    Directory of Open Access Journals (Sweden)

    Minjong Lee

    Full Text Available The accurate prognostic stratification of alcoholic hepatitis (AH is essential for individualized therapeutic decisions. The aim of this study was to develop a new prognostic model to predict liver-related mortality in Asian AH patients. We conducted a hospital-based, retrospective cohort study using 308 patients with AH between 1999 and 2011 (a derivation cohort and 106 patients with AH between 2005 and 2012 (a validation cohort. The Cox proportional hazards model was constructed to select significant predictors of liver-related death from the derivation cohort. A new prognostic model was internally validated using a bootstrap sampling method. The discriminative performance of this new model was compared with those of other prognostic models using a concordance index in the validation cohort. Bilirubin, prothrombin time, creatinine, potassium at admission, and a spontaneous change in bilirubin levels from day 0 to day 7 (SCBL were incorporated into a model for AH to grade the severity in an Asian patient cohort (MAGIC. For risk stratification, four risk groups were identified with cutoff scores of 29, 37, and 46 based on the different survival probabilities (P<0.001. In addition, MAGIC showed better discriminative performance for liver-related mortality than any other scoring system in the validation cohort. MAGIC can accurately predict liver-related mortality in Asian patients hospitalized for AH. Therefore, SCBL may help us decide whether patients with AH urgently require corticosteroid treatment.

  17. Fluorescence excitation spectrum of bilirubin in blood: a model for the action spectrum for phototherapy of neonatal jaundice.

    Science.gov (United States)

    Lamola, Angelo A; Russo, Marie

    2014-01-01

    A recent report (Lamola et al. 2013 Pediatric Research, 74, 54-60) presents a semiempirical model for facile calculation of an action spectrum for bilirubin photochemistry in vivo using the most current knowledge of the optics of neonatal skin. The calculations indicate that competition for phototherapy light by hemoglobin in the skin is the predominant factor that defines the spectrum of light absorbed by bilirubin. If the latter is correct, a valid physical analog of the calculated spectrum is the excitation spectrum of bilirubin in blood. The fluorescence excitation spectrum was recorded and, indeed, found to be very similar to the calculated spectrum. Both spectra exhibit maxima near 476 nm and widths at half height of about 50 nm. This result supports the conclusion that light between 460 and 490 nm is most effective for phototherapy of neonatal jaundice. PMID:23998276

  18. Effects of clinorotation on COL1A1- EGFP gene expression

    Institute of Scientific and Technical Information of China (English)

    DAI; Zhongquan; LI; Yinghui; DING; Bai; ZHANG; Yuguo; LIU

    2004-01-01

    Bone-formation related gene plays a critical role in bone loss induced by space microgravity, however the exact mechanism is unclear. In this study, we aim to investigate the effect of microgravity on the activity of α 1(I) collagen (COL1A1) gene promoter and the expression of osteoblast-related genes. COL1A1 promoter was digested by restriction enzymes resulting in three DNA fragments. The fragments were ligated with the enhanced green fluorescent protein report gene, and subcloned into expression vectors. ROS17/2.8 cells transfected by these vectors were screened by G418, and enhanced green fluorescent protein (EGFP) positive colonies were isolated and cultured under clinostat condition. EGFP and Collagen type I expression level were detected by fluorescence intensity analysis and immunocytochemistry methods respectively. The results showed that the expression of EGFP and collagen type I was increased 24 h, 48 h after the cells were cultured under stimulated microgravity, illustrating that the activity of COL1A1 promoter might be increased. In conclusion, osteoblasts can compensatively increase the expression of type I collagen by enhancing the activity of COL1A1 promoter under short-term simulated microgravity conditions.

  19. Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

    International Nuclear Information System (INIS)

    CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism

  20. Inhibitory effects of commonly used herbal extracts on UGT1A1 enzyme activity.

    Science.gov (United States)

    Mohamed, Mohamed-Eslam F; Tseng, Tiffany; Frye, Reginald F

    2010-10-01

    Commonly used herbal supplements were screened for their potential to inhibit UGT1A1 activity using human liver microsomes. Extracts screened included ginseng, echinacea, black cohosh, milk thistle, garlic, valerian, saw palmetto, and green tea epigallocatechin gallate (EGCG). Estradiol-3-O-glucuronide (E-3-G) formation was used as the index of UGT1A1 activity. All herbal extracts except garlic showed inhibition of UGT1A1 activity at one or more of the three concentrations tested. A volume per dose index (VDI) was calculated to estimate the volume in which the daily dose should be diluted to obtain an IC(50)-equivalent concentration. EGCG, echinacea, saw palmetto, and milk thistle had VDI values >2.0 L per dose unit, suggesting a higher potential for interaction. Inhibition curves were constructed for EGCG, echinacea, saw palmetto, and milk thistle. IC(50) values were (mean ± SE) 7.8 ± 0.9, 211.7 ± 43.5, 55.2 ± 9.2, and 30.4 ± 6.9 µg/ml for EGCG, echinacea, saw palmetto, and milk thistle extracts, respectively. Based on our findings, inhibition of UGT1A1 by milk thistle and EGCG and to a lesser extent by echinacea and saw palmetto is plausible, particularly in the intestine where higher extract concentrations are anticipated. Further clinical studies are warranted. PMID:20666626

  1. Analysis of CYP1A1 and COMT polymorphisms in women with cervical cancer.

    Science.gov (United States)

    Kleine, J P; Camargo-Kosugi, C M; Carvalho, C V; Silva, F C; Silva, I D C G

    2015-01-01

    The aim of this case-control study was to obtain a comprehensive panel of genetic polymorphisms present only in genes (cytochrome P-450 1A1--CYP1A1 and catechol-O-methyl transferase--COMT) within the metabolic pathway of sex steroids and determine their possible associations with the presence or absence of cervical cancer. Genotypes of 222 women were analyzed: a) 81 with cancer of the cervix treated at the Cancer Hospital Alfredo Abram, between June 2012 and May 2013, with diagnosis confirmed surgically and/or through histomorphological examination; and b) 141 healthy women who assisted at the Endocrine Gynecology and Climacteric Ambulatory, Department of Gynecology, UNIFESP-EPM. These polymorphisms were detected by polymerase chain reaction amplification-restriction fragment length polymorphism analysis and visualized on 3% agarose gels stained with ethidium bromide. We found a significant association between the frequency of the CYP1A1 polymorphism and the development of cervical cancer. A statistical difference was observed between patient and control groups for CYP1A1 polymorphism genotype distributions (P COMT gene polymorphism genotype distributions between the patient and control groups (P > 0.05) or between other risk variables analyzed. The CYP1A1 gene involved in the metabolic pathway of sex steroids might influence the emergence of pathological conditions such as cervical cancer in women who carry a mutated allele, and result in 1.80 and 13.46 times increased risk for women with heterozygous or homozygous mutated genotypes, respectively. PMID:26782546

  2. Correlation of third day TSH and thyroxine values with bilirubin levels detected by a neonatal screening system

    Directory of Open Access Journals (Sweden)

    Sinan Mahir Kayıran

    2010-01-01

    Full Text Available Objective: For the purpose of screening for congenital hypothyroidism and metabolic diseases blood is drawn for analysis from all newborns about 72 hours of postnatal age, which coincides with the approximate peak-time of bilirubin levels. Adding the measurement of serum bilirubin concentrations to the blood tests in programs of this kind will serve to detect high levels of bilirubin. The present study was designed to investigate a relationship, between neonatal TSH, T4 and total bilirubin levels in the blood samples of postnatal third day. Material and Methods: The population of the present study, which was conducted retrospectively in department of pediatrics in our hospital, was 450 healthy full-term newborns who had been born by cesarean section during the period January 1, 2008 and April 30, 2008. All data were analyzed by using SPSS 15.0 . Correlation between total bilirubin and thyroid hormone levels was computed by the Pearson’s correlation coefficient. Results: The mean age of the neonates when discharged from the hospital after birth was 76±1.2 hours. The mean birth weight was 3306±432 g and the mean gestational age was 269±8 days (384/7±11/7 weeks. The mean serum levels of T4 and TSH in the neonates of the study group were 13,73±2,2 µg/dl and 6,96±3,97 mU/mL respectively. The mean serum level of total bilirubin in the study group was 8,95±3,23 mg/dl. The Pearson’s correlation analysis revealed that r was -0.19 between TSH and total bilirubin levels and was significant but not so much powerful. Conclusion: Our results suggest that simultaneously measurement of T4, TSH, and bilirubin levels is a useful clinical tool for screening but there seems to be no significant clinical correlation between these parameters in healthy term newborns.

  3. COL1A1-shRNA表达质粒构建及抑制COL1A1表达的有效序列的筛选%Construction of COL1A1-shRNA expression plasmid and screening of effective sequences to inhibit COL1A1 expression

    Institute of Scientific and Technical Information of China (English)

    芦军; 赵金满; 孟艳; 余永红

    2008-01-01

    目的: 构建和筛选对大鼠肝星状细胞前Ⅰ型胶原α1链(COL1A1)mRNA有抑制作用的COL1A1短发夹RNA (shRNA)的表达质粒.方法:从NCBI网站获得大鼠的COL1A1 cDNA序列, 根据Whitehead研究所的siRNA设计软件设计3条理论上最佳的siRNA序列, 相应的双链DNA被插入pGPU6/GFP/Neo质粒中, 即pGPU6/GFP/Neo-shRNA-A、pGPU6/GFP/Neo-shRNA-B和pGPU6/GFP/Neo-shRNA-C. 为得到高效沉默COL1A1-siRNA, 以脂质体LipofectAMINE2000, 将1、2、3、4 μg DNA质粒转染至HSC-T6细胞中, 并观察转染效果. 将最佳沉默siRNA导入HSC-T6细胞, RT-PCR分析各组的COL1A1 mRNA表达水平.结果: 靶向COL1A1 mRNA的3个shRNA重组质粒载体pGPU6/GFP/Neo-shRNA-A、pGPU6/GFP/Neo-shRNA-B和pGPU6/GFP/Neo-shRNA-C经测序分析, shRNA编码序列与设计的片段完全一致, 经酶切凝胶电泳证实载体构建成功. 1、2、3、4 μg组转染效率分别为16.7%、20.3%、23.5%和22.3%, 以2 μg siRNA为最佳剂量, pGPU6/GFP/Neo-shRNA-A、pGPU6/GFP/Neo-shRNA-B和pGPU6/GFP/Neo-shRNA-C对COL1A1 mRNA的抑制率分别为16.6%, 63.3%和80.3%. 结论:筛选出的pGPU6/GFP/Neo-shRNA-C表达质粒能高效地抑制转染细胞COL1A1 mRNA的表达, 从而为肝纤维治疗提供新的方法和材料.

  4. The UGT1A1*28 allele and disease in childhood

    DEFF Research Database (Denmark)

    Petersen, Jesper Padkær

    været overvejet som en medvirkende faktor til neonatal hyperbilirubinæmi. Oxidativt stress er en mulig risiko faktor i udviklingen af akut lymphoblastær leukæmi (ALL) hos børn og respiratorisk sygdom hos for tidligt fødte. Vi undersøgte associationen mellem UGT1A1*28 genotyper og ALL hos børn, ekstrem...

  5. Cytochrome P450 1A1 expression in cetacean skin biopsies from the Indian Ocean

    OpenAIRE

    Jauniaux, Thierry; Farnir, Frédéric; Fontaine, Michael; Kiszka, Jeremy; Sarlet, Michaël; Coignoul, Freddy

    2011-01-01

    The study describes cytochrome P450 1A1 (CYPA1) expression in the skin of different cetacean species (Megaptera novaeangliae, n = 15; Stenella attenuata, n = 7 and Stenella longirostris, n = 24) from the Mozambique Channel island of Mayotte. Immunohistochemical examination was performed with a monoclonal antibody against scup cytochrome CYPA1. The sex was determined using a molecular approach consisting in the genotyping sex-specific genes. CYPA1 was detected at the junction between epidermis...

  6. Development of a theory of the variable quantum yield of the photoproducts from asymmetric bilirubin

    International Nuclear Information System (INIS)

    Full text: Bilirubin (BR) is the molecule responsible for neonatal jaundice, curable by phototherapy, and hence has been extensively studied. It is an asymmetric bichromophoric molecule; the excited states of the chromophores undergo the Davidoff (exciton, electric dipole) interaction. One of the peculiarities of BR is that the quantum yield of its photoproducts varies with wavelength. An account of the development of a theory for this will be given: part was given at a previous Wagga conference. It may well be that the Davidoff interaction parameter varies with wavelength, even though a constant interaction parameter gives rise to a variable quantum yield. Differences in the linewidths of the Davidoff lines also affect the quantum yield behaviour

  7. THE ASSOCIATION BETWEEN G6PD DEFICIENCY AND TOTAL SERUM BILIRUBIN LEVEL IN ICTERIC NEONATES

    Directory of Open Access Journals (Sweden)

    S. Behjati-Ardakani

    2007-07-01

    Full Text Available "nGlucose-6-phosphate dehydrogenase (G6PD deficiency is the most important disease of the hexose monophosphate pathway. Deficiency of this enzym can lead to hemolysis of red blood cells. Our aim was to study the prevalence of G6PD deficiency in relation to neonatal jaundice. We studied 456 clinically icteric neonates Laboratory investigations included determination of direct and indirect serum bilirubin concentrations, blood group typing, direct coomb's test, hemoglobin, blood smear, reticulocyte count and G6PD level. We divided these neonates to 3 groups based on total serum bilirubin level (TSB: TSB< 20 mg%, TSB=20-25 mg%, and TSB>25 mg%. In only 35 (7.6% of cases G6PD deficiency was diagnosed. All of these babies were male. From 456 icteric neonates, 213 cases belong to group 1 (TSB<20 mg%, 158 cases belong to group 2 (TSB=20-25 mg% and 85 cases belong to group 3 (TSB>25 mg%. 16 neonates from 213 neonates of group 1, 6 neonates from 158 neonates of group 2 and 13 neonates from 85 neonates of group 3 had G6PD deficiency. There was statistically significant difference of prevalence of G6PD deficiency between group 2 and 3 ( 15.3% vs 3.8%( P = 0.001. Between groups 1 vs 2 and 1 vs 3 no statistically significant difference was found. Early detection of this enzymopathy regardless of sex and close surveillance of the affected newborns may be important in reducing the risk of severe hyperbilirubinemia. This emphasizes the necessity of neonatal screening on cord blood samples for G6PD deficiency.

  8. The Effect of Clofibrate on Decreasing Serum Bilirubin in Healthy Term Neonates Under Home Phototherapy

    Directory of Open Access Journals (Sweden)

    Simin Sharafi

    2010-03-01

    Full Text Available Objective: this study was designed to determine the effect of clofibrate on neonatal uncomplicated jaundice treated with home phototherapy. Methods:This clinical trial study was performed on 60 newborns with jaundice that received home phototherapy. Inclusion criteria were body weight between 2500 to 4000 gr, breastfed, total serum bilirubin (TSB between 14 to 20 mg/dl, aged over 72 hours. The neonates were randomly divided into two groups. All received home phototherapy. Group i received a single dose of 50 mg/kg clofibrate and the other group served as control group. Total serum bilirubin level was measured every 24 hours. Findings:Two groups were matched regarding weight, sex, age and first TSB. At 24 and 48 hours of treatment, the mean values of TSB in the clofibrate group were 13.72 (1.56, 9.5 (0.56 and in the control group 15.30 (1.44, 12.6 (1.44. The results show that TSB was significantly decreased after 24 and 48 hours in clofibrate group (P<0.001. The mean duration of phototherapy in group I was 72(0.0 hours and in the control group 76.80 (±9.76 hours. The duration of phototherapy was significantly shorter in clofibrate group (P<0.001. Conclusion:Clofibrate is effective for outpatients with neonatal hyperbilirubinemia who are under home phototherapy. Of course, further studies are needed for approved routine use of this drug in the treatment of neonatal jaundice.

  9. Anti-cancer effects of blue-green alga Spirulina platensis, a natural source of bilirubin-like tetrapyrrolic compounds

    Czech Academy of Sciences Publication Activity Database

    Koníčková, R.; Vaňková, K.; Vaníková, J.; Váňová, K.; Muchová, L.; Subhanová, I.; Zadinová, M.; Zelenka, Jaroslav; Dvořák, Aleš; Kolář, Michal; Strnad, Hynek; Rimpelová, S.; Ruml, T.; Wong, R.J.; Vítek, L.

    2014-01-01

    Roč. 13, č. 2 (2014), s. 273-283. ISSN 1665-2681 Institutional support: RVO:67985823 ; RVO:68378050 Keywords : bilirubin * chlorophyll * heme oxygenase * phycocyanin * phycocyanobilin * Spirulina platensis * tetrapyrroles Subject RIV: FD - Oncology ; Hematology Impact factor: 2.065, year: 2014

  10. Polychlorinated biphenyls, cytochrome P450 1A1 (CYP1A1) polymorphisms, and breast cancer risk among African American women and white women in North Carolina: a population-based case-control study

    OpenAIRE

    Li, Yu; Millikan, Robert C.; Douglas A Bell; Cui, Lisa; Tse, Chiu-Kit J; Newman, Beth; Conway, Kathleen

    2004-01-01

    Introduction Epidemiologic studies have not shown a strong relationship between blood levels of polychlorinated biphenyls (PCBs) and breast cancer risk. However, two recent studies showed a stronger association among postmenopausal white women with the inducible M2 polymorphism in the cytochrome P450 1A1 (CYP1A1) gene. Methods In a population-based case-control study, we evaluated breast cancer risk in relation to PCBs and the CYP1A1 polymorphisms M1 (also known as CYP1A1*2A), M2 (CYP1A1*2C),...

  11. Transcutaneous bilirubin--comparing the accuracy of BiliChek(R) and JM 103(R) in a regional postnatal unit.

    LENUS (Irish Health Repository)

    Qualter, Yvonne M

    2012-01-31

    OBJECTIVE: Transcutaneous bilirubin (TcB) has the potential to reduce serum bilirubin sampling. During a recent survey on the use of TcB in postnatal units in the Republic of Ireland, we identified that only 58% of the 19 units were using TcB and that only two devices were in use, the BiliChek(R) and JM 103(R). We aimed to evaluate and compare these two devices in a regional postnatal unit. METHODS: To evaluate and compare the accuracy of the BiliChek(R) and JM 103(R), we studied simultaneous TcB and total serum bilirubin (TSB) measurements from a population of jaundiced term and near term infants. We evaluated each device with regard to correlation with TSB and potential to safely reduce serum bilirubin testing. RESULTS: Both TcB devices strongly correlated with TSB (r = 0.88 for BiliChek(R) and r = 0.70 for JM 103(R). The BiliChek(R) and JM 103(R) were accurate up to cut-off values of 200 mumol\\/L and 180 mumol\\/L, respectively. Using Bhutani\\'s nomogram, 100% sensitivity was achieved using the 75th percentile for BiliChek(R) and the 40th percentile for JM 103(R). CONCLUSION: Both TcB devices correlated closely with moderately increased TSB levels and are suitable screening tools to identify jaundiced infants that require a serum bilirubin, with upper limit cut-off values. Both devices reduced the need for TSB levels. We found the BiliChek(R) slightly more accurate than the JM 103(R) for our study population. TcB however, is not in widespread use.

  12. Effects of Bilirubin on Alveolar Macrophages in Rats with Emphysema and Expression of iNOS and NO in Them

    Institute of Scientific and Technical Information of China (English)

    李建强; 赵卉; 宋满景; 徐永健; 张珍祥

    2004-01-01

    To explore the effects of bilirubin on alveolar macrophages (AM) and expression of iNOS and NO in them in emphysema model, the rats were pretreated with bilirubin before exposed to smoke. AM were isolated from bronchoalveolar lavage fluid (BALF) and cultured. Pathological microscopic examination of AM and immunohistochemical analysis of iNOS were performed. Nitric oxide (NO) content in the samples was determined by nitrate reductase technique. The results showed both alveoli and alveolar septum appeared normal in size and shape in normal group. AM showed kidney-shaped nucleus and were rich in Golgi complexes and primary lysosomes in the cytoplasm. The inner membrane of mitochondrion was continuous. Most cristae of the mitochondria were intact. In model group, the alveoli were expanded, ruptured and bullaes were formed. Both the population and sizes of AM increased significantly. Secondary lysosomes were rich in the cytoplasm. Deformation and pyknosis of the nucleus, swelling of the mitochondrions and rupture of the inner mitochondrial membrane could also be seen. At high magnification, most of the mitochondrial cristae were broken, or completely lost at certain points. In bilirubin group, alveoli partly expanded and the population of AM also increased, with morphological changes being slighter than that in model group. Both NO contents and expression of iNOS in model group were higher than those in normal group (P<0.05). In bilirubin group the two indice were lower than those in model group (P<0.05). Our findings suggested that high expression of iNOS and high NO content in AM accelerate the development of emphysema associated with smoking in rats. Bilirubin may exert protective effects on AM and retards the development of emphysema in rats.

  13. Reduced inflammatory response in cigarette smoke exposed Mrp1/Mdr1a/1b deficient mice

    Directory of Open Access Journals (Sweden)

    Postma Dirkje S

    2007-07-01

    Full Text Available Abstract Background Tobacco smoke is the principal risk factor for chronic obstructive pulmonary disease (COPD, though the mechanisms of its toxicity are still unclear. The ABC transporters multidrug resistance-associated protein 1 (MRP1 and P-glycoprotein (P-gp/MDR1 extrude a wide variety of toxic substances across cellular membranes and are highly expressed in bronchial epithelium. Their impaired function may contribute to COPD development by diminished detoxification of noxious compounds in cigarette smoke. Methods We examined whether triple knock-out (TKO mice lacking the genes for Mrp1 and Mdr1a/1b are more susceptible to develop COPD features than their wild-type (WT littermates. TKO and WT mice (six per group were exposed to 2 cigarettes twice daily by nose-only exposure or room air for 6 months. Inflammatory infiltrates were analyzed in lung sections, cytokines and chemokines in whole lung homogenates, emphysema by mean linear intercept. Multiple linear regression analysis with an interaction term was used to establish the statistical significances of differences. Results TKO mice had lower levels of interleukin (IL-7, KC (mouse IL-8, IL-12p70, IL-17, TNF-alpha, G-CSF, GM-CSF and MIP-1-alpha than WT mice independent of smoke exposure (P P P Conclusion Mrp1/Mdr1a/1b knock-out mice have a reduced inflammatory response to cigarette smoke. In addition, the expression levels of several cytokines and chemokines were also lower in lungs of Mrp1/Mdr1a/1b knock-out mice independent of smoke exposure. Further studies are required to determine whether dysfunction of MRP1 and/or P-gp contribute to the pathogenesis of COPD.

  14. A full CI treatment of the 1A1-3B1 separation in methylene

    Science.gov (United States)

    Bauschlicher, Charles W., Jr.; Taylor, Peter R.

    1986-01-01

    The accuracy of recent theoretical computations of the total energies and the adiabatic separation of the 1A1 and 3B1 states of CH2 is investigated on the basis of complete CI calculations using the double-zeta basis sets of Dunning (1970). The results are presented in a table and characterized in detail. The errors in the separation values are found to range from less than 0.01 kcal/mol for a CASSCF/MRSDCI calculation, to 0.38 kcal/mol for a Davidson-corrected SCF/SDCI calculation, to 14.17 kcal/mol for an uncorrected SCF calculation.

  15. CYP1A1 expression in breast milk cells of Japanese population

    Energy Technology Data Exchange (ETDEWEB)

    Yonemoto, Junzo; Shiizaki, Kazuhiro; Sone, Hideko; Morita, Masatosi [National Institute for Environmental Studies, Tsukuba (Japan); Uechi, Hiroto [Uechi Obstetrics and Gynecology Clinic, Utsunomiya (Japan); Masuzaki, Yuko; Koizumi, Atsuko; Matzumura, Toru [Metocean Environment Inc., Ohigawa (Japan)

    2004-09-15

    Dioxins are persistent, lipophilic compounds that are ubiquitous in the environment. Concern over the reproductive and developmental toxicity of dioxins has been growing since they have endocrine-disrupting properties and have adversely affected the health of offspring in experimental and epidemiological studies. Monitoring of maternal body burdens of dioxins and their biological responses to dioxin exposure is needed to estimate the potential health risk to their offspring. Breast milk has been used for monitoring dioxins in humans for decades. Breast milk has some advantages in exposure monitoring. Sampling is non-invasive, and dioxin levels are relatively high because of the high lipid content. It is assumed that mammary glands are exposed to a higher level of dioxins than other tissues since mammary glands synthesize and store milk fat. Breast milk contains leukocytes and exfoliated ductal epithelial cells. If these cells responded to dioxins and expressed CYP enzymes, a sensitive biomarker for dioxin exposure, they would be useful as biomarkers for dioxin exposure. In the present study, the expression of CYP enzymes in intact milk cells or cells cultured with TCDD was investigated. In addition, breast milk samples were collected from mothers within one week of childbearing, and the expression of CYP1A1 mRNA in milk cells was determined. The relationship between CYP1A1 mRNA expression in milk cells and dioxin levels in the cream layer of breast milk was analyzed.

  16. ALDH1A1-overexpressing cells are differentiated cells but not cancer stem or progenitor cells in human hepatocellular carcinoma.

    Science.gov (United States)

    Tanaka, Kaori; Tomita, Hiroyuki; Hisamatsu, Kenji; Nakashima, Takayuki; Hatano, Yuichiro; Sasaki, Yoshiyuki; Osada, Shinji; Tanaka, Takuji; Miyazaki, Tatsuhiko; Yoshida, Kazuhiro; Hara, Akira

    2015-09-22

    Aldehyde dehydrogenase 1A1 (ALDH1A1) is considered to be a cancer stem cell marker in several human malignancies. However, the role of ALDH1A1 in hepatocellular carcinoma (HCC) has not been well elucidated. In this study, we investigated the relationship between ALDH1A1 and clinicopathological findings and examined whether ALDH1A1 deserves to be a cancer stem cell marker in HCC. Sixty HCC samples obtained from surgical resection were collected for immunohistochemical (IHC) staining. Of these 60 samples, 47 samples of HCC tumorous and non-tumorous tissues were evaluated with qRT-PCR. There was no significant difference in the ALDH1A1-mRNA level between tumorous and non-tumorous tissues. Tumorous ALDH1A1-mRNA level had no relationship with the clinicopathological features. Immunoreactivity of ALDH1A1 was classified into two groups based on the percentage of ALDH1A1-overexpressing cells. The ALDH1A1-high group was significantly associated with low serum levels of α-fetoprotein, small tumor diameter, very little lymphovascular invasion, more differentiated pathology and good stage. The ALDH1A1-high group showed more favorable prognosis for recurrence-free survival. In double-staining IHC, ALDH1A1 was not co-expressed with BMI1, EpCAM, CD13, CD24, CD90 and CD133, which reported as cancer stem cell markers in HCC. In conclusion, ALDH1A1-overexpressing cells could appear to be differentiated cells rather than cancer stem cells in HCC. PMID:26160842

  17. Research on prevention of bilirubin-induced brain injury and kernicterus: National Institute of Child Health and Human Development conference executive summary. 2003.

    Science.gov (United States)

    Blackmon, Lillian R; Fanaroff, Avroy A; Raju, Tonse N K

    2004-07-01

    In July 2003, the National Institute of Child Health and Human Development convened a conference, "Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus: Bench-to-Bedside." This article will provide a summary of presentations and discussions from this conference. The summary will focus on the identified knowledge gaps in 5 areas related to bilirubin-induced brain injury and kernicterus: 1) neurobiology and neuroimaging; 2) epidemiology and issues of clinical management; 3) methodologies for assessing clinical jaundice and direct and noninvasive measurement of serum bilirubin and hemolysis; 4) therapies for management of neonatal hyperbilirubinemia; and 5) public health surveillance and systems-based approaches to prevention. PMID:15231933

  18. Cytochrome P450 1A1 expression in cetacean skin biopsies from the Indian Ocean.

    Science.gov (United States)

    Jauniaux, Thierry; Farnir, Frédéric; Fontaine, Michaël; Kiszka, Jeremy; Sarlet, Michael; Coignoul, Freddy

    2011-06-01

    The study describes cytochrome P450 1A1 (CYPA1) expression in the skin of different cetacean species (Megaptera novaeangliae, n=15; Stenella attenuata, n=7 and Stenella longirostris, n=24) from the Mozambique Channel island of Mayotte. Immunohistochemical examination was performed with a monoclonal antibody against scup cytochrome CYPA1. The sex was determined using a molecular approach consisting in the genotyping sex-specific genes. CYPA1 was detected at the junction between epidermis and blubber on dolphins only, mostly in the endothelial cells. Similar observation was obtained in the dermis of one M. novaeangliae. Immunohistochemical slides were scored to evaluate the expression of the CYPA1 and a higher expression was observed in S. longirostris, suggesting a higher exposure to pollutants for this species. The difference of expression between sexes was not significant. PMID:21565363

  19. Characterization of erythrosine B binding to bovine serum albumin and bilirubin displacement.

    Science.gov (United States)

    Mathavan, Vinodaran M K; Boh, Boon Kim; Tayyab, Saad

    2009-08-01

    The interaction of crythrosine B (ErB), a commonly used dye for coloring foods and drinks, with bovine scrum albumin (BSA) was investigated both in the absence and presence of bilirubin (BR) using absorption and absorption difference spectroscopy. ErB binding to BSA was reflected from a significant red shift of 11 nm in the absorption maximum of ErB (527 nm) with the change in absorbance at lamdamax. Analysis of absorption difference spectroscopic titration results of BSA with increasing concentrations of ErB3 using Benesi-Hildebrand equation gave the association constant, K as 6.9 x 10(4) M(-1). BR displacing action of ErB was revealed by a significant blue shift in the absorption maximum, accompanied by a decrease in absorbance difference at lamdamax in the difference spectrum of BR-BSA complex upon addition of increasing concentrations of ErB. This was further substantiated by fluorescence spectroscopy, as addition of increasing concentrations of ErB to BR-BSA complex caused a significant decrease in fluoresccnce at 510 nm. The results suggest that ErB binds to a site in the vicinity of BR binding site on BSA. Therefore, intake of ErB may increase the risk of hyperbilirubinemia in the healthy subjects. PMID:19788065

  20. Theory of the variable quantum yield of Bilirubin-IX Photoisomers: the end of a chapter

    International Nuclear Information System (INIS)

    Full text: Bilirubin-IX (BR-IX), responsible for neonatal jaundice, has two slightly different chromophores which undergo the Davidoff (exciton) interaction. Because of this, BR-IX in certain solvents, e.g. human serum albumin (but not Me/OH) exhibits magnetic circular dichroism (MCD), due to the exciton lines only. The absoption spectrum of BR-IX in the exciton line region is best fitted by two gaussian lines of equal width, but the MCD spectrum best fit requires two gaussian of unequal width: the gaussian assumption is made for ease of calculation. The difference between the fitted spectra shows up as a single broad line of maximum smaller than that of the gaussian lines, and in the region of the central portion of the gaussians overlap. The origin of this line is as yet unknown, so that much further work needs to be done on the structure of the excited state of BR-IX giving rise to the exciton interaction. This is currently being undertaken. However, the variation of the exciton interaction energy with wavelength as deduced from present theory seems reasonably certain though its origin may not be

  1. Bilirubin oxidase based enzymatic air-breathing cathode: Operation under pristine and contaminated conditions.

    Science.gov (United States)

    Santoro, Carlo; Babanova, Sofia; Erable, Benjamin; Schuler, Andrew; Atanassov, Plamen

    2016-04-01

    The performance of bilirubin oxidase (BOx) based air breathing cathode was constantly monitored over 45 days. The effect of electrolyte composition on the cathode oxygen reduction reaction (ORR) output was investigated. Particularly, deactivation of the electrocatalytic activity of the enzyme in phosphate buffer saline (PBS) solution and in activated sludge (AS) was evaluated. The greatest drop in current density was observed during the first 3 days of constant operation with a decrease of ~60 μA cm(-2) day(-1). The rate of decrease slowed to ~10 μA cm(-2) day(-1) (day 3 to 9) and then to ~1.5 μA cm(-2)day(-1) thereafter (day 9 to 45). Despite the constant decrease in output, the BOx cathode generated residual current after 45 days operations with an open circuit potential (OCP) of 475 mV vs. Ag/AgCl. Enzyme deactivation was also studied in AS to simulate an environment close to the real waste operation with pollutants, solid particles and bacteria. The presence of low-molecular weight soluble contaminants was identified as the main reason for an immediate enzymatic deactivation within few hours of cathode operation. The presence of solid particles and bacteria does not affect the natural degradation of the enzyme. PMID:26544631

  2. Analysis of binding ability of two tetramethylpyridylporphyrins to albumin and its complex with bilirubin.

    Science.gov (United States)

    Solomonov, Alexey V; Shipitsyna, Maria K; Vashurin, Arthur S; Rumyantsev, Evgeniy V; Timin, Alexander S; Ivanov, Sergey P

    2016-11-01

    An interaction between 5,10,15,20-tetrakis-(N-methyl-x-pyridyl)porphyrins, x=2; 4 (TMPyPs) with bovine serum albumin (BSA) and its bilirubin (BR) complex was investigated by UV-Viz and fluorescence spectroscopy under imitated physiological conditions involving molecular docking studies. The parameters of forming intermolecular complexes (binding constants, quenching rate constants, quenching sphere radius etc.) were determined. It was showed that the interaction between proteins and TMPyPs occurs via static quenching of protein fluorescence and has predominantly hydrophobic and electrostatic character. It was revealed that obtained complexes are relatively stable, but in the case of TMPyP4 binding with proteins occurs better than TMPyP2. Nevertheless, both TMPyPs have better binding ability with free protein compared to BRBSA at the same time. The influence of TMPyPs on the conformational changes in protein molecules was studied using synchronous fluorescence spectroscopy. It was found that there is no competition of BR with TMPyPs for binging sites on protein molecule and BR displacement does not occur. Molecular docking calculations have showed that TMPyPs can bind with albumin via tryptophan residue in the hydrophilic binding site of protein molecule but it is not one possible interaction way. PMID:27267279

  3. Effect of bilirubin on expression and localization of PGP and Mrp1 in the central nervous system

    OpenAIRE

    Gazzin, Silvia

    2008-01-01

    INTRODUZIONE A basse concentrazioni la bilirubina non coniugata (unconjugated bilirubin, UCB) prodotta dalla degradazione dell’emoglobina, sembra essere un potente anti-ossidante, mentre è estremamente dannosa ad alte concentrazioni, causando encefalopatia nei neonati con severo ittero. Il 70% dei bambini che presentano kernittero muoiono entro sette giorni di vita, mentre il 30% dei sopravvissuti manifesta irreversibili conseguenze come sordità, ritardo mentale e danni cerebrali perman...

  4. X-ray analysis of bilirubin oxidase from Myrothecium verrucaria at 2.3 Å resolution using a twinned crystal

    International Nuclear Information System (INIS)

    The crystal structure of bilirubin oxidase (BOD) from M. verrucaria has been determined at 2.3 Å resolution using a merohedrally twinned crystal. BOD has four copper-coordination sites that are almost identical to those of other multicopper oxidases and is also very similar to them in overall structure. Bilirubin oxidase (BOD), a multicopper oxidase found in Myrothecium verrucaria, catalyzes the oxidation of bilirubin to biliverdin. Oxygen is the electron acceptor and is reduced to water. BOD is used for diagnostic analysis of bilirubin in serum and has attracted considerable attention as an enzymatic catalyst for the cathode of biofuel cells that work under neutral conditions. Here, the crystal structure of BOD is reported for the first time. Blue bipyramid-shaped crystals of BOD obtained in 2-methyl-2,4-pentanediol (MPD) and ammonium sulfate solution were merohedrally twinned in space group P63. Structure determination was achieved by the single anomalous diffraction (SAD) method using the anomalous diffraction of Cu atoms and synchrotron radiation and twin refinement was performed in the resolution range 33–2.3 Å. The overall organization of BOD is almost the same as that of other multicopper oxidases: the protein is folded into three domains and a total of four copper-binding sites are found in domains 1 and 3. Although the four copper-binding sites were almost identical to those of other multicopper oxidases, the hydrophilic Asn residue (at the same position as a hydrophobic residue such as Leu in other multicopper oxidases) very close to the type I copper might contribute to the characteristically high redox potential of BOD

  5. Bilirubin Oxidase from Bacillus pumilus: A promising enzyme for the elaboration of efficient cathodes in Biofuel cells

    OpenAIRE

    Durand, Fabien; Kjaergaard, Christian Hauge; Suraniti, Emmanuel; Gounel, Sébastien; Hadt, Ryan G.; Solomon, Edward I.; Mano, Nicolas

    2012-01-01

    A CotA Multicopper Oxidase (MCO) from Bacillus pumilus, previously identified as a laccase, has been studied and characterized as a new bacterial Bilirubin Oxidase (BOD). The 59kDa protein containing four coppers, was successfully over-expressed in Escherichia coli and purified to homogeneity in one step. This 509 amino-acid enzyme, having 67% and 26% sequence identity with CotA from Bacillus subtilis and BOD from Myrothecium verrucaria, respectively, shows higher turnover activity towards bi...

  6. On the Possibility of Uphill Intramolecular Electron Transfer in Multicopper Oxidases: Electrochemical and Quantum Chemical Study of Bilirubin Oxidase

    Czech Academy of Sciences Publication Activity Database

    Shleev, S.; Andoralov, V.; Falk, M.; Reimann, C. T.; Ruzgas, T.; Srnec, Martin; Ryde, U.; Rulíšek, Lubomír

    2012-01-01

    Roč. 24, č. 7 (2012), s. 1524-1540. ISSN 1040-0397 Grant ostatní: 7th Framework Program(XE) NMP4-SL-2009-229255 Institutional research plan: CEZ:AV0Z40550506 Keywords : bilirubin oxidase * intramolecular electron transfer * rate-limiting catalytic step * reorganization energy * QM/MM calculations Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 2.817, year: 2012

  7. Dimethyl ester of bilirubin exhibits anti-inflammatory activity through inhibition of secretory phospholipase A2, lipoxygenase and cyclooxygenase.

    Science.gov (United States)

    Joshi, Vikram; Umashankara, M; Ramakrishnan, Chandrasekaran; Nanjaraj Urs, Ankanahalli N; Suvilesh, Kanve Nagaraj; Velmurugan, Devadasan; Rangappa, Kanchugarakoppal S; Vishwanath, Bannikuppe Sannanaik

    2016-05-15

    Overproduction of arachidonic acid (AA) mediated by secretory phospholipase A2 group IIA (sPLA2IIA) is a hallmark of many inflammatory disorders. AA is subsequently converted into pro-inflammatory eicosanoids through 5-lipoxygenase (5-LOX) and cyclooxygenase-1/2 (COX-1/2) activities. Hence, inhibition of sPLA2IIA, 5-LOX and COX-1/2 activities is critical in regulating inflammation. We have previously reported unconjugated bilirubin (UCB), an endogenous antioxidant, as sPLA2IIA inhibitor. However, lipophilic UCB gets conjugated in liver with glucuronic acid into hydrophilic conjugated bilirubin (CB). Since hydrophobicity is pre-requisite for sPLA2IIA inhibition, conjugation reduces the efficacy of UCB. In this regard, UCB was chemically modified and derivatives were evaluated for sPLA2IIA, 5-LOX and COX-1/2 inhibition. Among the derivatives, BD1 (dimethyl ester of bilirubin) exhibited ∼ 3 fold greater inhibitory potency towards sPLA2IIA compared to UCB. Both UCB and BD1 inhibited human 5-LOX and COX-2 activities; however only BD1 inhibited AA induced platelet aggregation. Molecular docking studies demonstrated BD1 as better inhibitor of aforesaid enzymes than UCB and other endogenous antioxidants. These data suggest that BD1 exhibits strong anti-inflammatory activity through inhibition of AA cascade enzymes which is of great therapeutic importance. PMID:27060751

  8. Application of high-performance liquid chromatography combined with ultra-sensitive thermal lens spectrometric detection for simultaneous biliverdin and bilirubin assessment at trace levels in human serum.

    Science.gov (United States)

    Martelanc, Mitja; Žiberna, Lovro; Passamonti, Sabina; Franko, Mladen

    2016-07-01

    We present the applicability of a new ultra-sensitive analytical method for the simultaneous determination of biliverdin and bilirubin in human serum. The method comprises isocratic reversed-phase (RP) C18 high-performance liquid chromatography (HPLC) and thermal lens spectrometric detection (TLS) based on excitation by a krypton laser emission line at 407nm. This method enables the separation of IX-α biliverdin and IX-α bilirubin in 11min with limit of detection (LOD) and limit of quantitation (LOQ) for biliverdin of 1.2nM and 3nM, and 1nM and 2.8nM for bilirubin, respectively. In addition, a step-gradient elution was set up, by changing the mobile phase composition, in order to further enhance the sensitivity for bilirubin determination with LOD and LOQ of 0.5nM and 1.5nM, respectively. In parallel, an isocratic HPLC-DAD method was developed for benchmarking against HPLC-TLS methods. The LOD and LOQ for biliverdin were 6nM and 18nM, and 2.5nM and 8nM for bilirubin, respectively. Additionally, both isocratic methods were applied for measuring biliverdin and free bilirubin in human serum samples (from 2 male and 2 female healthy donors). Combining isocratic HPLC method with TLS detector was crucial for first ever biliverdin determination in serum together with simultaneous free bilirubin determination. We showed for the first time the concentration ratio of free bilirubin versus unbound biliverdin in human serum samples. PMID:27154653

  9. Human serum albumin-stabilized gold nanoclusters act as an electron transfer bridge supporting specific electrocatalysis of bilirubin useful for biosensing applications.

    Science.gov (United States)

    Santhosh, Mallesh; Chinnadayyala, Somasekhar R; Singh, Naveen K; Goswami, Pranab

    2016-10-01

    Human serum albumin (HSA)-stabilized Au18 nanoclusters (AuNCs) were synthesized and chemically immobilized on an Indium tin oxide (ITO) plate. The assembly process was characterized by advanced electrochemical and spectroscopic techniques. The bare ITO electrode generated three irreversible oxidation peaks, whereas the HSA-AuNC-modified electrode produced a pair of redox peaks for bilirubin at a formal potential of 0.27V (vs. Ag/AgCl). However, the native HSA protein immobilized on the ITO electrode failed to produce any redox peak for bilirubin. The results indicate that the AuNCs present in HSA act as electron transfer bridge between bilirubin and the ITO plate. Docking studies of AuNC with HSA revealed that the best docked structure of the nanocluster is located around the vicinity of the bilirubin binding site, with an orientation that allows specific oxidation. When the HSA-AuNC-modified electrode was employed for the detection of bilirubin using chronoamperometry at 0.3V (vs. Ag/AgCl), a steady-state current response against bilirubin in the range of 0.2μM to 7μM, with a sensitivity of 0.34μAμM(-1) and limit of detection of 86.32nM at S/N 3, was obtained. The bioelectrode was successfully applied to measure the bilirubin content in spiked serum samples. The results indicate the feasibility of using HSA-AuNC as a biorecognition element for the detection of serum bilirubin levels using an electrochemical technique. PMID:27126550

  10. Apoptosis in murine hepatoma hepa 1c1c7 wild-type, C12, and C4 cells mediated by bilirubin.

    Science.gov (United States)

    Seubert, John M; Darmon, Alison J; El-Kadi, Ayman O S; D'Souza, Sudhir J A; Bend, John R

    2002-08-01

    Elevated serum and tissue bilirubin concentrations that occur in pathological conditions such as cholestasis, jaundice, and other liver diseases are known to stimulate cytotoxic responses. In preliminary studies, we noted that bilirubin seemed to cause apoptosis in murine hepatoma Hepa 1c1c7 wild-type (WT) cells. Consequently, we investigated apoptosis caused by bilirubin in WT, mutant C12 [aryl hydrocarbon receptor (AHR)-deficient], and C4 (AHR nuclear translocator-deficient) Hepa 1c1c7 cells. Three independent measures of apoptosis were used to quantify the effects of exogenous bilirubin (0, 1, 10, 25, 50, or 100 microM). Caspase-3 activity and cytochrome c release from mitochondria increased at 3 h post-treatment, before increased caspase-8 activity at 6 h, and nuclear condensation by 24 h after treatment with bilirubin. No differences in whole-cell lipid peroxidation were observed between the cell types; however, intracellular reactive oxygen species (ROS) production was greater in WT cells than C12 or C4 cells 3 h after bilirubin exposure. Pretreatment of cells for 1 h with 1 or 10 microM alpha-naphthoflavone, an AHR antagonist, before bilirubin exposure resulted in decreased caspase-3 activity at 6 h and nuclear condensation at 24 h in WT cells. These results indicate that bilirubin, a potential AHR ligand, causes apoptosis in murine Hepa 1c1c7 WT cells by a mechanism(s) partially involving the AHR, disruption of membrane integrity, and increased intracellular ROS production. PMID:12130676

  11. Gly71Arg UGT1A1 polymorphism is associated with breast cancer susceptibility in Han Chinese women.

    Science.gov (United States)

    Shi, J; Li, L H; Duan, X Y; Liu, Q; Sun, L L; Tian, Y T

    2016-01-01

    Breast cancer is among the most common causes of cancer-related death in women worldwide. Previous studies have demonstrated an association between prolonged estrogen exposure and increased risk of breast cancer. Uridine 5'-diphospho-glucuronosyltransferase 1-1 (UGT1A1) plays a significant role in the detoxification of estrogens. Two major genetic polymorphisms have been identified in the UGT1A1 locus. UGT1A1*28 has been previously linked to increased risk of breast cancer. The aim of this study was to elucidate the possible correlation between UGT1A1*6, a single nucleotide polymorphism causing a Gly71Arg substitution, and breast cancer susceptibility. Forty-six women diagnosed with breast cancer, 15 patients with gastrointestinal cancer, and 13 healthy women were recruited to this study. The genotype in the polymorphic UGT1A1 locus was determined by DNA sequencing. The frequency of each genotype was compared among the three groups. The frequency of the UGT1A1*6 allele was significantly higher in breast cancer and gastrointestinal cancer patients than that in healthy females (both P 0.05). Therefore, the UGT1A1*6 polymorphism was deduced to be a risk factor for breast cancer in women of Han Chinese ethnicity. UGT1A1 may serve as a therapeutic target for the prevention and treatment of breast cancer and other estrogen-related diseases. PMID:27525948

  12. Osteoporosis and Related Genes: VDR, ESR And COL1A1

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    Sabriye Kocaturk Sel

    2011-08-01

    Full Text Available Osteoporosis is now considered as one of the major and growing health care problems around the world. Osteoporosis is the most prevalent metabolic bone disease among developed countries and it is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. Bone is a highly metabolically active tissue in which the processes of osteoblastic bone formation and osteoclastic bone resorption are continuous throughout life. Coupling of osteoblast and osteoclast action ensures that a normal bone structure is maintained. A loss of bone homeostasis may result in a decrease in bone mass leading to osteoporosis or in a defect in the mineralization of bone. Numerous genetic, hormonal, nutritional and life-style factors contribute to the acquisition and maintenance of bone mass. Among them, genetic variations explain as much as 50-80% of the variance for bone mineral density (BMD in the population. Many genes that could be related to osteoporosis have been studied and of them all Vitamin D receptor (VDR, estrogen receptor alpha (ESRα and collagen 1 alpha 1 chain (COL1A1 genes have been the most focused on. [Archives Medical Review Journal 2011; 20(4.000: 246-269

  13. Biliverdin reductase/bilirubin mediates the anti-apoptotic effect of hypoxia in pulmonary arterial smooth muscle cells through ERK1/2 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Song, Shasha [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Wang, Shuang [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China); Ma, Jun; Yao, Lan; Xing, Hao; Zhang, Lei; Liao, Lin [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Zhu, Daling, E-mail: dalingz@yahoo.com [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China)

    2013-08-01

    Inhibition of pulmonary arterial smooth muscle cell (PASMC) apoptosis induced by hypoxia plays an important role in pulmonary arterial remodeling leading to aggravate hypoxic pulmonary arterial hypertension. However, the mechanisms of hypoxia acting on PASMC apoptosis remain exclusive. Biliverdin reductase (BVR) has many essential biologic roles in physiological and pathological processes. Nevertheless, it is unclear whether the hypoxia-induced inhibition on PASMC apoptosis is mediated by BVR. In the present work, we found BVR majorly localized in PASMCs and was up-regulated in levels of protein and mRNA by hypoxia. Then we studied the contribution of BVR to anti-apoptotic response of hypoxia in PASMCs. Our results showed that siBVR, blocking generation of bilirubin, reversed the effect of hypoxia on enhancing cell survival and apoptotic protein (Bcl-2, procasepase-9, procasepase-3) expression, preventing nuclear shrinkage, DNA fragmentation and mitochondrial depolarization in starved PASMCs, which were recovered by exogenous bilirubin. Moreover, the inhibitory effect of bilirubin on PASMC apoptosis under hypoxic condition was blocked by the inhibitor of ERK1/2 pathway. Taken together, our data indicate that BVR contributes to the inhibitory process of hypoxia on PASMC apoptosis, which is mediated by bilirubin through ERK1/2 pathway. Highlights: • BVR expresses in PASMC and is up-regulated by hypoxia in protein and mRNA levels. • BVR/bilirubin contribute to the inhibitive process of hypoxia on PASMC apoptosis. • Bilirubin protects PASMC from apoptosis under hypoxia via ERK1/2 pathway.

  14. Biliverdin reductase/bilirubin mediates the anti-apoptotic effect of hypoxia in pulmonary arterial smooth muscle cells through ERK1/2 pathway

    International Nuclear Information System (INIS)

    Inhibition of pulmonary arterial smooth muscle cell (PASMC) apoptosis induced by hypoxia plays an important role in pulmonary arterial remodeling leading to aggravate hypoxic pulmonary arterial hypertension. However, the mechanisms of hypoxia acting on PASMC apoptosis remain exclusive. Biliverdin reductase (BVR) has many essential biologic roles in physiological and pathological processes. Nevertheless, it is unclear whether the hypoxia-induced inhibition on PASMC apoptosis is mediated by BVR. In the present work, we found BVR majorly localized in PASMCs and was up-regulated in levels of protein and mRNA by hypoxia. Then we studied the contribution of BVR to anti-apoptotic response of hypoxia in PASMCs. Our results showed that siBVR, blocking generation of bilirubin, reversed the effect of hypoxia on enhancing cell survival and apoptotic protein (Bcl-2, procasepase-9, procasepase-3) expression, preventing nuclear shrinkage, DNA fragmentation and mitochondrial depolarization in starved PASMCs, which were recovered by exogenous bilirubin. Moreover, the inhibitory effect of bilirubin on PASMC apoptosis under hypoxic condition was blocked by the inhibitor of ERK1/2 pathway. Taken together, our data indicate that BVR contributes to the inhibitory process of hypoxia on PASMC apoptosis, which is mediated by bilirubin through ERK1/2 pathway. Highlights: • BVR expresses in PASMC and is up-regulated by hypoxia in protein and mRNA levels. • BVR/bilirubin contribute to the inhibitive process of hypoxia on PASMC apoptosis. • Bilirubin protects PASMC from apoptosis under hypoxia via ERK1/2 pathway

  15. Heme oxygenase-1 induction prevents neuronal damage triggered during mitochondrial inhibition: role of CO and bilirubin.

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    Orozco-Ibarra, Marisol; Estrada-Sánchez, Ana María; Massieu, Lourdes; Pedraza-Chaverrí, José

    2009-06-01

    Heme oxygenase (HO) catalyzes the breakdown of heme to iron, carbon monoxide (CO), and biliverdin, the latter being further reduced to bilirubin (BR). A protective role of the inducible isoform, HO-1, has been described in pathological conditions associated with reactive oxygen species (ROS) and oxidative damage. The aim of this study was to investigate the role of HO-1 in the neurotoxicity induced by the mitochondrial toxin 3-nitropropionic acid (3-NP) in primary cultures of cerebellar granule neurons (CGNs). Toxicity of 3-NP is associated with ROS production, and this metabolic toxin has been used to mimic pathological conditions such as Huntington's disease. We found that cell death caused by 3-NP exposure was exacerbated by inhibition of HO with tin mesoporphyrin (SnMP). In addition, HO-1 up-regulation induced by the exposure to cobalt protoporphyrin (CoPP) before the incubation with 3-NP, prevented the cell death and the increase in ROS induced by 3-NP. Interestingly, addition of SnMP to CoPP-pretreated CGNs exposed to 3-NP, abolished the protective effect of CoPP suggesting that HO activity was responsible for this protective effect. This was additionally supported by the fact that CORM-2, a CO-releasing molecule, and BR, were able to protect against cell death and the increase in ROS induced by 3-NP. Our data clearly show that HO-1 elicits in CGNs a neuroprotective action against the neurotoxicity of 3-NP and that CO and BR may be involved, at least in part, in this protective effect. The present results increase our knowledge about the role of HO-1 in neuropathological conditions. PMID:19063990

  16. Total bilirubin in nasogastric aspirates: A potential new indicator of postoperative gastrointestinal recovery

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    Go Miyano

    2013-01-01

    Full Text Available Background: The aim of our study was to investigate if total bilirubin (T-bil, amylase (Amy, and sodium (Na in nasogastric (NG aspirates can reflect gastrointestinal motility reliably. Materials and Methods: NG aspirates from all laparotomies lasting more than 150 min in children less than 12 months old were studied for 3 months. Color of aspirates and intensity of bowel sounds were graded every 3 h by nursing staff and aspirate samples for measuring T-bil, Amy, and Na were collected independently every 12 h until an oral fluid challenge was tolerated. Results: There were 26 subjects. Mean age at surgery was 5.6 months; mean body weight at surgery was 5.8 kg. No postoperative complications occurred. While there was no reduction in average volume of NG aspirates, color change was subjective, and bowel sounds could not be standardized, T-bil decreased over time (0d: 4.4 mg/dL; 0.5d: 2.7 mg/dL; 1.0d: 1.6 mg/dL; 1.5d: 1.3 mg/dL; 2.0d: 0.4 mg/dL; 2.5d: 0.33 mg/dL; 3.0d: 0.21 mg/dL; 3.5d: 0.15 mg/dL; 4.0d: 0.06 mg/dL; 4.5d: 0.05 mg/dL; 5.0d: 0.02 mg/dL; 5.5d: 0.02 mg/dL; 6.0d: 0.01 mg/dL. Amy and Na were inconclusive. Conclusion: T-bil levels in NG aspirates may be useful as a reliable objective quantitative marker of gastrointestinal motility postoperatively.

  17. Correlation of dysfunction of nonmuscle myosin IIA with increased induction of Cyp1a1 in Hepa-1 cells.

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    Ebina, Masayuki; Shibazaki, Masahiko; Kudo, Kyoko; Kasai, Shuya; Kikuchi, Hideaki

    2011-03-01

    The aryl hydrocarbon receptor (AhR) is one of the best known ligand-activated transcription factors and it induces Cyp1a1 transcription by binding with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recent focus has been on the relationship of AhR with signaling pathways that modulate cell shape and migration. In nonmuscle cells, nonmuscle myosin II is one of the key determinants of cell morphology, but it has not been investigated whether its function is related to Cyp1a1 induction. In this study, we observed that (-)-blebbistatin, which is a specific inhibitor of nonmuscle myosin II, increased the level of CYP1A1-mRNA in Hepa-1 cells. Comparison of (-)-blebbistatin with (+)-blebbistatin, which is an inactive enantiomer, indicated that the increase of CYP1A1-mRNA was due to nonmuscle myosin II inhibition. Subsequent knockdown experiments observed that reduction of nonmuscle myosin IIA, which is only an isoform of nonmuscle myosin II expressed in Hepa-1 cells, was related to the enhancement of TCDD-dependent Cyp1a1 induction. Moreover, chromatin immunoprecipitation assay indicated that the increase of Cyp1a1 induction was the result of transcriptional activation due to increased binding of AhR and RNA polymerase II to the enhancer and proximal promoter regions of Cyp1a1, respectively. These findings provide a new insight into the correlation between the function of nonmuscle myosin II and gene induction. PMID:21216307

  18. Strong synergistic induction of CYP1A1 expression by andrographolide plus typical CYP1A inducers in mouse hepatocytes

    International Nuclear Information System (INIS)

    The effects of andrographolide, the major diterpenoid constituent of Andrographis paniculata, on the expression of cytochrome P450 superfamily 1 members, including CYP1A1, CYP1A2, and CYP1B1, as well as on aryl hydrocarbon receptor (AhR) expression in primary cultures of mouse hepatocytes were investigated in comparison with the effects of typical CYP1A inducers, including benz[a]anthracene, β-naphthoflavone, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Andrographolide significantly induced the expression of CYP1A1 and CYP1A2 mRNAs in a concentration-dependent manner, as did the typical CYP1A inducers, but did not induce that of CYP1B1 or AhR. Interestingly, andrographolide plus the typical CYP1A inducers synergistically induced CYP1A1 expression, and the synergism was blocked by an AhR antagonist, resveratrol. The CYP1A1 enzyme activity showed a similar pattern of induction. This is the first report that shows that andrographolide has a potency to induce CYP1A1 enzyme and indicates that andrographolide could be a very useful compound for investigating the regulatory mechanism of the CYP1A1 induction pathway. In addition, our findings suggest preparing advice for rational administration of A. paniculata, according to its ability to induce CYP1A1 expression

  19. Osteogenesis imperfecta IIC caused by a novel heterozygous mutation in the C-propeptide region of COL1A1

    OpenAIRE

    Takagi, Masaki; Matsushita, Mitsuru; Nishimura, Gen; Hasegawa, Tomonobu

    2014-01-01

    Osteogenesis imperfecta IIC (OI IIC), which is a rare variant of lethal OI that has been considered to be an autosomal recessive trait, is characterized by twisted, slender long bones with dense metaphyseal margins. Here, we report a typical case of OI IIC caused by a novel heterozygous mutation in the C-propeptide region of COL1A1. OI IIC seems to be caused by a dominant mutation of COL1A1.

  20. PREDICTION OF SIGNIFICANT NEONATAL HYPERBILIRUBINAEMIA IN HEALTHY TERM NEW BORNS USING 22-26 HOURS’ SPECIFIC SERUM BILIRUBIN – A PROSPECTIVE STUDY

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    Reddy

    2016-03-01

    Full Text Available INTRODUCTION Hyperbilirubinemia invariably occurs in the newborns and is discerned as clinical jaundice in nearly 50% of infants. It is a cause of concern not only for the parents but also for the paediatricians. Bilirubin production is 2-3 times higher in normal term newborns compared with adults. The colour in jaundice usually results from accumulation of unconjugated, non-polar, lipid soluble, bilirubin pigment in the skin which is formed from haemoglobin by the action of heme oxygenase, biliverdin reductase and non-enzymatic reducing agents in the reticulo-endothelial cells. AIMS & OBJECTIVE To determine hour specific serum bilirubin (22-26 hrs which will predict, subsequent significant hyperbilirubinemia in healthy term newborns. MATERIALS & METHODS A total of 250 healthy full term newborns were enrolled into the study. First bilirubin estimation (TSB 1 was estimated at 22- 26 hrs. The neonates were followed up clinically every 12 hrs for 72 hrs (till discharge. Second bilirubin estimation (TSB S was done whenever clinical suspicion of jaundice was present (usually at 72 hours. Depending upon the TSB 1 value, the infants were evaluated by using two available protocols (Arbitrary cut off value of 5 mg/dl and average value of 4.06 mg%. Sensitivity, specificity, negative and positive predictive values and likelihood ratio of the test were calculated. P-value was used to determine the level of significance. RESULTS Of 250 neonates included in the study, 13 neonates developed hyperbilirubinemia and were subjected to phototherapy. No infants with average bilirubin value of ≤4.06 mg% developed subsequent hyperbilirubinemia. However, 2 infants with arbitrary cut off value of ≤5 mg/dl developed hyperbilirubinemia. There was significant difference in TSB I value of neonates who subsequently did and those who did not developed significant hyperbilirubinemia (P-value-<0.01. The negative predictive value to these two applied protocol is very high

  1. The Relationship between the Behavioral Hearing Thresholds and Maximum Bilirubin Levels at Birth in Children with a History of Neonatal Hyperbilirubinemia

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    Rasool Panahi

    2013-06-01

    Full Text Available Introduction: Neonatal hyperbilirubinemia is one of the most important factors affecting the auditory system and can cause sensorineural hearing loss. This study investigated the relationship between behavioral hearing thresholds in children with a history of jaundice and the maximum level of bilirubin concentration in the blood.   Materials and Methods: This study was performed on 18 children with a mean age of 5.6 years and with a history of neonatal hyperbilirubinemia. Behavioral hearing thresholds, transient evoked emissions and brainstem evoked responses were evaluated in all children.   Results: Six children (33.3 % had normal hearing thresholds and the remaining (66.7 % had some degree of hearing loss. There was no significant relationship (r= -0.28, P= 0.09 between the mean total bilirubin levels and behavioral hearing thresholds in all samples. A transient evoked emission was seen only in children with normal hearing thresholds however in eight cases brainstem evoked responses had not detected.   Conclusion:  Increased blood levels of bilirubin at the neonatal period were potentially one of the causes of hearing loss. There was a lack of a direct relationship between neonatal bilirubin levels and the average hearing thresholds which emphasizes on the necessity of monitoring the various amounts of bilirubin levels.

  2. Evaluating the role of indirect bilirubin, urobilinogen and Shine AND Lal index as an alternative screening tool for beta thalassemia minor

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    Ridham A. Khanderia

    2015-06-01

    Methods: The present study was conducted on 100 (n=100 subjects in blood bank, department of pathology, government medical college Rajkot, Gujarat, India. In first group 50 subjects (Thalassemia minor were selected while in second group 50 (n2=50 normal individuals from hospital staff were selected. Complete-haemogram, serum-direct, indirect and total bilirubin, urine urobilinogen and their sensitivity and specificity were calculated. Results: Of the 50 cases in test group, 41 had higher Indirect Bilirubin level (>0.7 mg/dl, 35 had high urobilinogen level (>1 mg/dl. In control group out of 50 cases, 3 had high indirect bilirubin levels, 4 had high urobilinogen levels. Indirect-bilirubin had sensitivity of 82%, specificity of 94%. Urobilinogen showed sensitivity of 70% and specificity of 92%. Conclusion: Indirect bilirubin and urine-urobilinogen is a valuable, cost-effective screening test for beta-thalassemia-trait with sensitivity and specificity comparable to RBC indices. [Int J Res Med Sci 2015; 3(3.000: 730-737

  3. Suppression of CYP1A1 expression by naringenin in murine Hepa-1c1c7 cells.

    Science.gov (United States)

    Kim, Ji Young; Han, Eun Hee; Shin, Dong Weon; Jeong, Tae Cheon; Lee, Eung Seok; Woo, Eun-Rhan; Jeong, Hye Gwang

    2004-08-01

    Naringenin, dietary flavonoid, is antioxidant constituents of many citrus fruits. In the present study, we investigated the effect of naringenin on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible CYP1A1 gene expression in mouse hepatoma Hepa-1c1c7 cells. Naringenin alone did not affect CYP1A1-specific 7-ethoxyresorufin O-deethylase (EROD) activity. In contrast, the TCDD-inducible EROD activities were markedly reduced upon concomitant treatment with TCDD and naringenin in a dose dependent manner. TCDD-induced CYP1A1 mRNA level was also markedly suppressed by naringenin. A transient transfection assay using dioxin-response element (DRE)-linked luciferase and electrophoretic mobility shift assay revealed that naringenin reduced transformation of the aryl hydrocarbons receptor(AhR) to a form capable of specifically binding to the DRE sequence in the promoter of the CYP1A1 gene. These results suggest the down regulation of the CYP1A1 gene expression by either naringenin in Hepa-1c1c7 cells might be antagonism of the DRE binding potential of nuclear AhR. PMID:15460448

  4. Suppression of CYP1A1 expression by 4-nonylphenol in murine Hepa-1c1c7 cells.

    Science.gov (United States)

    Jeong, H G; Kim, J Y; Choi, C Y; You, H J; Hahm, K

    2001-04-10

    This study investigated the effects that 4-nonylphenol (NP) has on CYP1A1 expression in Hepa-1c1c7 cell cultures. NP alone did not affect CYP1A1-specific 7-ethoxyresorufin-O-deethylase (EROD) activity. In contrast, the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible EROD activities were markedly reduced upon concomitant treatment with TCDD and NP in a dose-dependent manner. Treatment with tamoxifen, an anti-estrogen that acts through the estrogen receptor, did not affect the suppressive effects that NP has on TCDD-inducible EROD activity. The TCDD-inducible CYP1A1 mRNA levels were markedly suppressed upon concomitant treatment with TCDD and NP that is consistent with their effects on EROD activity. A transient transfection assay using dioxin-response element (DRE)-linked luciferase and an electrophoretic mobility shift assay revealed that NP reduced the transformation of the aryl hydrocarbon (Ah) receptor to a form capable of binding specifically to the DRE sequence of the CYP1A1 gene promoter. These results suggest that the down-regulation of CYP1A1 gene expression by NP in Hepa-1c1c7 cells might be an antagonism of the DRE-binding potential of the nuclear Ah receptor, but is not mediated through the estradiol receptor. PMID:11248424

  5. The role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity.

    Science.gov (United States)

    Wu, Qiangen; Ning, Baitang; Xuan, Jiekun; Ren, Zhen; Guo, Lei; Bryant, Matthew S

    2016-06-24

    Amiodarone is a widely used potent antiarrhythmic for the treatment of cardiac disease; however, its use is often discontinued due to numerous adverse effects, including hepatotoxicity. To investigate the role of drug metabolism in this liver toxicity, amiodarone and its major metabolite desethylamiodarone were incubated with HepG2 cells overexpressing a series of cytochrome P450 (CYP) isoforms. Significantly higher cytotoxicity of amiodarone was observed in HepG2 cells overexpressing CYP3A4 or CYP1A1, compared with that observed in empty vector transduced control cells. Further, higher levels of the more potent hepatotoxic metabolite desethylamiodarone were detected in CYP3A4 or CYP1A1 expressed cells. The CYP3A4 inhibitor ketoconazole and the CYP1A1 inhibitor α-naphthoflavone drastically inhibited the metabolism of amiodarone to desethylamiodarone. Along with the inhibition of CYP1A1 or CYP3A4, the cytotoxicity of amiodarone was significantly reduced. These data indicate that the metabolism of amiodarone to desethylamiodarone by CYP1A1 or CYP3A4 plays an important role in the hepatocellular toxicity of amiodarone. PMID:27113703

  6. A COMPARISON STUDY: CORD SERUM ALBUMIN IS COMPARED WITH CORD SERUM BILIRUBIN AS A RISK INDICATOR IN PREDICTING NEONATAL JAUNDICE

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    Venkatamurthy

    2014-04-01

    Full Text Available : OBJECTIVE: 1. Comparing Cord Serum Albumin level (CSA with Cord Serum Bilirubin (CSB in predicting neonatal hyperbilirubinemia. 2. To know the sensitivity, specificity, Positive predictive value and negative predictive value of CSA and CSB in predicting neonatal jaundice in term neonates. METHOD: Prospective study was performed on 174 healthy term neonates. Relevant maternal history is collected. Cord blood was collected from the healthy term neonates at birth, CSA and CSB measured. Neonate was assessed clinically every day. Total Serum Bilirubin (TSB and blood group were assessed in neonate during 72-96 hours of life. TSB value ≥17mg/dl is considered Neonatal Hyperbilirubinemia (NH which requires intervention like phototherapy (PT or Exchange transfusion (ExT. RESULT: Study cohort is grouped in Group 1, Group 2 and Group 3 based on Cord Serum Albumin level ≤2.8g/dl, 2.9-3.3g/dl and ≥3.4g/dl, respectively. Based on CSB, study cohort divided into neonates with CSB ≤ 2mg/dl and CSB ≥ 2.1mg/dl. Statistical analysis done for correlation of CSA and CSB with NH. Statistical significance is seen for both CSA and CSB. CONCLUSION: Both CSA and CSB are equally effective in predicting NH at birth. These study variables can be considered as neonatal screening tool for NH for term neonates.

  7. A transcriptome analysis identifies molecular effectors of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells

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    Giraudi Pablo

    2009-11-01

    Full Text Available Abstract Background The deposition of unconjugated bilirubin (UCB in selected regions of the brain results in irreversible neuronal damage, or Bilirubin Encephalopathy (BE. Although UCB impairs a large number of cellular functions in other tissues, the basic mechanisms of neurotoxicity have not yet been fully clarified. While cells can accumulate UCB by passive diffusion, cell protection may involve multiple mechanisms including the extrusion of the pigment as well as pro-survival homeostatic responses that are still unknown. Results Transcriptome changes induced by UCB exposure in SH-SY5Y neuroblastoma cell line were examined by high density oligonucleotide microarrays. Two-hundred and thirty genes were induced after 24 hours. A Gene Ontology (GO analysis showed that at least 50 genes were directly involved in the endoplasmic reticulum (ER stress response. Validation of selected ER stress genes is shown by quantitative RT-PCR. Analysis of XBP1 splicing and DDIT3/CHOP subcellular localization is presented. Conclusion These results show for the first time that UCB exposure induces ER stress response as major intracellular homeostasis in surviving neuroblastoma cells in vitro.

  8. Involvement of CYP1A1, GST, 72TP53 polymorphisms in the pathogenesis of thyroid nodules.

    Science.gov (United States)

    Reis, A A S; Silva, D M; Curado, M P; da Cruz, A D

    2010-01-01

    Specific genotypes appear to be related to the development of thyroid disease. We examined whether polymorphisms of the genes CYP1A1, GSTM1, GSTT1, and TP53 at codon 72 are associated with increased risk for thyroid nodules. Blood samples were obtained from 122 thyroid patients with nodules and from 134 healthy control individuals from Goiânia city, GO, Brazil. We found no significant association of CYP1A1m1 and CYP1A1m2 genotypes with thyroid diseases (P > 0.05). The null genotypes of GSTM1 and GSTT1 genes were predominant in patients with nodules, indicating that individuals that possess these genotypes have a predisposition for thyroid disease. The genotype p53Arg Arg was associated with a low risk for thyroid cancer (OR = 0.15; P benefit from treatment, depending on specific polymorphic profiles. PMID:21086258

  9. NOVEL SPLICING MUTATION OF COL1A1 GENE CAUSING OSTEOGENESIS IMPERFECTA TYPE I IN CHINESE PEDIGREE

    Institute of Scientific and Technical Information of China (English)

    WU Xiao-lin; GU Ming-min; CUI Bing; LI Xi-hua; LU Zhen-yu; WANG Zhu-gang; YUAN Wen-tao; SONG Huai-dong

    2007-01-01

    Objective To detect the peculiar mutation in a Chinese family with osteogenesis imperfecta,COL1A1 and COL1A2 being analysed. Methods A genome screen was undertaken covering COL1A1 at 17q21-22 and COL1A2 at 7q22.1. The Linkage ( Version 5.1 ) was used for 2-point analysis. DNA sequencing was used to screen and identify the mutation. Results A linkage to the markers on chromosome 17q21-22 was observed. Sequence analysis of COL1A1 revealed a splicing mutation ( IVS8-2A > G) that converted the 3' end of intron 8 from AG to GG. Conclusion This mutation ( IVS 8-2A > G) is novel, and has not yet been registered in the Human Type Ⅰ and Type Ⅲ Collagen Mutations Database.

  10. Improvement of enzymatic saccharification yield in Arabidopsis thaliana by ectopic expression of the rice SUB1A-1 transcription factor

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    Lizeth Núñez-López

    2015-03-01

    Full Text Available Saccharification of polysaccharides releases monosaccharides that can be used by ethanol-producing microorganisms in biofuel production. To improve plant biomass as a raw material for saccharification, factors controlling the accumulation and structure of carbohydrates must be identified. Rice SUB1A-1 is a transcription factor that represses the turnover of starch and postpones energy-consuming growth processes under submergence stress. Arabidopsis was employed to test if heterologous expression of SUB1A-1 or SUB1C-1 (a related gene can be used to improve saccharification. Cellulolytic and amylolytic enzymatic treatments confirmed that SUB1A-1 transgenics had better saccharification yield than wild-type (Col-0, mainly from accumulated starch. This improved saccharification yield was developmentally controlled; when compared to Col-0, young transgenic vegetative plants yielded 200–300% more glucose, adult vegetative plants yielded 40–90% more glucose and plants in reproductive stage had no difference in yield. We measured photosynthetic parameters, starch granule microstructure, and transcript abundance of genes involved in starch degradation (SEX4, GWD1, juvenile transition (SPL3-5 and meristematic identity (FUL, SOC1 but found no differences to Col-0, indicating that starch accumulation may be controlled by down-regulation of CONSTANS and FLOWERING LOCUS T by SUB1A-1 as previously reported. SUB1A-1 transgenics also offered less resistance to deformation than wild-type concomitant to up-regulation of AtEXP2 expansin and BGL2 glucan-1,3,-beta-glucosidase. We conclude that heterologous SUB1A-1 expression can improve saccharification yield and softness, two traits needed in bioethanol production.

  11. Interaction between maternal passive smoking during pregnancy and CYP1A1 and GSTs polymorphisms on spontaneous preterm delivery.

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    Yi-Juan Luo

    Full Text Available OBJECTIVE: The present study aimed to examine the association between maternal passive smoking during pregnancy and the risk of spontaneous PTD and to explore the potential interaction of the single or joint gene polymorphism of CYP1A1 and GSTs with maternal passive smoking on the risk of spontaneous PTD. METHOD: We investigated whether the association between maternal passive smoking and PTD can be modified by 2 metabolic genes, i.e. cytochrome P4501A1 (CYP1A1 and glutathione S-transferases (GSTs, in a case-control study with 198 spontaneous preterm and 524 term deliveries in Shenzhen and Foshan, China. We used logistic regression to test gene-passive smoking interaction, adjusting for maternal socio-demographics and prepregnancy body mass index. RESULTS: Overall, maternal passive smoking during pregnancy was associated with higher risk of PTD (adjusted odds ratio = 2.20 [95% confidence interval: 1.56-3.12]. This association was modified by CYP1A1 and GSTs together, but not by any single genotype. For cross-categories of CYP1A1 Msp I and GSTs, maternal passive smoking was associated with higher risk of PTD among those women with CYP1A1 "TC/CC"+ GSTs "null", but not among women with other genotypes; and this interaction was significant (OR = 2.66 [95% CI: 1.19-5.97]; P-value: 0.017. For cross-categories of CYP1A1 BsrD I and GSTs, maternal passive smoking was associated with higher risk of PTD only among those women with CYP1A1"AG/GG"+ GSTs "null", but not among women with other genotypes; and this interaction was significant (OR = 3.00 [95% CI: 1.17-7.74]; P-value: 0.023. CONCLUSIONS: Our findings suggest that the combined genotypes of CYP1A1 and GSTs can help to identify vulnerable pregnant women who are subject to high risk of spontaneous PTD due to passive smoking.

  12. COL1A1 transgene expression in stably transfected osteoblastic cells. Relative contributions of first intron, 3'-flanking sequences, and sequences derived from the body of the human COL1A1 minigene

    Science.gov (United States)

    Breault, D. T.; Lichtler, A. C.; Rowe, D. W.

    1997-01-01

    Collagen reporter gene constructs have be used to identify cell-specific sequences needed for transcriptional activation. The elements required for endogenous levels of COL1A1 expression, however, have not been elucidated. The human COL1A1 minigene is expressed at high levels and likely harbors sequence elements required for endogenous levels of activity. Using stably transfected osteoblastic Py1a cells, we studied a series of constructs (pOBColCAT) designed to characterize further the elements required for high level of expression. pOBColCAT, which contains the COL1A1 first intron, was expressed at 50-100-fold higher levels than ColCAT 3.6, which lacks the first intron. This difference is best explained by improved mRNA processing rather than a transcriptional effect. Furthermore, variation in activity observed with the intron deletion constructs is best explained by altered mRNA splicing. Two major regions of the human COL1A1 minigene, the 3'-flanking sequences and the minigene body, were introduced into pOBColCAT to assess both transcriptional enhancing activity and the effect on mRNA stability. Analysis of the minigene body, which includes the first five exons and introns fused with the terminal six introns and exons, revealed an orientation-independent 5-fold increase in CAT activity. In contrast the 3'-flanking sequences gave rise to a modest 61% increase in CAT activity. Neither region increased the mRNA half-life of the parent construct, suggesting that CAT-specific mRNA instability elements may serve as dominant negative regulators of stability. This study suggests that other sites within the body of the COL1A1 minigene are important for high expression, e.g. during periods of rapid extracellular matrix production.

  13. Thymoquinone, an active constituent of Nigella sativa seeds, binds with bilirubin and protects mice from hyperbilirubinemia and cyclophosphamide-induced hepatotoxicity.

    Science.gov (United States)

    Laskar, Amaj A; Khan, Masood A; Rahmani, Arshad H; Fatima, Sana; Younus, Hina

    2016-08-01

    Some reports indicate that thymoquinone (TQ), the main constituent of Nigella sativa seeds, is hepatoprotective. The aim of this study was to determine whether TQ is able to bind directly to bilirubin, and whether TQ or liposomal formulation of TQ (Lip-TQ) can reduce cyclophosphamide (CYP)-induced liver toxicity, serum bilirubin level in mice. The binding of TQ with bilirubin was studied by UV-VIS, fluorescence and Near-UV CD spectroscopy. Inhibition of binding of bilirubin to erythrocytes by TQ was also examined. To increase the in vivo efficacy, Lip-TQ was prepared and used against CYP-induced toxicity. The protective role of TQ or Lip-TQ against CYP-induced toxicity was assessed by determining the liver function parameters, the levels of superoxide dismutase (SOD) and catalase (CAT), and histological studies. It was found that TQ binds to bilirubin and significantly inhibits the binding of bilirubin to erythrocytes. Lip-TQ (10 mg/kg) significantly reduced the levels of aspartate transaminase (AST) from 254 ± 48 to 66 ± 18 IU/L (P < 0.001), alanine transaminase (ALT) from 142 ± 28 to 47.8 ± 16 IU/L (P < 0.05) and serum bilirubin from 2.8 ± 0.50 to 1.24 ± 0.30 mg/dl (P < 0.05). Treatment with Lip-TQ reduced the CYP-induced inflammation and hemorrhage in liver tissues. Moreover, treatment with free or Lip-TQ protected the activity of SOD and CAT in CYP-injected mice. Therefore, TQ can reduce the level of bilirubin in systemic circulation in disease conditions that lead to hyperbilirubinemia and liver toxicity and hence may be used as a supplement in the treatment of liver ailments. PMID:27265787

  14. Low solubility of unconjugated bilirubin in dimethylsulfoxide – water systems: implications for pKa determinations

    OpenAIRE

    Ostrow J Donald; Mukerjee Pasupati; Tiribelli Claudio

    2002-01-01

    Abstract Background Aqueous pKa values of unconjugated bilirubin are important determinants of its solubility and transport. Published pKa data on an analog, mesobilirubin-XIIIα, studied by 13C-NMR in buffered solutions containing 27 and 64 vol% (C2H3)2SO because of low aqueous solubility of mesobilirubin, were extrapolated to obtain pKa values in water of 4.2 and 4.9. Previous chloroform-water partition data on bilirubin diacid led to higher estimates of its pKa, 8.12 and 8.44, and its aqueo...

  15. Adjusting CA19-9 values to predict malignancy in obstructive jaundice: Influence of bilirubin and C-reactive protein

    Institute of Scientific and Technical Information of China (English)

    Gaetano La Greca; Maria Sofia; Rosario Lombardo; Saverio Latteri; Agostino Ricotta; Stefano Puleo; Domenico Russello

    2012-01-01

    AIM:To find a possible relationship between inflammation and CA19-9 tumor marker by analyzing data from patients with benign jaundice (BJ) and malignant jaundice (MJ).METHODS:All patients admitted for obstructive jaundice,in the period 2005-2009,were prospectively enrolled in the study,obtaining a total of 102 patients.On admission,all patients underwent complete standard blood test examinations including C-reactive protein (CRP),bilirubin,CA19-9.Patients were considered eligible for the study when they presented obstructive jaundice confirmed by instrumental examinations and increased serum bilirubin levels (total bilirubin > 2.0 mg/dL).The standard cut-off level for CA19-9 was 32 U/mL,whereas for CRP this was 1.5 mg/L.The CA19-9 level was adjusted by dividing it by the value of serum bilirubin or by the CRP value.The patients were divided into 2 groups,MJ and BJ,and after the adjustment a comparison between the 2 groups of patients was performed.Sensitivity,specificity and positive predictive values were calculated before and after the adjustment.RESULTS:Of the 102 patients,51 were affected by BJ and 51 by MJ.Pathologic CA19-9 levels were found in 71.7% of the patients.In the group of 51 BJ patients there were 29 (56.9%) males and 22 (43.1%) females with a median age of 66 years (range 24-96 years),whereas in the MJ group there were 24 (47%) males and 27 (53%) females,with a mean age of 70 years (range 30-92 years).Pathologic CA19-9 serum level was found in 82.3% of MJ.CRP levels were pathologic in 66.6% of the patients with BJ and in 49% with MJ.Bilirubin and CA19-9 average levels were significantly higher in MJ compared with BJ (P =0.000 and P =0.02),while the CRP level was significantly higher in BJ (P =0.000).Considering a CA19-9 cut-off level of 32 U/mL,82.3% in the MJ group and 54.9% in the BJ group were positive for CA19-9 (P =0.002).A CA19-9 cut-off of 100 U/mL increases the difference between the two groups:35.3% in BJ and 68.6

  16. CYP1A1 genotypes and haplotypes and risk of oral cancer: a case-control study in South Indians

    Directory of Open Access Journals (Sweden)

    Lakshmi Balaji

    2012-01-01

    Full Text Available The CYP1A1 gene encodes for the enzyme, aryl hydrocarbon hydroxylase, which is involved in the biotransformation of various aromatic tobacco precarcinogens. In the present study, the association between CYP1A1 gene polymorphisms (IVS1-728G > A, Thr461Asn and Ile462Val, and the risk of oral cancer, was examined among 157 patients with oral cancer and 132 age-matched controls, in a south Indian population. The strength of the association between CYP1A1 variants and oral cancer was estimated by logistic regression. It was found that Thr461Asn was not polymorphic. Both IVS1-728G > A and Ile462Val frequencies were consistent with Hardy-Weinberg equilibrium in the control group. There were no significant differences in genotype or haplotype frequencies between controls and cases with oral cancer. Hence, CYP1A1 SNPs can be considered as not being associated with oral cancer at either the genotype or haplotype levels in the population studied.

  17. Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: an analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial

    DEFF Research Database (Denmark)

    Andersson, Charlotte; Weeke, Peter; Fosbøl, Emil Loldrup;

    2009-01-01

    Low levels of bilirubin are associated with an increased risk of cardiovascular adverse events. Weight reduction is known to reduce several cardiovascular risk factors, but effects on bilirubin levels have not been reported. We studied the response of weight loss therapy with sibutramine and life...

  18. Characterization of the Ala62Pro polymorphic variant of human cytochrome P450 1A1 using recombinant protein expression

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Heon; Kang, Sukmo [College of Veterinary Medicine, BK21plus Program for Creative Veterinary Science Research, and Research Institute for Veterinary Science, Seoul National University, Seoul (Korea, Republic of); Dong, Mi Sook [School of Life Sciences and Biotechnology, Korea University, Seoul (Korea, Republic of); Park, Jung-Duck [College of Medicine, Chung-Ang University, Seoul (Korea, Republic of); Park, Jinseo; Rhee, Sangkee [College of Agriculture of Life Science, Seoul National University, Seoul (Korea, Republic of); Ryu, Doug-Young, E-mail: dyryu@snu.ac.kr [College of Veterinary Medicine, BK21plus Program for Creative Veterinary Science Research, and Research Institute for Veterinary Science, Seoul National University, Seoul (Korea, Republic of)

    2015-06-15

    Cytochrome P450 (CYP) 1A1 is a heme-containing enzyme involved in detoxification of hydrophobic pollutants. Its Ala62Pro variant has been identified previously. Ala62 is located in α-helix A of CYP1A1. Residues such as Pro and Gly are α-helix breakers. In this study, the Ala62Pro variant was characterized using heterologous expression. E. coli expressing the Ala62Pro variant, and the purified variant protein, had lower CYP (i.e. holoenzyme) contents than their wild-type (WT) equivalents. The CYP variant from E. coli and mammalian cells exhibited lower 7-ethoxyresorufin O-dealkylation (EROD) and benzo[a]pyrene hydroxylation activities than the WT. Enhanced supplementation of a heme precursor during E. coli culture did not increase CYP content in E. coli expressing the variant, but did for the WT. As for Ala62Pro, E. coli expressing an Ala62Gly variant had a lower CYP content than the WT counterpart, but substitution of Ala62 with α-helix-compatible residues such as Ser and Val partially recovered the level of CYP produced. Microsomes from mammalian cells expressing Ala62Pro and Ala62Gly variants exhibited lower EROD activities than those expressing the WT or Ala62Val variant. A region harboring α-helix A has interactions with another region containing heme-interacting residues. Site-directed mutagenesis analyses suggest the importance of interactions between the two regions on holoenzyme expression. Together, these findings suggest that the Ala62Pro substitution leads to changes in protein characteristics and function of CYP1A1 via structural disturbance of the region where the residue is located. - Highlights: • Ala62 is located in α-helix A of the carcinogen-metabolizing enzyme CYP1A1. • Pro acts as an α-helix breaker. • A variant protein of CYP1A1, Ala62Pro, had lower heme content than the wild-type. • The variant of CYP1A1 had lower enzyme activities than the wild-type.

  19. Characterization of the Ala62Pro polymorphic variant of human cytochrome P450 1A1 using recombinant protein expression

    International Nuclear Information System (INIS)

    Cytochrome P450 (CYP) 1A1 is a heme-containing enzyme involved in detoxification of hydrophobic pollutants. Its Ala62Pro variant has been identified previously. Ala62 is located in α-helix A of CYP1A1. Residues such as Pro and Gly are α-helix breakers. In this study, the Ala62Pro variant was characterized using heterologous expression. E. coli expressing the Ala62Pro variant, and the purified variant protein, had lower CYP (i.e. holoenzyme) contents than their wild-type (WT) equivalents. The CYP variant from E. coli and mammalian cells exhibited lower 7-ethoxyresorufin O-dealkylation (EROD) and benzo[a]pyrene hydroxylation activities than the WT. Enhanced supplementation of a heme precursor during E. coli culture did not increase CYP content in E. coli expressing the variant, but did for the WT. As for Ala62Pro, E. coli expressing an Ala62Gly variant had a lower CYP content than the WT counterpart, but substitution of Ala62 with α-helix-compatible residues such as Ser and Val partially recovered the level of CYP produced. Microsomes from mammalian cells expressing Ala62Pro and Ala62Gly variants exhibited lower EROD activities than those expressing the WT or Ala62Val variant. A region harboring α-helix A has interactions with another region containing heme-interacting residues. Site-directed mutagenesis analyses suggest the importance of interactions between the two regions on holoenzyme expression. Together, these findings suggest that the Ala62Pro substitution leads to changes in protein characteristics and function of CYP1A1 via structural disturbance of the region where the residue is located. - Highlights: • Ala62 is located in α-helix A of the carcinogen-metabolizing enzyme CYP1A1. • Pro acts as an α-helix breaker. • A variant protein of CYP1A1, Ala62Pro, had lower heme content than the wild-type. • The variant of CYP1A1 had lower enzyme activities than the wild-type

  20. A meaningful appraisal of cholestasis in serum total bilirubin, cholyglyine, alpha-fetoprotein and carbohydrate antigen19-9

    International Nuclear Information System (INIS)

    Objective: Appraise the clinical significant how the serum total bilirubin (TB), cholylglycine (CG), α-fetoprotein (AFP), carbohydrate antigen 19-9 (CA 19-9) have their concentration changes in the pathological changes of intrahepatic cholestasis through a combined detection to them. Methods: The serum samples from 96 cases of chronic virus hepatitis, 26 cases of liver cirrhosis and 50 cases of normal people were detected by biochemistry for TB, by radioimmunoassay for CG, by electro chemiluminescence for AFP and CA19-9. Results: There is no obvious deference of serum TB in the group without intrahepatic cholestasis, the group of cholestasis without clinical symptoms and the control groups. There is also a marked deference (P<0.01) in the group of cholestasis with clinical symptoms, the group of liver cirrhosis, the group without intrahepatic cholestasis, the control group and the group of cholestasis without clinical symptoms. the serum CG from the groups of intrahepatic cholestasis, the group without intrahepatic cholestasis, and the control group all show a very obvious deference (P<0.01). The serum CA19-9 from the groups of intrahepatic cholestasis and the group without intrahepatic cholestasis show an obvious deference. The serum AFP, CA19-9 from the group of liver cancer show a very obvious deference (P<0.01). Conclusions: In clinc bilirubin is a rough index to reflect cholestasis. It has its own limit in deciding patterns of deferent bile obstruction. In the early stage of intrahepatic cholestasis, that the index of CG is high obviously points out existence of intrahepatic cholestasis. CG and the liver impairment are well interrelated and they are comparatively sensitive indexes of liver function. AFP reflects the regeneration of the liver cell necrosis and it means alarm to the seriousness of intrahepatic cholestasis. CA19-9 is a marker of tumor of biliary tract. The index increase through an initial observation is interrelated to the seriousness of

  1. Higher plasma bilirubin predicts veno-occlusive disease in early childhood undergoing hematopoietic stem cell transplantation with cyclosporine

    Science.gov (United States)

    Kim, Kwi Suk; Moon, Aree; Kang, Hyoung Jin; Shin, Hee Young; Choi, Young Hee; Kim, Hyang Sook; Kim, Sang Geon

    2016-01-01

    AIM: To analyze the association between plasma bilirubin levels and veno-occlusive disease (VOD) in non-adult patients undergoing hematopoietic stem cell transplantation (HSCT) during cyclosporine therapy. METHODS: A total of 123 patients taking cyclosporine were evaluated using an electronic medical system at the Seoul National University Children’s Hospital from the years 2004 through 2011. Patients were grouped by age and analyzed for incidence and type of adverse drug reactions (ADRs) including VOD. RESULTS: The HSCT patients were divided into three age groups: G#1 ≥ 18; 9 ≤ G#2 ≤ 17; and G#3 ≤ 8 years of age). The majority of transplant donor types were cord blood transplantations. Most prevalent ADRs represented acute graft-vs-host disease (aGVHD) and VOD. Although the incidences of aGVHD did not vary among the groups, the higher frequency ratios of VOD in G#3 suggested that an age of 8 or younger is a risk factor for developing VOD in HSCT patients. After cyclosporine therapy, the trough plasma concentrations of cyclosporine were lower in G#3 than in G#1, indicative of its increased clearance. Moreover, in G#3 only, a maximal total bilirubin level (BILmax) of ≥ 1.4 mg/dL correlated with VOD incidence after cyclosporine therapy. CONCLUSION: HSCT patients 8 years of age or younger are more at risk for developing VOD, diagnosed as hyperbilirubinemia, tender hepatomegaly, and ascites/weight gain after cyclosporine therapy, which may be represented by a criterion of plasma BILmax being ≥ 1.4 mg/dL, suggestive of more sensitive VOD indication in this age group. PMID:27358786

  2. 用于清除胆红素的磁性亲和分离方法%Study on Removal of Bilirubin with Magnetic Affinity Separation Technique

    Institute of Scientific and Technical Information of China (English)

    徐辉; 张国亮; 张凤宝; 王淑兰

    2003-01-01

    An affinity adsorbent, Cibacron Blue 3GA immobilized magnetic polyvinyl alcohol (PVA) microsphereswas used for bilirubin removal taking the advantage of easy separation of magnetic sorbent from the biosystem.Fe3 O4 superparamagnetic particles was synthesized with hydrothermal reaction of ferrous chloride (FeCl2) and ferricchloride (FeCl3). Such magnetic particles are then encapsulated in biocompatible PVA to form magnetic polymermicrospheres sized from 2 to 15 nm with hydroxyl groups on its surface. Cibacron Blue 3GA, a dye-ligand, wascovalently coupled with the polyvinyl alcohol through the nucleophilic reaction between the chloride of its triazinering and the hydroxyl groups of PVA molecules under alkaline condition. The affinity adsorbent carried 21.1 μmolCibacron Blue 3GA per gram magnetic polymer microspheres was used to remove unconjugated and conjugatedbilirubin from the solution which was composed of bilirubin or bilirubin and protein. After the adsorption, theadsorbent loaded with bilirubin was removed easily in the magnetic field.

  3. Indicators of inflammation and cellular damage in chronic asymptomatic or oligosymptomatic alcoholics: correlation with alteration of bilirubin and hepatic and pancreatic enzymes

    Directory of Open Access Journals (Sweden)

    Borini Paulo

    1999-01-01

    Full Text Available Biochemical and hematimetric indicators of inflammation and cell damage were correlated with bilirubin and hepatic and pancreatic enzymes in 30 chronic male alcoholics admitted into psychiatric hospital for detoxification and treatment of alcoholism. Aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, and total bilirubin were altered, respectively, in 90%, 63%, 87%, 23% and 23% of the cases. None of the indicators of inflammation (lactic dehydrogenase, altered in 16% of the cases; alpha-1 globulin, 24%; alpha-2 globulin, 88%; leucocyte counts, 28% was correlated with alterations of bilirubin or liver enzymes. Lactic dehydrogenase was poorly sensitive for detection of hepatocytic or muscular damage. Alterations of alpha-globulins seemed to have been due more to alcohol metabolism-induced increase of lipoproteins than to inflammation. Among indicators of cell damage, serum iron, increased in 40% of the cases, seemed to be related to liver damage while creatine phosphokinase, increased in 84% of the cases, related to muscle damage. Hyperamylasemia was found in 20% of the cases and significantly correlated with levels of bilirubin, alkaline phosphatase and gamma-glutamyltransferase. It was indicated that injuries of liver, pancreas, salivary glands, and muscle occurred in asymptomatic or oligosymptomatic chronic alcoholics.

  4. ELTRABAJO EN ELAULA Y LA COMPETENCIA DIGITAL EN EL MODELO 1A1 DE LA COMUNIDAD DE MADRID

    Directory of Open Access Journals (Sweden)

    Pablo Sánchez Antolín

    2015-01-01

    Full Text Available Se presenta un análisis del tipo de competencia digital incorporada por los estudiantes de primeros cursos de Educación Secundaria Obligatoria de la Comunidad de Madrid cuyos centros participan en un programa 1a1 de introducción de un ordenador por estudiante. La metodología es un estudio intercasos. Hay observaciones de aula, entrevistas al profesorado observado, encuesta a estudiantes y análisis documental relevante. Se observan diferentes procesos de alfabetización para una competencia digital según la experiencia en proyectos con tecnologías de la información y la comunicación (TIC de los profesores participantes. Asimismo, se observan pequeños espacios de resistencia y de cambio al modelo 1a1 impulsado en Madrid.

  5. Anharmonic Franck-Condon Factors for the X̃(2)B1 ← X̃(1)A1 Photoionization of Ketene.

    Science.gov (United States)

    Rauhut, Guntram

    2015-10-15

    The X̃(2)B1 ← X̃(1)A1 photoelectron spectra of ketene and its doubly deuterated isotopologue have been computed from correlated vibrational wave functions as determined from vibrational configuration interaction theory relying on multidimensional Born-Oppenheimer potential energy surfaces being obtained from explicitly correlated coupled-cluster calculations. Duschinsky effects were accounted for in all cases. Excellent agreement with available experimental data was achieved. PMID:26418552

  6. The role of aldehyde dehydrogenase-1 (ALDH1A1 polymorphisms in harmful alcohol consumption in a Finnish population

    Directory of Open Access Journals (Sweden)

    Lind Penelope A

    2008-09-01

    Full Text Available Abstract Liver cystolic aldehyde dehydrogenase 1 (ALDH1A1 has been previously associated with both alcohol dependence and alcohol consumption behaviour, and has been implicated in alcohol-induced flushing and alcohol sensitivity in Caucasians. The present study tested for association between ALDH1A1 and alcohol consumption behaviour and susceptibility to problem drinking or alcohol dependence in Finnish cohorts of unrelated male subjects recruited from alcoholism clinical treatment facilities (n = 104 and from the general population (n = 201. All participants completed the Alcohol Use Disorder Identification Test (AUDIT and were genotyped for eight single nucleotide polymorphisms (SNPs within or flanking ALDH1A1. To test for association between alcohol consumption behaviour and these polymorphisms, we used generalised linear models and haplotypic analysis. Three SNPs were nominally associated (rs348449, p = 0.043; rs610529, p = 0.013; rs348479, p = 0.025 with the quantitative AUDIT score, which evaluates alcohol consumption behaviour. Two-locus (rs6I0529-rs2288087 haplotype analysis increased the strength of association with AUDIT score (p = 0.00I5. Additionally, rs348449 is highly associated with problem drinking (allelic odds ratio [OR] 7.87, 95 per cent confidence interval [CI] 1.67-37.01 but due to the low minor allele frequency (0.01 and 0.07 in controls and problem drinkers, respectively, more samples are required to validate this observation. Conversely, rs348479 (p = 0.019 and rs6I0529 (allelic OR 0.65, 95 per cent CI 0.43-0.98; genotypic OR 0.32, 95 per cent CI 0.12-0.84 are implicated in alcohol dependence status. This study provides further evidence for a role for ALDH1A1 in alcohol consumption behaviour, including problem drinking and possibly alcohol dependence, in our Finnish population.

  7. Akt1 is essential for postnatal mammary gland development, function, and the expression of Btn1a1.

    Directory of Open Access Journals (Sweden)

    Jessica LaRocca

    Full Text Available Akt1, a serine-threonine protein kinase member of the PKB/Akt gene family, plays critical roles in the regulation of multiple cellular processes, and has previously been implicated in lactation and breast cancer development. In this study, we utilized Akt1+/+ and Akt1-/- C57/Bl6 female mice to assess the role that Akt1 plays in normal mammary gland postnatal development and function. We examined postnatal morphology at multiple time points, and analyzed gene and protein expression changes that persist into adulthood. Akt1 deficiency resulted in several mammary gland developmental defects, including ductal outgrowth and defective terminal end bud formation. Adult Akt1-/- mammary gland composition remained altered, exhibiting fewer alveolar buds coupled with increased epithelial cell apoptosis. Microarray analysis revealed that Akt1 deficiency altered expression of genes involved in numerous biological processes in the mammary gland, including organismal development, cell death, and tissue morphology. Of particular importance, a significant decrease in expression of Btn1a1, a gene involved in milk lipid secretion, was observed in Akt1-/- mammary glands. Additionally, pseudopregnant Akt1-/- females failed to induce Btn1a1 expression in response to hormonal stimulation compared to their wild-type counterparts. Retroviral-mediated shRNA knockdown of Akt1 and Btn1a1 in MCF-7 human breast epithelial further illustrated the importance of Akt1 in mammary epithelial cell proliferation, as well as in the regulation of Btn1a1 and subsequent expression of ß-casein, a gene that encodes for milk protein. Overall these findings provide mechanistic insight into the role of Akt1 in mammary morphogenesis and function.

  8. Transcriptional regulation of the human ALDH1A1 promoter by the oncogenic homeoprotein TLX1/HOX11

    Directory of Open Access Journals (Sweden)

    Kim Rice

    2009-08-01

    Full Text Available The homeoprotein TLX1, which is essential to spleen organogenesis and oncogenic when aberrantly expressed in immature T cells, functions as a bifunctional transcriptional regulator, being capable of activation or repression depending on cell type and/or promoter context. However, the detailed mechanisms by which it regulates the transcription of target genes such as ALDH1A1 remains to be elucidated. We therefore functionally assessed the ability of TLX1 to regulate ALDH1A1 expression in two hematopoietic cell lines, PER-117 T-leukemic cells and human erythroleukemic (HEL cells, by use of luciferase reporter and mobility shift assays. We showed that TLX1 physically interacts with the general transcription factor TFIIB via its homeodomain, and identified two activities in respect to TLX1-mediated regulation of the CCAAT box-containing ALDH1A1 promoter. The first involved CCAAT-dependent transcriptional repression via perturbation of GATA factor-containing protein complexes assembled at a non-canonical TATA (GATA box. A structurally intact homeodomain was essential for repression by TLX1 although direct DNA binding was not required. The second activity, which involved CCAAT-independent transcriptional activation did not require an intact homeodomain, indicating that the activation and repression functions of TLX1 are distinct. These findings confirm ALDH1A1 gene regulation by TLX1 and support an indirect model for TLX1 function, in which protein-protein interactions, rather than DNA binding at specific sites, are crucial for its transcriptional activity.

  9. Polymorphisms of CYP1A1*4 and GST as Susceptibility and Prognostic Genes for Acute Myeloid Leukemia

    OpenAIRE

    Sheriff, E.; Ahmed, A.; Heba, M

    2010-01-01

    Associations between polymorphisms for genes encoding enzymes involved in biotransformation of xenobiotics and susceptibility to several cancers have been shown in several studies. The aim of the study is to investigate the influence of cytochromes P450 (CYP1A1*4) and Glutathione S-transferases (GSTs) (T1 and M1) gene polymorphisms in susceptibility to acute myeloid leukemia (AML) as well as their prognostic role for the treatment outcome in AML patients. Material and Methods: This study incl...

  10. Porcine EEF1A1 and EEF1A2 genes: genomic structure, polymorphism, mapping and expression

    Czech Academy of Sciences Publication Activity Database

    Svobodová, K.; Horák, Pavel; Stratil, Antonín; Bartenschlager, H.; Van Poucke, M.; Chalupová, P.; Dvořáková, Věra; Knorr, Ch.; Stupka, R.; Čítek, J.; Šprysl, M.; Palánová, Anna; Peelman, L. J.; Geldermann, H.; Knoll, A.

    2015-01-01

    Roč. 42, č. 8 (2015), s. 1257-1264. ISSN 0301-4851 R&D Projects: GA ČR(CZ) GA523/06/1302; GA ČR GA523/09/0844 Institutional support: RVO:67985904 Keywords : EEF1A1 * EEF1A2 * gene expression Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.024, year: 2014

  11. Vliv typu mutace v genu COL1A1 na fenotyp osob s diagnózou osteogenesis imperfecta

    Czech Academy of Sciences Publication Activity Database

    Šormová, L.; Mazurová, F.; Mazura, Ivan

    2008-01-01

    Roč. 15, 3-4 (2008), s. 332-338. ISSN 1212-4575. [Diagnostic, Comprehensive Treatment and Biomechanics of Locomotor Effects. Prague-Sydney-Lublin Symposium /10./. Prague, 24.09.2008-25.09.2008] R&D Projects: GA MŠk(CZ) 1M06014 Institutional research plan: CEZ:AV0Z10300504 Keywords : osteogenesis imperfecta * COL1A1 * kolagen * kolagenopatie * mutace Subject RIV: EB - Genetics ; Molecular Biology

  12. Metabolic activation of the antibacterial agent triclocarban by cytochrome P450 1A1 yielding glutathione adducts.

    Science.gov (United States)

    Schebb, Nils Helge; Muvvala, Jaya B; Morin, Dexter; Buckpitt, Alan R; Hammock, Bruce D; Rice, Robert H

    2014-07-01

    Triclocarban (3,4,4'-trichlorocarbanilide; TCC) is an antibacterial agent used in personal care products such as bar soaps. Small amounts of chemical are absorbed through the epidermis. Recent studies show that residues of reactive TCC metabolites are bound covalently to proteins in incubations with keratinocytes, raising concerns about the potential toxicity of this antimicrobial agent. To obtain additional information on metabolic activation of TCC, this study characterized the reactive metabolites trapped as glutathione conjugates. Incubations were carried out with (14)C-labeled TCC, recombinant CYP1A1 or CYP1B1, coexpressed with cytochrome P450 reductase, glutathione-S-transferases (GSH), and an NADPH-generating system. Incubations containing CYP1A1, but not 1B1, led to formation of a single TCC-GSH adduct with a conversion rate of 1% of parent compound in 2 hours. Using high-resolution mass spectrometry and diagnostic fragmentation, the adduct was tentatively identified as 3,4-dichloro-3'-glutathionyl-4'-hydroxycarbanilide. These findings support the hypothesis that TCC is activated by oxidative dehalogenation and oxidation to a quinone imine. Incubations of TCDD-induced keratinocytes with (14)C-TCC yielded a minor radioactive peak coeluting with TCC-GSH. Thus, we conclude that covalent protein modification by TCC in TCDD-induced human keratinocyte incubations is mainly caused by activation of TCC by CYP1A1 via a dehalogenated TCC derivative as reactive species. PMID:24733789

  13. Hop (Humulus lupulus L.) Extract and 6-Prenylnaringenin Induce P450 1A1 Catalyzed Estrogen 2-Hydroxylation.

    Science.gov (United States)

    Wang, Shuai; Dunlap, Tareisha L; Howell, Caitlin E; Mbachu, Obinna C; Rue, Emily A; Phansalkar, Rasika; Chen, Shao-Nong; Pauli, Guido F; Dietz, Birgit M; Bolton, Judy L

    2016-07-18

    Humulus lupulus L. (hops) is a popular botanical dietary supplement used by women as a sleep aid and for postmenopausal symptom relief. In addition to its efficacy for menopausal symptoms, hops can also modulate the chemical estrogen carcinogenesis pathway and potentially protect women from breast cancer. In the present study, an enriched hop extract and the key bioactive compounds [6-prenylnarigenin (6-PN), 8-prenylnarigenin (8-PN), isoxanthohumol (IX), and xanthohumol (XH)] were tested for their effects on estrogen metabolism in breast cells (MCF-10A and MCF-7). The methoxyestrones (2-/4-MeOE1) were analyzed as biomarkers for the nontoxic P450 1A1 catalyzed 2-hydroxylation and the genotoxic P450 1B1 catalyzed 4-hydroxylation pathways, respectively. The results indicated that the hop extract and 6-PN preferentially induced the 2-hydroxylation pathway in both cell lines. 8-PN only showed slight up-regulation of metabolism in MCF-7 cells, whereas IX and XH did not have significant effects in either cell line. To further explore the influence of hops and its bioactive marker compounds on P450 1A1/1B1, mRNA expression and ethoxyresorufin O-dealkylase (EROD) activity were measured. The results correlated with the metabolism data and showed that hop extract and 6-PN preferentially enhanced P450 1A1 mRNA expression and increased P450 1A1/1B1 activity. The aryl hydrocarbon receptor (AhR) activation by the isolated compounds was tested using xenobiotic response element (XRE) luciferase construct transfected cells. 6-PN was found to be an AhR agonist that significantly induced XRE activation and inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced XRE activity. 6-PN mediated induction of EROD activity was also inhibited by the AhR antagonist CH223191. These data show that the hop extract and 6-PN preferentially enhance the nontoxic estrogen 2-hydroxylation pathway through AhR mediated up-regulation of P450 1A1, which further emphasizes the importance of

  14. Investigation of selective inhibitory effects of glycyrol on human CYP 1A1 and 2C9.

    Science.gov (United States)

    Kim, Sun Joo; Kim, Su Jin; Hong, Miri; Choi, Hyun Gyu; Kim, Jeong Ah; Lee, Sangkyu

    2016-10-01

    1. Glycyrol is a coumarin derivative isolated from the roots of Glycyrrhiza uralensis called Gamcho in Korea and commonly used as a sweetener in oriental medicine. Glycyrol shows several biological activities, including anti-oxidative, anti-inflammatory, antibacterial, anti-angiogenic, and anti-allergenic properties. Although there have been studies on the biological effects of glycyrol, the inhibitory effects of glycyrol on cytochrome P450 (CYP) activities have not been investigated. 2. We investigated the inhibitory effects of glycyrol on the activities of CYP isoforms using a cocktail of probe substrates in pooled human liver microsome (HLM) and human recombinant cDNA-expressed CYPs. Glycyrol strongly inhibited CYP1A-mediated phenacetin O-deethylation and CYP2C9-mediated diclofenac 4'-hydroxylation in HLMs, which were the result of competitive inhibition as revealed by a Dixon plot. In addition, glycyrol showed selective inhibition of CYP1A1- and CYP1A2-catalyzed phenacetin O-deethylase activity with a half-maximal inhibitory concentration of (IC50) 1.3 and 16.1 μM in human recombinant cDNA-expressed CYP1A1 and CYP1A2, respectively. 3. Glycyrol decreased CYP2C9-catalyzed diclofenac 4'-hydroxylation activity with IC50 values of 0.67 μM in human recombinant cDNA-expressed CYP2C9. This is the first investigation of competitive inhibitory effects on CYP1A1 and CYP2C9 in HLMs. PMID:26750984

  15. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans

    DEFF Research Database (Denmark)

    Ghisari, Mandana; Long, Manhai; Bonefeld-Jørgensen, Eva Cecilie

    2013-01-01

    contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), and an elucidation of gene–environment interactions in relation to health risks is needed....... We observed a significant difference in serum polychlorinated biphenyl (CB-153) and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p′-DDE) levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Conclusion...

  16. Col1a1-cre mediated activation of β-catenin leads to aberrant dento-alveolar complex formation

    OpenAIRE

    Kim, Tak-Heun; Bae, Cheol-Hyeon; Jang, Eun-Ha; Yoon, Chi-Young; Bae, Young; Ko, Seung-O; Taketo, Makoto M.; Cho, Eui-Sic

    2012-01-01

    Wnt/β-catenin signaling plays a critical role in bone formation and regeneration. Dentin and cementum share many similarities with bone in their biochemical compositions and biomechanical properties. Whether Wnt/β-catenin signaling is involved in the dento-alveolar complex formation is unknown. To understand the roles of Wnt/β-catenin signaling in the dento-alveolar complex formation, we generated conditional β-catenin activation mice through intercross of Catnb+/lox(ex3) mice with Col1a1-cre...

  17. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Christoph Schulz; Volker Heinemann; Andreas Schalhorn; Nikolas Moosmann; Thomas Zwingers; Stefan Boeck; Clemens Giessen; Hans-Joachim Stemmler

    2009-01-01

    AIM: To investigate the correlation between uridine diphosphate glucuronosyl transferase 1A1 ( UGT1A1) gene polymorphisms and irinotecan-associated side effects and parameters of drug efficacy in patients with metastatic colorectal cancer (mCRC) receiving a lowdose weekly irinotecan chemotherapeutic regimen.METHODS: Genotypes were retrospectively evaluated by gene scan analysis on the ABI 310 sequencer of the TATAA box in the promoter region of the UGT1A1 gene in blood samples from 105 patients who had received 1st line irinotecan-based chemotherapy for mCRC.RESULTS: The distribution of the genotypes was as follows: wild type genotype (WT) ( 6/6) 39.0%,heterozygous genotype ( 6/7) 49.5%, and homozygous genotype ( 7/7) 9.5%. The overall response rate (OR) was similar between patients carrying the ( 6/7, 7/7) or the WT genotype ( 6/6) (44.3% vs 43.2%, P = 0.75).Neither time to progression [(TTP) 8.1 vs 8.2 mo, P = 0.97] nor overall survival [(OS) 21.2 vs 18.9 mo, P = 0.73] differed significantly in patients who carried the ( 6/6) when compared to the ( 6/7, 7/7) genotype. No significant differences in toxicity were observed: Grade 3 and 4 delayed diarrhoea [( 6/7, 7/7) vs ( 6/6); 13.0% vs 6.2%, P =0.08], treatment delays [( 6/7, 7/7) vs ( 6/6); 25.1% vs 19.3%, P = 0.24] or dose reductions [( 6/7, 7/7) vs ( 6/6); 21.5% vs 27.2%, P = 0.07].CONCLUSION: This analysis demonstrates the nonsignificant influence of the UGT1A1 gene polymorphism on efficacy and rate of irinotecan-associated toxicity in mCRC patients receiving low-dose irinotecan based chemotherapy.

  18. The role of genes AMPD1, CNB and COL1A1 in the propensity to employment rowing.

    Directory of Open Access Journals (Sweden)

    Kozyrev A.V.

    2011-04-01

    Full Text Available The question of the frequency distribution of polymorphic alleles of genes AMPD1, CNB and COL1A1. In the experiment, was attended by athletes, rowers qualifications at the age of 21 to 28 years, and people without experience of regular sport at the age of 20 to 22 years. Established that certain combinations of alleles can be recommended as a diagnostic complex genetic markers to assess the propensity to develop and display of strength, endurance and speed. It is shown that upon receipt of positive results may conduct a successful selection in rowing, the implementation of the individualization of the training process and improve its efficiency.

  19. Complex Behavior of ALDH1A1 and IGFBP1 in Liver Metastasis from a Colorectal Cancer

    Science.gov (United States)

    Kim, Jin Cheon; Ha, Ye Jin; Tak, Ka Hee; Roh, Seon Ae; Kim, Chan Wook; Kim, Tae Won; Kim, Seon-Kyu; Kim, Seon-Young; Cho, Dong-Hyung; Kim, Yong Sung

    2016-01-01

    Using our data set (GSE50760) previously established by RNA sequencing, the present study aimed to identify upregulated genes associated with colorectal cancer (CRC) liver metastasis (CLM) and verify their biological behavior. The potential roles of candidate genes in tumors were assessed using cell proliferation and invasion assays. Tissue samples were collected from 18 CRC patients with synchronous CLM and two CRC cell lines (SW480 and SW620) were used for transfection and cloning. The roles of the genes identified in CLM were verified using immunohistochemistry in 48 nude mice after intrasplenic transplantation of CRC cells. mRNA and protein expression was determined by quantitative real-time reverse transcription polymerase chain reaction and western blot, respectively. Nine genes were initially selected according to the relevance of their molecular function and biological process and, finally, ALDH1A1 and IGFBP1 were chosen based on differential mRNA expression and a positive correlation with protein expression. The overexpression of ALDH1A1 and IGFBP1 significantly and time-dependently decreased cell proliferation (p ≤ 0.001–0.003) and suppressed invasiveness by ≥3-fold over control cells (p < 0.001) in the SW480 cell line, whereas they had a slight effect on reducing SW620 cell proliferation. The protein expression levels of E-cadherin, N-cadherin, claudin-1, and vimentin were significantly higher in CLM than in primary tumor tissues (p < 0.05). However, the cadherin switch, namely, N-cadherin overexpression with reduced E-cadherin expression, was not observed in CLM tissues and transfected CRC cells. Irrespective of reduced proliferation and invasion found on in vitro cell assays, persistent overexpression of β-catenin, vimentin, and ZO-1 in IGFBP1-overexpressing SW480 cells possibly contributed to CLM development in mice implanted with IGFBP1-overexpressing SW480 cells (CLM occurrences: SW480/IGFBP1-transfected mice vs. SW480/vector- and SW480/ALDH1

  20. Associations of CYP1A1 gene polymorphisms and risk of breast cancer in Indian women: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Eloisa Singian

    2015-10-01

    Full Text Available Reported associations of CYP1A1 polymorphisms with breast cancer have been inconsistent. In this meta-analysis examining breast cancer associations of three CYP1A1 polymorphisms (M1, M2 and M4 among Indian women may yield information that may be of clinical and epidemiological use for this particular demography. We searched MEDLINE using PubMed and Embase for association studies. From seven published case-control studies, we estimated overall associations and applied subgroup analysis to explore differential effects. All three polymorphisms exhibited overall increased risk, significant in M1 (OR 1.61-1.65, p = 0.04 and M4 (OR 2.02-3.92, p = 0.02-0.04. Differential effects were observed only in the M1 polymorphism where M1 effects were significant in South Indians (OR 2.20-4.34, p < 0.0001 but not the North population, who were at reduced risk (OR 0.64-0.77, p = 0.03-0.55. These populations were not materially different in regard to M2 and M4 as did the women stratified by menopausal status. In this meta-analysis, M1 and M4 effects may render Indian women susceptible, but may be limited by heterogeneity of the studies. Differential effects of the M1 polymorphism in breast cancer render South Indians susceptible compared to those in the North.

  1. Deficient Expression of Aldehyde Dehydrogenase 1A1 Is Consistent with Increased Sensitivity of Gorlin Syndrome Patients to Radiation Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Wright, Aaron T.; Magnaldo, Thierry; Sontag, Ryan L.; Anderson, Lindsey N.; Sadler, Natalie C.; Piehowski, Paul D.; Gache, Yannick; Weber, Thomas J.

    2015-06-01

    Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of relevant pathways/networks. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol-reactive probes with a flexible click chemistry functional group to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. We observe qualitative differences in protein thiol profiles by SDS-PAGE analysis when detection by iodoacetamide vs maleimide probe chemistries are compared, and pretreatment of cells with hydrogen peroxide eliminates detection of the majority of SDS-PAGE bands. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent donors, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and this deficiency was confirmed by Western blot. Redox probes revealed additional protein thiol differences between GDFs and NHDFs, including radiation responsive annexin family members. Our results indicate a multifactorial basis for the unusual sensitivity of Gorlin syndrome to radiation carcinogenesis, and the pathways identified have plausible implications for radiation health effects.

  2. Impact of Alternaria toxins on CYP1A1 expression in different human tumor cells and relevance for genotoxicity.

    Science.gov (United States)

    Pahlke, G; Tiessen, C; Domnanich, K; Kahle, N; Groh, I A M; Schreck, I; Weiss, C; Marko, D

    2016-01-01

    The Alternaria toxins alternariol (AOH) and alternariol monomethyl ether (AME) have been reported previously to act as activators of the aryl hydrocarbon receptor (AhR) in murine hepatoma cells, thus enhancing the expression of cytochrome P450 (CYP) 1A monooxygenases. Concomitantly, both benzopyrones represent substrates of CYP1A, giving rise to catecholic metabolites. The impact of AOH and AME on CYP1A expression in human cells of different tissue origin colon (HT29), esophagus (KYSE510), liver (HepG2) and their effects on cell viability, generation of reactive oxygen species (ROS) and DNA integrity were investigated. ROS production was induced by both mycotoxins in all cell lines with AOH exhibiting the highest potency in esophageal cells concomitant with the most prominent CYP1A induction level. Of note, altertoxin-II (ATX-II), the more potent DNA-damaging mutagen formed by Alternaria alternata, induces CYP1A even at significant lower concentrations. AhR-siRNA knockdown in human esophageal cells supported the hypothesis of AhR-mediated CYP1A1 induction by AOH. However, DNA damage was minor at CYP1A1-inducing AOH concentrations. AhR-depletion did not affect the DNA-damaging properties of AOH indicating no substantial impact of AhR in this regard. However, in combination with xenobiotics prone to metabolic activation by CYP1A the induction of CYP1A by Alternaria toxins deserves further attention. PMID:26474839

  3. Assessment of total suspended sediment concentrations in Poyang Lake using HJ-1A/1B CCD imagery

    Institute of Scientific and Technical Information of China (English)

    YU Zhifeng; CHEN Xiaoling; ZHOU Bin; TIAN Liqiao; YUAN Xiaohong; FENG Lian

    2012-01-01

    We explored the potential of the environment and disaster monitoring and forecasting small satellite constellations (HJ-1A/1B satellites) charge-coupled device (CCD) imagery (spatial resolution of 30 m,revisit time of 2 days) in the monitoring of total suspended sediment (TSS) concentrations in dynamic water bodies using Poyang Lake,the largest freshwater lake in China,as an example.Field surveys conducted during October 17-26,2009 showed a wide range of TSS concentration (3-524 mg/L).Atmospheric correction was implemented using the Fast Line-of-sight Atmospheric Analysis of Spectral Hypercubes (FLAASH) module in ENVI with the aid of aerosol information retrieved from concurrent Terra/Moderate Resolution Imaging Spectroradiometer (MODIS) surveys,which worked well at the CCD bands with relatively high reflectance.A practical exponential retrieval algorithm was created between satellite remote sensing reflectance and in-situ measured TSS concentration.The retrieved results for the whole water area matched the in-situ data well at most stations.The retrieval errors may be related to the problem of scale matching and mixed pixel.In three selected subregions of Poyang Lake,the distribution trend of retrieved TSS was consistent with that of the field investigation.It was shown that HJ-1A/1B CCD imagery can be used to estimate TSS concentrations in Poyang Lake over synoptic scales after applying an appropriate atmospheric correction method and retrieval algorithm.

  4. PHENOBARBITAL AFFECTS THYROID HISTOLOGY AND LARVAL DEVELOPMENT IN THE AFRICAN CLAWED FROG XENOPUS LAEVIS

    Science.gov (United States)

    The abstract highlights our recent study to explore endocrine disrupting effects of phenobarbital in the African clawed frog, Xenopus laevis. In mammals, this chemical is known to induce the biotransforming enzyme UDP-glucuronosyltransferase (UDPGT) resulting in increased thyroid...

  5. Bilirubin isomer distribution in jaundiced neonates during phototherapy with LED light centered at 497 nm (turquoise) vs. 459 nm (blue)

    DEFF Research Database (Denmark)

    Ebbesen, Finn; Madsen, Poul H; Vandborg, Pernille K;

    2016-01-01

    of jaundiced neonates after 24 h of therapy with narrow-band (LED) light centered at 497 nm (turquoise) vs. 459 nm (blue), of essentially equal irradiance. MATERIALS: Eighty-three neonates (≥33 wk gestational age) with uncomplicated hyperbilirubinemia were included in the study. Forty neonates were...... difference was found between concentrations of E,Z-lumirubin. CONCLUSION: Therapy with LED light centered at 497 nm vs. 459 nm, applied with equal irradiance on the infants, resulted in a different distribution of bilirubin isomers in serum.Pediatric Research (2016); doi:10.1038/pr.2016.115.......BACKGROUND: Phototherapy using blue light is the treatment of choice worldwide for neonatal hyperbilirubinemia. However, treatment with turquoise light may be a desirable alternative. Therefore, the aim of this randomized, controlled study was to compare the bilirubin isomer distribution in serum...

  6. Modulation of defect-mediated energy transfer from ZnO nanoparticles for the photocatalytic degradation of bilirubin

    Directory of Open Access Journals (Sweden)

    Tanujjal Bora

    2013-11-01

    Full Text Available In recent years, nanotechnology has gained significant interest for applications in the medical field. In this regard, a utilization of the ZnO nanoparticles for the efficient degradation of bilirubin (BR through photocatalysis was explored. BR is a water insoluble byproduct of the heme catabolism that can cause jaundice when its excretion is impaired. The photocatalytic degradation of BR activated by ZnO nanoparticles through a non-radiative energy transfer pathway can be influenced by the surface defect-states (mainly the oxygen vacancies of the catalyst nanoparticles. These were modulated by applying a simple annealing in an oxygen-rich atmosphere. The mechanism of the energy transfer process between the ZnO nanoparticles and the BR molecules adsorbed at the surface was studied by using steady-state and picosecond-resolved fluorescence spectroscopy. A correlation of photocatalytic degradation and time-correlated single photon counting studies revealed that the defect-engineered ZnO nanoparticles that were obtained through post-annealing treatments led to an efficient decomposition of BR molecules that was enabled by Förster resonance energy transfer.

  7. Evaluation of treatment thresholds for unconjugated hyperbilirubinemia in preterm infants: effects on serum bilirubin and on hearing loss?

    Directory of Open Access Journals (Sweden)

    Christian V Hulzebos

    Full Text Available BACKGROUND: Severe unconjugated hyperbilirubinemia may cause deafness. In the Netherlands, 25% lower total serum bilirubin (TSB treatment thresholds were recently implemented for preterm infants. OBJECTIVE: To determine the rate of hearing loss in jaundiced preterms treated at high or at low TSB thresholds. DESIGN/METHODS: In this retrospective study conducted at two neonatal intensive care units in the Netherlands, we included preterms (gestational age 35 dB. RESULTS: There were 479 patients in the high and 144 in the low threshold group. Both groups had similar gestational ages (29.5 weeks and birth weights (1300 g. Mean and mean peak TSB levels were significantly lower after the implementation of the novel thresholds: 152 ± 43 µmol/L and 212 ± 52 µmol/L versus 131 ± 37 µmol/L and 188 ± 46 µmol/L for the high versus low thresholds, respectively (P<0.001. The incidence of hearing loss was 2.7% (13/479 in the high and 0.7% (1/144 in the low TSB threshold group (NNT = 50, 95% CI, 25-3302. CONCLUSIONS: Implementation of lower treatment thresholds resulted in reduced mean and peak TSB levels. The incidence of hearing impairment in preterms with a gestational age <32 weeks treated at low TSB thresholds was substantially lower compared to preterms treated at high TSB thresholds. Further research with larger sample sizes and power is needed to determine if this effect is statistically significant.

  8. Oxygen reduction reactions of the thermostable bilirubin oxidase from Bacillus pumilus on mesoporous carbon-cryogel electrodes

    International Nuclear Information System (INIS)

    This study demonstrates the bioelectrocatalytic reactions of a new bilirubin oxidase (BOD) from Bacillus pumilus on a mesoporous carbon cryogel (CCG) electrode, in the presence and absence of a mediator. BOD, physically adsorbed on the mesoporous matrix of a CCG electrode, allowed a direct electron transfer (DET) from the carbon electrode to the type I copper site of the enzyme. The current from the dioxygen reduction reaction (ORR), catalyzed by BOD, depended on the temperature and pH of the electrolyte. The mediated ORR catalyzed by BOD on CCG electrode was also investigated using osmium based redox polymers. The catalytic current on the CCG electrode modified with 0.2 mg cm−2 of hydrogel consisting of an enzyme, a redox polymer and a cross linker, was 1.8 mA cm−2, which was almost five times higher than that on a flat glassy carbon electrode for the same hydrogel composition and loading. The catalytic current linearly increased with the total amount of hydrogel on the porous carbon electrode while the catalytic current on the flat electrode was indifferent to the loading

  9. Phenobarbital and Phototherapy Combination Enhances Decline of Total Serum Bilirubin and May Decrease the Need for Blood Exchange Transfusion in Newborns with Isoimmune Hemolytic Disease

    OpenAIRE

    Mahmoud A.F. Kaabneh; Ghassan S. A. Salama; Ayoub G.A Shakkoury; Ibrahim M. H. Al-abdallah; Afrah Alshamari; Ruba A.A. Halaseh

    2015-01-01

    OBJECTIVE The objective of this study was to evaluate the effect of phenobarbital and phototherapy combination on the total serum bilirubin of the newborn infants with isoimmune hemolytic disease (IHD) and its impact on blood exchange transfusion rates. PATIENTS AND METHOD This single-blinded, prospective, randomized, controlled trial was conducted between March 2013 and December 2014 at the pediatric ward of two Military Hospitals in Jordan. A total of 200 full-term neonates with IHD were di...

  10. 新生儿胆红素脑病43例临床分析%Clinical Analysis of 43 Cases With Neonatal Bilirubin Encephalopathy

    Institute of Scientific and Technical Information of China (English)

    刘向红; 郎玉洁

    2015-01-01

    目的:了解胆红素脑病的病因及后遗症的发生情况,重视胆红素脑病的早期诊断、早期干预。方法43例胆红素脑病患儿进行病因、辅助检查、治疗、转归及随访结果进行分析研究。结果胆红素脑病的病因主要为感染占46.5%(23/43),出血占34.9%(15/43)和溶血占18.6%(8/43),后遗症的发生率为40.6%。结论应早期就诊,针对病因综合积极治疗,可减少智力落后、脑瘫等后遗症的发生。%Objective To investigate the etiology and the sequelae of bilirubin encephalopathy,pay attention to early diagnosis and early intervention of neonatal bilirubin encephalopathy.Methods 43 cases of bilirubin encephalopathy etiology,auxiliary examination,treatment,prognosis and folow-up results were analyzed.ResultsThe causes of bilirubin encephalopathy were mainly infection accounted for 46.5%(23/43),hemorrhage accounted for 34.9%(15/43)and hemolysis accounted for 18.6%(8/43),the incidence of sequelae rate was 40.6%.Conclusion Early treatment,comprehensive treatment for the cause,and can reduce mental retardation,cerebral palsy sequela.

  11. Correlations between periparturient serum concentrations of non-esterified fatty acids, beta-hydroxybutyric acid, bilirubin, and urea and the occurrence of clinical and subclinical postpartum bovine endometritis

    OpenAIRE

    Tenhagen Bernd-Alois; Drillich Marc; Kaufmann Toschi B; Heuwieser Wolfgang

    2010-01-01

    Abstract Background Postpartum endometritis in cattle is a multifactorial disease with high economic impact. Both, clinical endometritis (CE) and subclinical endometritis (SCE) result in decreased reproductive performance. Results from in vitro studies led to the implication that non-esterified fatty acids (NEFA), beta-hydroxybutyric acid (BHBA), bilirubin, and urea could be used as predictors for endometritis in veterinary practice. In this field study, we set out to establish optimal predic...

  12. Development and validation of serum bilirubin nomogram to predict the absence of risk for severe hyperbilirubinaemia before discharge: a prospective, multicenter study

    OpenAIRE

    Romagnoli Costantino; Tiberi Eloisa; Barone Giovanni; De Curtis Mario; Regoli Daniela; Paolillo Piermichele; Picone Simonetta; Anania Stefano; Finocchi Maurizio; Cardiello Valentina; Giordano Lucia; Paolucci Valentina; Zecca Enrico

    2012-01-01

    Abstract Background Early discharge of healthy late preterm and full term newborn infants has become common practice because of the current social and economic necessities. Severe jaundice, and even kernicterus, has developed in some term infants discharged early. This study was designed to elaborate a percentile-based hour specific total serum bilirubin (TSB) nomogram and to assess its ability to predict the absence of risk for subsequent non physiologic severe hyperbilirubinaemia before dis...

  13. Validation of transcutaneous bilirubin nomogram for identifying neonatal hyperbilirubinemia in healthy Chinese term and late-preterm infants: a multicenter study

    OpenAIRE

    Zhangbin Yu; Shuping Han; Jinxia Wu; Mingxia Li; Huaiyan Wang; Jimei Wang; Jiebo Liu; Xinnian Pan; Jie Yang; Chao Chen

    2014-01-01

    OBJECTIVE: to prospectively validate a previously constructed transcutaneous bilirubin (TcB) nomogram for identifying severe hyperbilirubinemia in healthy Chinese term and late-preterm infants. METHODS: this was a multicenter study that included 9,174 healthy term and late-preterm infants in eight hospitals of China. TcB measurements were performed using a JM-103 bilirubinometer. TcB values were plotted on a previously developed TcB nomogram, to identify the predictive ability for subseq...

  14. Metastable and equilibrium phase diagrams of unconjugated bilirubin IXα as functions of pH in model bile systems: Implications for pigment gallstone formation

    OpenAIRE

    Berman, Marvin D.; Carey, Martin C.

    2014-01-01

    Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment gallstone formation. Also, UCB is a molecule of considerable biomedical importance because it is a potent antioxidant and an inhibitor of atherogenesis. We employed principally a titrimetric approach to obtain metastable and equilibrium UCB solubilities in model bile systems composed of taurine-conjugated bile salts, egg yolk lecit...

  15. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans

    Directory of Open Access Journals (Sweden)

    Mandana Ghisari

    2013-06-01

    Full Text Available Background. The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and detoxification mechanisms of environmental contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs such as polychlorinated biphenyls (PCBs and organochlorine pesticides (OCPs, and an elucidation of gene–environment interactions in relation to health risks is needed. Objectives. The aim of this study was to determine and compare the genotype and allele frequencies of the cytochrome P450 CYP1A1 Ile462Val (rs1048943, CYP1B1 Leu432Val (rs1056836 and catechol-O-methyltransferase COMT Val158Met (rs4680 in Greenlandic Inuit (n=254 and Europeans (n=262 and explore the possible relation between the genotypes and serum levels of POPs. Results. The genotype and allele frequency distributions of the three genetic polymorphisms differed significantly between the Inuit and Europeans. For Inuit, the genotype distribution was more similar to those reported for Asian populations. We observed a significant difference in serum polychlorinated biphenyl (CB-153 and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl-ethylene (p,p′-DDE levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Conclusion. Our data provide new information on gene polymorphisms in Greenlandic Inuit that might support evaluation of susceptibility to environmental contaminants and warrant further studies.

  16. Influence of Phosphatidylcholine and Calcium on Self-Association and Bile Salt Mixed Micellar Binding of the Natural Bile Pigment, Bilirubin Ditaurate.

    Science.gov (United States)

    Neubrand, Michael W; Carey, Martin C; Laue, Thomas M

    2015-11-17

    Recently [Neubrand, M. W., et al. (2015) Biochemistry 54, 1542-1557], we determined a concentration-dependent monomer-dimer-tetramer equilibrium in aqueous bilirubin ditaurate (BDT) solutions and explored the nature of high-affinity binding of BDT monomers with monomers and micelles of the common taurine-conjugated bile salts (BS). We now investigate, employing complementary physicochemical methods, including fluorescence emission spectrophotometry and quasi-elastic light scattering spectroscopy, the influence of phosphatidylcholine (PC), the predominant phospholipid of bile and calcium, the major divalent biliary cation, on these self-interactions and heterointeractions. We have used short-chain, lyso and long-chain PC species as models and contrasted our results with those of parallel studies employing unconjugated bilirubin (UCB) as the fully charged dianion. Both bile pigments interacted with the zwitterionic headgroup of short-chain lecithins, forming water-soluble (BDT) and insoluble ion-pair complexes (UCB), respectively. Upon micelle formation, BDT monomers apparently remained at the headgroup mantle of short-chain PCs, but the ion pairs with UCB became internalized within the micelle's hydrophobic core. BDT interacted with the headgroups of unilamellar egg yolk (EY) PC vesicles; however, with the simultaneous addition of CaCl2, a reversible aggregation took place, but not vesicle fusion. With mixed EYPC/BS micelles, BDT became bound to the hydrophilic surface (as with simple BS micelles), and in turn, both BDT and BS bound calcium, but not other divalent cations. The calcium complexation of BDT and BS was enhanced strongly with increases in micellar EYPC, suggesting calcium-mediated cross-bridging of hydrophilic headgroups at the micelle's surface. Therefore, the physicochemical binding of BDT to BS in an artificial bile medium is influenced not only by BS species and concentration but also by long-chain PCs and calcium ions that exert a specific rather

  17. Epigenetic Determinants of CYP1A1 Induction by the Aryl Hydrocarbon Receptor Agonist 3,3',4,4',5-Pentachlorobiphenyl (PCB 126

    Directory of Open Access Journals (Sweden)

    Sabine U. Vorrink

    2014-08-01

    Full Text Available Many enzymes involved in xenobiotic metabolism, including cytochrome P450 (CYP 1A1, are regulated by the aryl hydrocarbon receptor (AhR. 3,3',4,4',5-Penta chlorobiphenyl (PCB 126 is a potent ligand for AhR and can thus induce the expression of CYP1A1. Interestingly, we observed that human carcinoma cell lines derived from different types of epithelial cells displayed divergent degrees of CYP1A1 induction after exposure to PCB 126. Since epigenetic mechanisms are known to be involved in cell type-specific gene expression, we sought to assess the epigenetic determinants of CYP1A1 induction in these carcinoma cell lines. In contrast to HepG2 hepatocarcinoma cells, HeLa cervical carcinoma cells showed significantly lower levels of CYP1A1 mRNA expression following PCB 126 exposure. Our results show that the two cell lines maintained differences in the chromatin architecture along the CYP1A1 promoter region. Furthermore, treatment with the epigenetic modifiers, trichostatin A (TSA and 5-aza-2'-deoxycytidine (5-Aza-dC, significantly increased the expression of CYP1A1 after PCB 126 treatment in HeLa cells. However, we did not observe apparent differences in methylation levels or specific location of CpG DNA methylation between the two cell lines in the analyzed CYP1A1 promoter region. Taken together, our findings suggest that the differences in CYP1A1 expression between HepG2 and HeLa cells are due to differences in the chromatin architecture of the CYP1A1 promoter and thus establish a role of epigenetic regulation in cell-specific CYP1A1 expression.

  18. HCV inter-subtype 1a/1b recombinant detected by complete-genome next-generation sequencing.

    Science.gov (United States)

    Gaspareto, Karine Vieira; Ribeiro, Roberto Marques; de Mello Malta, Fernanda; Gomes-Gouvêa, Michele Soares; Muto, Nair Hideko; Mendes-Correa, Maria Cassia; Rozanski, Andrei; Carrilho, Flair José; Sabino, Ester Cerdeira; Pinho, João Renato Rebello

    2016-08-01

    Next-generation sequencing (NGS) provides a practical approach to HCV complete-genome sequencing, detecting low-frequency variants and allowing analysis of viral genetic diversity (quasispecies) in the sample, and so far, it is very useful for identifying preexisting drug-resistant mutants and emerging escape mutations, as well as detecting viral recombinants containing genomic regions from different genotypes and subtypes. The aim of this study was to analyze the complete coding region of hepatitis C virus (HCV) genotype 1 (subtypes 1a and 1b) from patients with chronic infection who were direct-acting antiviral (DAA) naïve. Next-generation sequencing (Ion Torrent™ PGM) was used to determine the sequence of the complete coding region of 100 HCV-monoinfected DAA-naïve patients (51 and 49 subtypes 1a and 1b, respectively). We report the first description of nearly complete HCV genome sequences of subtype 1a and 1b isolates from a large population of Brazilian patients with chronic hepatitis C, and HCV-1a grouped in two different clades. Using this methodology, an inter-subtype 1a/1b recombinant was identified in this study. PMID:27194536

  19. Synergism of aromatic amines and benzo[a]pyrene in induction of Ah receptor-dependent genes.

    Science.gov (United States)

    Borza, Alexandra; Plöttner, Sabine; Wolf, Alexander; Behm, Claudia; Selinski, Silvia; Hengstler, Jan G; Roos, Peter H; Bolt, Hermann M; Kuhlmann, Jürgen; Föllmann, Wolfram

    2008-12-01

    Aromatic amines have been shown to cause bladder cancer. However, epithelial cells of the urinary bladder, cells of origin of bladder cancer, may be exposed to numerous substances besides aromatic amines. In the present study, we analysed possible interactions between the aromatic amines 4-aminobiphenyl (4-ABP) as well as 2-naphthylamine (2-NA) and the polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P). For this purpose we incubated primary porcine urinary bladder epithelial cells (PUBEC) with concentrations of 1 to 50 microM 4-ABP with and without co-exposure to B[a]P. As expected B[a]P increased mRNA expression of cytochrome P450 1A1 (CYP1A1), whereas 4-ABP had no effect. However, when co-exposed 4-ABP enhanced the induction of CYP1A1 by B[a]P. This result was confirmed by Western blot analysis of CYP1A1 protein expression. A similar effect as for CYP1A1 was also observed for cyclooxygenase-2 (COX-2) and UDP-glucuronosyltransferase 1 (UGT1). Next, we studied co-exposures of 2-NA and B[a]P. Similar as for 4-ABP also 2-NA enhanced B[a]P-mediated induction of CYP1A1. Our results demonstrate that some aromatic amines may enhance the influence of B[a]P on Ah receptor-dependent genes. PMID:18989657

  20. ALDH1A1 expression correlates with clinicopathologic features and poor prognosis of breast cancer patients: a systematic review and meta-analysis

    International Nuclear Information System (INIS)

    Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) has been identified as a putative cancer stem cell (CSC) marker in breast cancer. However, the clinicopathological and prognostic significance of this protein in breast cancer patients remains controversial. This meta-analysis was conducted to address the above issues using 15 publications covering 921 ALDH1A1+ cases and 2353 controls. The overall and subcategory analyses were performed to detect the association between ALDH1A1 expression and clinicopathological/prognostic parameters in breast cancer patients. The overall analysis showed that higher expression of ALDH1A1 is associated with larger tumor size, higher histological grade, greater possibility of lymph node metastasis (LNM), higher level expression of epidermal growth factor receptor 2 (HER2), and lower level expression of estrogen receptor (ER)/progesterone receptor (PR). The prognosis of breast cancer patients with ALDH1A1+ tumors was poorer than that of the ALDH1A1- patients. Although the relationships between ALDH1A1 expression and some clinicopathological parameters (tumor size, LNM, and the expression of HER2) was not definitive to some degree when we performed a subcategory analysis, the predictive values of ALDH1A1 expression for histological grade and survival of breast cancer patients were significant regardless of the different cutoff values of ALDH1A1 expression, the different districts where the patients were located, the different clinical stages of the patients, the difference in antibodies used in the studies, and the surgery status. Our results indicate that ALDH1A1 is a biomarker to predict tumor progression and poor survival of breast cancer patients. This marker should be taken into consideration in the development of new diagnostic and therapeutic program for breast cancer

  1. Induction of cytochrome P450 1A1 gene expression by a vitamin K3 analog in mouse hepatoma Hepa-1c1c7 cells.

    Science.gov (United States)

    Chun, Y J; Lee, B Y; Yang, S A; Ryu, C K; Kim, M Y

    2001-10-31

    Nine vitamin K3 analogs were compared with respect to the induction of the cytochrome P450 1A1 (CYP1A1) expression in mouse hepatoma Hepa-1c1c7 cells. 6-(4-Diethylamino)phenyl-7-chloro-5,8-quinolinedione (EA4) caused a significant induction of the CYP1A1-mediated ethoxyresorufin O-deethylase activity in a time- and concentration-dependent manner. The induction was accompanied by an increase of the Cyp1a1 mRNA transcription. The transient expression of the mouse Cyp1a1-CAT gene into cells showed that EA4 induced CAT activity. However, the aryl hydrocarbon receptor and its nuclear partner, aryl hydrocarbon receptor nuclear translocator mRNA transcription, were unaffected by the EA4 treatment. When the cells were incubated with EA4 in the presence of 1 nM TCDD, the ethoxyresorufin O-deethylase activity that was induced by TCDD was significantly suppressed by EA4. Inhibition of protein synthesis by cycloheximide strongly enhanced the EA4-dependent Cyp1a1 mRNA expression. Up-regulation of protein kinase C by a 2 h preincubation with phorbol 12-myristate 13-acetate increased the EA4-dependent expression of the Cyp1a1 gene. In human cells, such as HepG2 (human hepatocarcinoma), MCF-7 (human breast adenocarcinoma cell line), and HL-60 (human promyelocytic cell line), the expression of CYP1A1 mRNA was also induced by EA4 treatment. Moreover, CYP1B1 mRNA was increased by EA4 in MCF-7 cells. These results indicate that EA4 modulates CYP1A1 and CYP1B1 expressions by transcriptional activation. Also, protein kinase C may be involved in the induction mechanism of CYP1A1 by EA4. PMID:11710520

  2. Arecoline inhibits the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 1A1 activation in human hepatoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Eddy Essen [Lab. of Molecular Toxicology, Div. of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China); Miao Zhifeng [Lab. of Molecular Toxicology, Div. of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China); Lee, W.-J. [Dept. of Environmental Engineering, National Cheng Kung Univ., Tainan 701, Taiwan (China)]|[Sustainable Environment Research Center, National Cheng Kung Univ., Tainan 701, Taiwan (China); Chao, H.-R. [Dept. of Environmental Science and Engineering, National Pingtung Univ. of Science and Technology, Pingtung 912, Taiwan (China); Li, Lih-Ann [Lab. of Molecular Toxicology, Div. of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China); Wang, Y.-F. [Dept. of Chemical Engineering, Chung Yuan Christian University, Chungli 320, Taiwan (China); Ko, Y.-C. [Lab. of Molecular Toxicology, Div. of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China)]|[Dept. of Public Health, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan (China); Tsai, F.-Y. [Lab. of Molecular Toxicology, Div. of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China); Yeh, S.C. [Lab. of Molecular Toxicology, Div. of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China); Tsou, T.-C. [Lab. of Molecular Toxicology, Div. of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China)]. E-mail: tctsou@nhri.org.tw

    2007-07-19

    In the present study, we investigated the effect of arecoline, a major areca nut alkaloid, on the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of cytochrome P4501A1 (CYP1A1) in a human hepatoma cell line Huh-7. We treated Huh-7 cells with 10 nM TCDD in the presence of different concentrations of arecoline (50-300 {mu}M). Our results indicated that arecoline attenuated the TCDD-induced CYP1A1 enzyme activation with an inhibitory effect on cell proliferation. By using real-time RT-PCR, we demonstrated that arecoline inhibited the TCDD-induced activations of CYP1A1 and AhR repressor (AhRR) mRNA expression in a similar pattern. Our results revealed that arecoline inhibited AhR mRNA expression with no direct effect on CYP1A1 enzyme activity. Therefore, in our present study, the observed inhibitory effect of arecoline on CYP1A1 activation was not due to the up-regulation of AhRR or direct inhibitory effect on CYP1A1. Taken together, here we have demonstrated that arecoline attenuates the TCDD-induced CYP1A1 activation mainly via down-regulation of AhR expression in human hepatoma cells, suggesting the possible involvement of arecoline in the AhR-mediated metabolism of environmental toxicants in liver.

  3. Arecoline inhibits the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 1A1 activation in human hepatoma cells

    International Nuclear Information System (INIS)

    In the present study, we investigated the effect of arecoline, a major areca nut alkaloid, on the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of cytochrome P4501A1 (CYP1A1) in a human hepatoma cell line Huh-7. We treated Huh-7 cells with 10 nM TCDD in the presence of different concentrations of arecoline (50-300 μM). Our results indicated that arecoline attenuated the TCDD-induced CYP1A1 enzyme activation with an inhibitory effect on cell proliferation. By using real-time RT-PCR, we demonstrated that arecoline inhibited the TCDD-induced activations of CYP1A1 and AhR repressor (AhRR) mRNA expression in a similar pattern. Our results revealed that arecoline inhibited AhR mRNA expression with no direct effect on CYP1A1 enzyme activity. Therefore, in our present study, the observed inhibitory effect of arecoline on CYP1A1 activation was not due to the up-regulation of AhRR or direct inhibitory effect on CYP1A1. Taken together, here we have demonstrated that arecoline attenuates the TCDD-induced CYP1A1 activation mainly via down-regulation of AhR expression in human hepatoma cells, suggesting the possible involvement of arecoline in the AhR-mediated metabolism of environmental toxicants in liver

  4. MeIQx-induced DNA adduct formation and mutagenesis in DNA repair deficient CHO cells expressing human CYP1A1 and rapid or slow acetylator NAT2

    Science.gov (United States)

    Bendaly, Jean; Zhao, Shuang; Neale, Jason R.; Metry, Kristin J.; Doll, Mark A.; States, J. Christopher; Pierce, William M.; Hein, David W.

    2007-01-01

    2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx) is one of the most potent and abundant mutagens in the western diet. Bioactivation includes N-hydroxylation catalyzed by cytochrome P450s followed by O-acetylation catalyzed by N-acetyltransferase 2 (NAT2). Nucleotide excision repair-deficient chinese hamster ovary (CHO) cells were constructed by stable transfection of human cytochrome P4501A1 (CYP1A1) and a single copy of either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles. CYP1A1 and NAT2 catalytic activities were undetectable in untransfected CHO cell lines. CYP1A1 activity did not differ significantly (p > 0.05) among the CYP1A1-transfected cell lines. Cells transfected with NAT2*4 had significantly higher levels of sulfamethazine N-acetyltransferase (p = 0.0001) and N-hydroxy-MeIQx O-acetyltransferase (p = 0.0093) catalytic activity than cells transfected with NAT2*5B. Only cells transfected with both CYP1A1 and NAT2*4 showed concentration-dependent cytotoxicity and hypoxanthine phosphoribosyl transferase (hprt) mutagenesis following MeIQx treatment. dG-C8-MeIQx was the primary DNA adduct formed and levels were dose-dependent in each cell line and in the order: untransfected < transfected with CYP1A1 < transfected with CYP1A1 & NAT2*5B < transfected with CYP1A1 & NAT2*4. MeIQx DNA adduct levels were significantly higher (p < 0.001) in CYP1A1/NAT2*4 than CYP1A1/NAT2*5B cells at all concentrations of MeIQx tested. MeIQx-induced DNA adduct levels correlated very highly (r2 = 0.88) with MeIQx-induced mutants. These results strongly support extrahepatic activation of MeIQx by CYP1A1 and a robust effect of human NAT2 genetic polymorphism on MeIQx –induced DNA adducts and mutagenesis. The results provide laboratory-based support for epidemiological studies reporting higher frequency of heterocyclic amine-related cancers in rapid NAT2 acetylators. PMID:17627018

  5. Interactions between genetic polymorphism of cytochrome P450-1B1, sulfotransferase 1A1, catechol-o-methyltransferase and tobacco exposure in breast cancer risk.

    Science.gov (United States)

    Saintot, Monique; Malaveille, Christian; Hautefeuille, Agnès; Gerber, Mariette

    2003-11-20

    Genetic polymorphisms of enzymes involved in the metabolism of xenobiotics and estrogens might play a role in breast carcinogenesis related to environmental exposures. In a case-only study on 282 women with breast cancer, we studied the interaction effects (ORi) between smoking habits and the gene polymorphisms of Cytochrome P450 1B1 (Val432Leu CYP1B1), Phenol-sulfotransferase 1A1 (Arg213His SULT1A1) and Catechol-O-methyltransferase (Val158Met COMT). The smokers carrying the Val CYP1B1 allele associated with a high hydroxylation activity had a higher risk of breast cancer than never smokers with the Leu/Leu genotype (ORi=2.32, 95%CI: 1.00-5.38). Also, the smokers carrying the His SULT1A1 allele associated with a low sulfation activity had a 2-fold excess risk compared to never smokers carrying Arg/Arg SULT1A1 common genotype (ORi= 2.55, 95%CI: 1.21-5.36). The His SULT1A1 allele increased the risk only in premenopausal patients. The Met COMT allele with a lower methylation activity than Val COMT did not modify the risk among smokers. The excess risk due to joint effect could result from a higher exposure to activated tobacco-compounds for women homo/heterozygous for the Val CYP1B1 allele. Also, a lower sulfation of the tobacco carcinogens among women with His SULT1A1 could increase exposure to genotoxic compounds. Alternatively, the Val CYP1B1 or His SULT1A1 allele with modified ability to metabolize estrogens could increase the level of genotoxic catechol estrogen (i.e., 4-hydroxy-estradiol) among smokers. Our study showed that gene polymorphisms of CYP1B1 and SULT1A1 induce an individual susceptibility to breast cancer among current smokers. PMID:14520706

  6. Identification of the collagen type 1 alpha 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death especially among Asian and African populations. It is urgent that we identify carcinogenesis-related genes to establish an innovative treatment strategy for this disease. Triple-combination array analysis was performed using one pair each of HCC and noncancerous liver samples from a 68-year-old woman. This analysis consists of expression array, single nucleotide polymorphism array and methylation array. The gene encoding collagen type 1 alpha 1 (COL1A1) was identified and verified using HCC cell lines and 48 tissues from patients with primary HCC. Expression array revealed that COL1A1 gene expression was markedly decreased in tumor tissues (log2 ratio –1.1). The single nucleotide polymorphism array showed no chromosomal deletion in the locus of COL1A1. Importantly, the methylation value in the tumor tissue was higher (0.557) than that of the adjacent liver tissue (0.008). We verified that expression of this gene was suppressed by promoter methylation. Reactivation of COL1A1 expression by 5-aza-2′-deoxycytidine treatment was seen in HCC cell lines, and sequence analysis identified methylated CpG sites in the COL1A1 promoter region. Among 48 pairs of surgical specimens, 13 (27.1%) showed decreased COL1A1 mRNA expression in tumor sites. Among these 13 cases, 10 had promoter methylation at the tumor site. The log-rank test indicated that mRNA down-regulated tumors were significantly correlated with a poor overall survival rate (P = 0.013). Triple-combination array analysis successfully identified COL1A1 as a candidate survival-related gene in HCCs. Epigenetic down-regulation of COL1A1 mRNA expression might have a role as a prognostic biomarker of HCC

  7. Association of sulfotransferase SULT1A1 with breast cancer risk: a meta-analysis of case-control studies with subgroups of ethnic and menopausal statue

    OpenAIRE

    Shao Zhimin; Shen Zhenzhou; Yan Tingting; Zhou Liheng; Jiang Yiwei; Lu Jinsong

    2010-01-01

    Abstract Background Sulfotransferase (SULT) plays an important role in the formation of estrogen which is usually conferred as a risk factor for breast cancer. Polymorphism of the SULT1A1 may be closely associated with breast cancer. However, studies on the association between polymorphism and breast cancer have yielded inconsistent results. We performed a meta-analysis including ethnic subgroup and menopausal statue subgroup to investigate the association of SULT1A1 Arg213His polymorphism wi...

  8. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review

    OpenAIRE

    Palomaki, Glenn E; Bradley, Linda A.; Douglas, Michael P.; Kolor, Katherine; Dotson, W. David

    2009-01-01

    This evidence-based review addresses the question of whether testing for UGT1A1 mutations in patients with metastatic colorectal cancer treated with irinotecan leads to improvement in outcomes (e.g., irinotecan toxicity, response to treatment, morbidity, and mortality), when compared with no testing. No studies were identified that addressed this question directly. The quality of evidence on the analytic validity of current UGT1A1 genetic testing methods is adequate (scale: convincing, adequa...

  9. Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyung Gyun [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Han, Eun Hee [Division of Life Science, Korea Basic Science Institute, Daejeon (Korea, Republic of); Im, Ji Hye; Lee, Eun Ji; Jin, Sun Woo [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2015-09-25

    Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Taken together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction. - Highlights: • CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. • CAPE inhibited 3-MC-induced CYP1A1 expression. • CAPE induced HIF-1α induction. • CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 expression.

  10. Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α

    International Nuclear Information System (INIS)

    Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Taken together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction. - Highlights: • CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. • CAPE inhibited 3-MC-induced CYP1A1 expression. • CAPE induced HIF-1α induction. • CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 expression

  11. A functional 12T-insertion polymorphism in the ATP1A1 promoter confers decreased susceptibility to hypertension in a male Sardinian population.

    Directory of Open Access Journals (Sweden)

    Victoria L Herrera

    Full Text Available Identification of susceptibility genes for essential hypertension in humans has been a challenge due to its multifactorial pathogenesis complicated by gene-gene and gene-environment interactions, developmental programing and sex specific differences. These concurrent features make identification of causal hypertension susceptibility genes with a single approach difficult, thus requiring multiple lines of evidence involving genetic, biochemical and biological experimentation to establish causal functional mutations. Here we report experimental evidence encompassing genetic, biochemical and in vivo modeling that altogether support ATP1A1 as a hypertension susceptibility gene in males in Sardinia, Italy. ATP1A1 encodes the α1Na,K-ATPase isoform, the sole sodium pump in vascular endothelial and renal tubular epithelial cells. DNA-sequencing detected a 12-nucleotide long thymidine (12T insertion(ins/deletion(del polymorphism within a poly-T sequence (38T vs 26T in the ATP1A1 5'-regulatory region associated with hypertension in a male Sardinian population. The 12T-insertion allele confers decreased susceptibility to hypertension (P = 0.035; OR = 0.50 [0.28-0.93] accounting for 12.1 mmHg decrease in systolic BP (P = 0.02 and 6.6 mmHg in diastolic BP (P = 0.046. The ATP1A1 promoter containing the 12T-insertion exhibited decreased transcriptional activity in in vitro reporter-assay systems, indicating decreased α1Na,K-ATPase expression with the 12T-insertion, compared with the 12T-deletion ATP1A1 promoter. To test the effects of decreased α1Na,K-ATPase expression on blood pressure, we measured blood pressure by radiotelemetry in three month-old, highly inbred heterozygous knockout ATP1A1+/- male mice with resultant 58% reduction in ATP1A1 protein levels. Male ATP1A1+/- mice showed significantly lower blood pressure (P < 0.03 than age-matched male wild-type littermate controls. Concordantly, lower ATP1A1 expression is expected to lower Na

  12. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

    Energy Technology Data Exchange (ETDEWEB)

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong; Khanal, Tilak; Choi, Jae Ho [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Chung, Young Chul [Department of Food Science and Culinary, International University of Korea, Jinju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyeongsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2014-10-01

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO expression.

  13. CYP1A1 and CYP1B1 in human lymphocytes as biomarker of exposure: effect of dioxin exposure and polymorphisms

    Energy Technology Data Exchange (ETDEWEB)

    Duursen, M. van; Sanderson, T.; Berg, M. van den [Inst. for Risk Assessment Sciences, Utrecht (Netherlands)

    2004-09-15

    There are several known genetic polymorphisms of the CYP1A1 and CYP1B1 genes. A polymorphism in the 3'-untranslated region of the CYP1A1 gene (CYP1A1 MspI or CYP1A1 m1) is often studied in relation with breast or lung cancer, but little is known about the functional effect of this polymorphism. An amino acid substitution in codon 432 (Val to Leu) of the CYP1B1 gene is associated with a lower catalytic activity of the enzyme. However, the involvement of these polymorphisms on the inducibility of CYP1A1 and CYP1B1 gene expression is unclear. CYP1A1 and CYP1B1 mRNA expression levels can be determined in peripheral blood lymphocytes. This makes them potential candidates for use as biomarker of exposure to environmental compounds. Interindividual variations in mRNA expression patterns, catalytic activity and polymorphisms are very important factors when CYP1A1 and CYP1B1 expression patterns are used as biomarker of exposure, but little is known about it. Spencer et al. showed a concentration-dependent increase of CYP1B1 mRNA in lymphocytes upon exposure in vitro to 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD), the most potent dioxin. Yet, only a few studies describe the in vivo correlation between polymorphisms, mRNA expression level and exposure to environmental factors. In this study, we wanted to obtain a better insight in the CYP1A1 and CYP1B1 mRNA expression and enzyme activity in human lymphocytes. We determined the constitutive CYP1A1 and CYP1B1 mRNA expression in lymphocytes of ten healthy volunteers and the variability in sensitivity toward enzyme induction by TCDD. Further, the CYP1A1 m1 and CYP1B1 Val432Leu polymorphisms were determined.

  14. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

    International Nuclear Information System (INIS)

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO expression

  15. Simultaneous determination of probe drugs, metabolites, inhibitors and inducer in human plasma by liquid chromatography/tandem mass spectrometry and its application to pharmacokinetic study.

    Science.gov (United States)

    Hee, Kim H; Yao, Zhangyan; Lee, Lawrence S

    2014-01-01

    Cytochrome P450 3A4 (CYP3A4) and UDP-glucuronosyltransferase 1A1 (UGT1A1) are important enzymes responsible for the metabolism of many xenobiotics. To investigate their induction and inhibition properties, administering probe drugs and monitoring their concentration in plasma under the effects of inducers/inhibitors is the gold standard method. A rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of midazolam, raltegravir (probe drugs for CYP3A4 and UGT1A1), their major metabolites, 1'-hydroxymidazolam, 1'-hydroxymidazolam glucuronide and raltegravir glucuronide, rifampicin (inducer), ritonavir and ketoconazole (inhibitors). Analytes were extracted from 100μl of plasma using solid-phase extraction followed by chromatographic separation on a reversed-phase C18 column (50mm×2.1mm, particle size 1.8μm). The mass spectrometer was operated under positive ionization mode. Excellent linearity (r(2)≥0.995) was achieved for all. The method was validated and found to be accurate (88-111%), precise (CV%inhibitor of important drug metabolism enzymes. The method was successfully applied in a clinical study to investigate the degree of induction and inhibition of CYP3A4 and UGT1A1 among ethnic groups in Singapore. PMID:24211708

  16. Modulation of CYP1A1 and CYP1A2 hepatic enzymes after oral administration of Chios mastic gum to male Wistar rats.

    Directory of Open Access Journals (Sweden)

    Efrosini S Katsanou

    Full Text Available Chios mastic gum (CMG, a resin derived from Pistacia lentiscus var. chia, is known since ancient times for its pharmacological activities. CYP1A1 and CYP1A2 enzymes are among the most involved in the biotransformation of chemicals and the metabolic activation of pro-carcinogens. Previous studies referring to the modulation of these enzymes by CMG have revealed findings of unclear biological and toxicological significance. For this purpose, the modulation of CYP1A1 and CYP1A2 enzymes in the liver of male Wistar rats following oral administration of CMG extract (CMGE, at the levels of mRNA and CYP1A1 enzyme activity, was compared to respective enzyme modulation following oral administration of a well-known bioactive natural product, caffeine, as control compound known to involve hepatic enzymes in its metabolism. mRNA levels of Cyp1a1 and Cyp1a2 were measured by reverse transcription real-time polymerase chain reaction and their relative quantification was calculated. CYP1A1 enzyme induction was measured through the activity of ethoxyresorufin-O-deethylase (EROD. The results indicated that administration of CMGE at the recommended pharmaceutical dose does not induce significant transcriptional modulation of Cyp1a1/2 and subsequent enzyme activity induction of CYP1A1 while effects of the same order of magnitude were observed in the same test system following the administration of caffeine at the mean daily consumed levels. The outcome of this study further confirms the lack of any toxicological or biological significance of the specific findings on liver following the administration of CMGE.

  17. Modulation of CYP1A1 and CYP1A2 hepatic enzymes after oral administration of Chios mastic gum to male Wistar rats.

    Science.gov (United States)

    Katsanou, Efrosini S; Kyriakopoulou, Katerina; Emmanouil, Christina; Fokialakis, Nikolas; Skaltsounis, Alexios-Leandros; Machera, Kyriaki

    2014-01-01

    Chios mastic gum (CMG), a resin derived from Pistacia lentiscus var. chia, is known since ancient times for its pharmacological activities. CYP1A1 and CYP1A2 enzymes are among the most involved in the biotransformation of chemicals and the metabolic activation of pro-carcinogens. Previous studies referring to the modulation of these enzymes by CMG have revealed findings of unclear biological and toxicological significance. For this purpose, the modulation of CYP1A1 and CYP1A2 enzymes in the liver of male Wistar rats following oral administration of CMG extract (CMGE), at the levels of mRNA and CYP1A1 enzyme activity, was compared to respective enzyme modulation following oral administration of a well-known bioactive natural product, caffeine, as control compound known to involve hepatic enzymes in its metabolism. mRNA levels of Cyp1a1 and Cyp1a2 were measured by reverse transcription real-time polymerase chain reaction and their relative quantification was calculated. CYP1A1 enzyme induction was measured through the activity of ethoxyresorufin-O-deethylase (EROD). The results indicated that administration of CMGE at the recommended pharmaceutical dose does not induce significant transcriptional modulation of Cyp1a1/2 and subsequent enzyme activity induction of CYP1A1 while effects of the same order of magnitude were observed in the same test system following the administration of caffeine at the mean daily consumed levels. The outcome of this study further confirms the lack of any toxicological or biological significance of the specific findings on liver following the administration of CMGE. PMID:24950217

  18. No association between polymorphisms and haplotypes of COL1A1 and COL1A2 genes and osteoporotic fracture in postmenopausal Chinese women

    Institute of Scientific and Technical Information of China (English)

    Wei-wei HU; Miao LI; Yu-juan LIU; Zhen-Iin ZHANG; Jin-wei HE; Hao ZHANG; Chun WANG; Jie-mei GU; Hua YUE; Yao-hua KE; Yun-qiu HU; Wen-zhen FU

    2011-01-01

    Aim: To study whether genetic polymorphisms of COL1A1 and COL1A2 genes affected the onset of fracture in postmenopausal Chinese women.Methods: SNPs in COL1A1 and COL1A2 genes were identified via direct sequencing in 32 unrelated postmenopausal Chinese women.Ten SNPs were genotyped in 1252 postmenopausal Chinese women. The associations were examined using both single-SNP and hapIotype tests using logistic regression.Results: Twenty four (4 novel) and 28 (7 novel) SNPs were identified in COL1A1 and COL1A2 gene, respectively. The distribution frequencies of 2 SNPs in COL1A1 (rs2075554 and rs2586494) and 3 SNPs in COL1A2 (rs42517, rs1801182, and rs42524) were significantly different from those documented for the European Caucasian population. No significant difference was observed between fracture and control groups with respect to allele frequency or genotype distribution in 9 selected SNPs and haplotype. No significant association was found between fragility fracture and each SNP or haplotype. The results remained the same after additional corrections for other risk factors such as weight, height, and bone mineral density.Conclusion: Our results show no association between common genetic variations of COL1A1 and COL1A2 genes and fracture, suggesting the complex genetic background of osteoporotic fractures.

  19. Induction and inhibition of cytochrome P450 1A1 and ethoxyresorufin-O-deethylation activity by polybrominated diphenyl ethers (PBDEs) in cynomolgus monkey primary hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Peters, L.; Sanderson, J.T.; Berg, M. van den [Utrecht Univ. (Netherlands). Inst. for Risk Assessment Sciences; Bergman, A. [Stockholm Univ. (Sweden). Dept. of Environmental Chemistry

    2004-09-15

    Brominated flame retardants (BFRs) make up for 39% of the worldwide flame-retardants market. One groups of BFR, Polybrominated diphenylethers (PBDEs) are used as additive flameretardants in plastic materials, paints, and textile fabrics. Some PBDEs have been found to be lipophilic and persistent, and consequently bioaccumulate. Recently, levels of some PBDEs have been increasing in fish, wildlife, and in human tissue. The structural similarity of certain PBDE congeners to other polyhalogenated aromatic hydrocarbons such as polychlorinated biphenyls (PCBs) has raised concerns that these compounds might act as agonists for the aryl hydrocarbon receptor (AhR). If some of these PBDEs were to act as Ah receptor agonists, they would warrant inclusion in the toxic equivalence factor (TEF) concept. CYP1A1 is a cytochrome P450 (CYP) enzyme that is involved in phase 1 biotransformation of xenobiotics and endogenous compounds such as estrogens. Many CYP enzymes detoxify xenobiotics or bioactivate xenobiotics to reactive intermediates. Although CYP1A1 is expressed in all mammals, there are differences in expression levels among species and tissues. To study the possible dioxin-like effects of environmentally most relevant PBDEs (BDE47, 77, 99, 100, 153, 154, 183, 209), the Ah receptor-mediated induction CYP1A1 was studied in cynomolgus monkey (Macaca fascicularis) primary hepatocytes. CYP 1A1 is the major enzyme that catalyses the deethylation of 7-ethoxyresorufin to resorufin. This ethoxyresorufin-Odeethylation (EROD) activity was used as a marker for CYP1A1 activity.

  20. eEF1A1 binds and enriches protoporphyrin IX in cancer cells in 5-aminolevulinic acid based photodynamic therapy

    Science.gov (United States)

    Fan, Zhichao; Cui, Xiaojun; Wei, Dan; Liu, Wei; Li, Buhong; He, Hao; Ye, Huamao; Zhu, Naishuo; Wei, Xunbin

    2016-05-01

    Photodynamic therapy (PDT) with protoporphyrin IX (PpIX), which is endogenously derived from 5-aminolevulinic acid (5-ALA) or its derivatives, is a promising modality for the treatment of both pre-malignant and malignant lesions. However, the mechanisms of how ALA-induced PpIX selectively accumulated in the tumors are not fully elucidated. Here we discovered that eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) interacted with PpIX (with an affinity constant of 2.96 × 106 M‑1). Microscopy imaging showed that ALA-induced PpIX was co-localized with eEF1A1 in cancer cells. eEF1A1 was found to enrich ALA-induced PpIX in cells by competitively blocking the downstream bioavailability of PpIX. Taken together, our study discovered eEF1A1 as a novel photosensitizer binding protein, which may play an essential role in the enrichment of ALA-induced PpIX in cancer cells during PDT. These suggested eEF1A1 as a molecular marker to predict the selectivity and efficiency of 5-ALA based PDT in cancer therapy.

  1. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension

    DEFF Research Database (Denmark)

    Beuschlein, Felix; Boulkroun, Sheerazed; Osswald, Andrea;

    2013-01-01

    Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na+/K+ ATPase α...... subunit) and ATP2B3 (encoding a Ca2+ ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced...... affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation...

  2. Harmine and Harmaline Downregulate TCDD-Induced Cyp1a1 in the Livers and Lungs of C57BL/6 Mice

    Directory of Open Access Journals (Sweden)

    Mohamed A. M. El Gendy

    2013-01-01

    Full Text Available We previously demonstrated that Peganum harmala L. extract and its main active constituents, harmine and harmaline inhibit the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD-mediated induction of the carcinogen-activating enzyme, Cyp1a1, in vitro. However, the effect of both alkaloids on Cyp1a1 in vivo has not been investigated. Therefore, the aim of this study is to examine the effect of harmine and harmaline on TCDD-mediated induction of Cyp1a1 in mice livers and lungs. C57BL/6 male mice were distributed into four groups (n=6. First group received vehicle, while the second group received TCDD (i.p.. The third and fourth groups received either harmine or harmaline (i.p. × 3 times along with TCDD one time with the mid dose of harmine and harmaline. All mice were sacrificed after 14 h from TCDD injection, and livers and lungs were isolated. The effect of harmine and harmaline on TCDD-mediated induction of Cyp1a1 mRNA, protein, and activity levels was determined using real-time PCR, Western blot analysis, and 7-ethoxyresurofin as a substrate, respectively. Our results showed that harmine and harmaline significantly decreased the TCDD-mediated induction of Cyp1a1 in both the livers and lungs. We concluded that harmine and harmaline are promising candidate to inhibit TCDD-mediated induction of Cyp1a1 in mice hepatic and extrahepatic tissues.

  3. Sulforaphane inhibits CYP1A1 activity and promotes genotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Fangxing, E-mail: fxyang@zju.edu.cn [MOE Key Laboratory of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058 (China); Zhuang, Shulin [MOE Key Laboratory of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058 (China); Zhang, Chao; Dai, Heping [State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072 (China); Liu, Weiping, E-mail: wliu@zju.edu.cn [MOE Key Laboratory of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058 (China)

    2013-06-15

    Increasing environmental pollution by carcinogens such as some of persistent organic pollutants (POPs) has prompted growing interest in searching for chemopreventive compounds which are readily obtainable. Sulforaphane (SFN) is isolated from cruciferous vegetables and has the potentials to reduce carcinogenesis through various pathways. In this study, we studied the effects of SFN on CYP1A1 activity and genotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The results showed that SFN inhibited TCDD-induced CYP1A1 activity in H4IIE cells by directly inhibiting CYP1A1 activity, probably through binding to aryl hydrocarbon receptor and/or CYP1A1 revealed by molecular docking. However, SFN promoted TCDD-induced DNA damage in yeast cells and reduced the viability of initiated yeast cells. Besides, it is surprising that SFN also failed to reduce genotoxicity induced by other genotoxic reagents which possess different mechanisms to lead to DNA damage. Currently, it is difficult to predict whether SFN has the potentials to reduce the risk of TCDD based on the conflicting observations in the study. Therefore, further studies should be urgent to reveal the function and mechanism of SFN in the stress of such POPs on human health. - Highlights: • Sulforaphane inhibited TCDD-induced CYP1A1 activity in H4IIE cells. • Sulforaphane may bind to aryl hydrocarbon receptor and/or CYP1A1. • Sulforaphane promoted TCDD-induced DNA damage in yeast cells. • Sulforaphane may promote DNA damage by DNA strand breaks or DNA alkylation.

  4. Uridine diphosphate glucuronide transferase 1A1FNx0128 gene polymorphism and the toxicity of irinotecan in recurrent and refractory small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Fan Yun

    2014-01-01

    Full Text Available Objective: The aim was to investigate the association between uridine diphosphate glucuronide transferase 1A1 (UGT1A1 gene promoter region polymorphism and irinotecan-related adverse effects and efficacy on recurrent and refractory small cell lung cancer (SCLC. Materials and Methods: A total of 31 patients with recurrent and refractory SCLC were enrolled in this study from June 2012 to August 2013 and received at least two cycles of single-agent irinotecan chemotherapy. The efficacy and adverse effects of irinotecan were evaluated. DNA was extracted from peripheral blood and direct sequencing method was employed to test UGT1A1FNx0128 polymorphism, thus analyzing the correlation between UGT1A1FNx0128 polymorphism and irinotecan-related side-effects and efficacy. Results: A total of 25 cases (80.6% were UGT1A1FNx0128 wild-type (TA 6 /(TA 6 ; 6 cases (19.4% were heterozygous mutant (TA 6 /(TA 7 , no homozygous mutant genotype (TA 7 /(TA 7 was found. The incidences of grade 3/4 neutropenia, diarrhea and thrombocytopenia were 35.5%, 25.8% and 22.6% in all the patients, respectively. The incidence of 3/4 adverse effects in patients with genotype (TA 6 /(TA 6 and heterozygous (TA 6 /(TA 7 had no statistical difference (P > 0.05 for all. The overall response rate (ORR was 32.3%. Median progression free survival (PFS and overall survival (OS were 4 months and 7.5 months in all patients, respectively. There was no statistical difference in ORR, PFS and OS between genotype (TA 6 /(TA 6 patients and heterozygous (TA 6 /(TA 7 patients. Conclusion: Irinotecan showed efficacy in patients with recurrent and refractory SCLC; UGT1A1 FNx01 28 polymorphism failed to predict the incidence of serious adverse effects and efficacy of irinotecan.

  5. Evaluación del modelo 1 a 1 en Iberoamérica: efectos del uso de computadoras portátiles en el aula

    OpenAIRE

    Raúl Choque-Larrauri

    2011-01-01

    En Iberoamérica alrededor de dos millones de estudiantes usan laptops en el modelo 1 a 1 (una computadora por cada estudiante) en la educación básica. Se proyecta que en 2015 treinta millones de estudiantes en esa región estarán usando computadoras. Actualmente, un tercio de la población en Iberoamérica es internauta y hay un crecimiento sostenido de la población que tiene acceso al Internet. Se han realizado una serie de evaluaciones sobre los efectos del modelo 1 a 1 en la educación. Los ef...

  6. The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium

    OpenAIRE

    Rawlins, Emma L.; Okubo, Tadashi; Xue, Yan; Brass, David M; Auten, Richard L.; Hasegawa, Hiroshi; Wang, Fan; Hogan, Brigid L.M.

    2009-01-01

    To directly test the contribution of Scgb1a1+ Clara cells to postnatal growth, homeostasis and repair of lung epithelium, we generated a Scgb1a1-CreERTM “knock-in” mouse line for lineage tracing these cells. Under all conditions tested the majority of Clara cells in the bronchioles both self-renew and generate ciliated cells. In the trachea, Clara cells give rise to ciliated cells but do not self-renew extensively. Nevertheless, they can contribute to tracheal repair. In the postnatal mouse l...

  7. Correlations between periparturient serum concentrations of non-esterified fatty acids, beta-hydroxybutyric acid, bilirubin, and urea and the occurrence of clinical and subclinical postpartum bovine endometritis

    Directory of Open Access Journals (Sweden)

    Tenhagen Bernd-Alois

    2010-10-01

    Full Text Available Abstract Background Postpartum endometritis in cattle is a multifactorial disease with high economic impact. Both, clinical endometritis (CE and subclinical endometritis (SCE result in decreased reproductive performance. Results from in vitro studies led to the implication that non-esterified fatty acids (NEFA, beta-hydroxybutyric acid (BHBA, bilirubin, and urea could be used as predictors for endometritis in veterinary practice. In this field study, we set out to establish optimal predictor cut points of these metabolic parameters for the detection of CE and SCE. Serum samples were collected one week prior to parturition (wk -1, in the first week postpartum (wk +1 and between 28 and 35 days postpartum (wk +5 from 209 Holstein-Friesian cows. At wk +5, all cows were examined for signs of CE and SCE. Results Higher concentrations of urea at wk +1 were associated with increased odds of CE (OR = 1.7, P = 0.04 in primiparous (PP cows. A predictor cut point of 3.9 mmol/L (sensitivity: 61%, specificity: 70% was determined. In multiparous (MP cows, the logistic regression model revealed that higher concentrations of NEFA at wk -1 were associated with increased odds of CE and SCE (healthy vs. CE: OR = 9.1, P = 0.05; healthy vs. SCE: OR = 12.1, P = 0.04. A predictor cut point of 0.3 mmol/L (sensitivity: 38%, specificity: 87% and sensitivity: 35%, specificity: 89%, respectively was determined. Increasing concentrations of urea at wk +5 were associated with decreased odds of CE (healthy vs. CE: OR = 0.6, P = 0.01; SCE vs. CE: OR = 0.5, P = 0.03. A predictor cut point of 3.8 mmol/L (sensitivity: 52%, specificity: 81% was determined. For BHBA and bilirubin relationships with CE or SCE were not detected. Conclusions The corresponding combinations of sensitivity and specificity of the determined predictor cut points were not satisfactory for practical use. Thus, the analysed parameters, i.e. NEFA, BHBA, bilirubin, and urea, at the chosen time points, i.e. at wk

  8. Evaluation of time dependence and interindividual differences in benzo[a]pyrene-mediated CYP1A1 induction and genotoxicity in porcine urinary bladder cell cultures.

    Science.gov (United States)

    Plottner, Sabine; Borza, Alexandra; Wolf, Alexander; Bolt, Hermann M; Kuhlmann, Jurgen; Follmann, Wolfram

    2008-01-01

    Exposure to tobacco smoke is an established cause of cancer in humans and cigarette smoking is a risk factor for urinary bladder cancer development. Aromatic amines are believed responsible for the bladder-specific carcinogenic effect, but polycyclic aromatic hydrocarbons (PAHs) are also of potential relevance. Urothelial cells contain a number of xenobiotic-metabolizing enzymes, which enable them to convert pro-carcinogens into reactive intermediates. In a preceding study, it was demonstrated using cultured porcine urinary bladder epithelial cells (PUBEC) that CYP1A1 mRNA is induced in a potent manner by treatment with benzo[a]pyrene (BaP). In the present study, the time dependence of these effects was evaluated and whether PUBEC cultures derived from individual donors respond differently to BaP treatment was determined. CYP1A1 induction was analyzed by quantitative reverse-transcription polymerase chain reaction (RT-PCR), and genotoxic effects were studied using the Comet assay. Incubation of PUBEC with BaP increased CYP1A1 expression and induction of DNA strand breaks in a time-dependent manner. Interindividual differences were found between PUBEC cultures derived from several donor animals with respect to the response to BaP, such that the extent of CYP1A1 induction and magnitude of DNA damage was interrelated. Hence, individual differences in metabolic capacities and responsiveness to xenobiotics of urothelial cells from individual donors may be factors in susceptibility to genotoxic effects induced by PAHs. PMID:18569604

  9. Identification of leads for antiproliferative activity on MDA-MB-435 human breast cancer cells through pharmacophore and CYP1A1-mediated metabolism.

    Science.gov (United States)

    Nandekar, Prajwal P; Khomane, Kailas; Chaudhary, Vikas; Rathod, Vijay P; Borkar, Roshan M; Bhandi, Murali Mohan; Srinivas, R; Sangamwar, Abhay T; Guchhait, Sankar K; Bansal, Arvind K

    2016-06-10

    CYP1A1 is a potential target for anticancer drug development due to its overexpression in certain cancer cells and role in cancer progression. To identify new leads for CYP1A1 mediated anticancer action, we attempted ligand based pharmacophore mapping, virtual screening of databases, molecular docking, MetaSite based filtering, and molecular dynamics simulations. Initial computational and in vitro screening identified 11 compounds from which we identified two lead compounds, ZINC33468944 and ZINC32101539, showed potential antitumor activity on MDA-MB-435 cell lines (GI50 < 0.1 μM) and CYP1A1 inhibition of 0.13 and 0.3 μM, respectively. Furthermore, the lead compounds were evaluated for CYP1A1 mediated metabolism, showing N-hydroxylated metabolites, which have potential of DNA adduct formation and cause cancerous cell death. Analysis of molecular dynamics simulations provided important guidelines for the further modification of the lead compounds. Hence, we claim the lead molecules for further development in anticancer drug discovery. PMID:26994845

  10. Rats fed soy protein isolate (SPI) have impaired hepatic CYP1A1 induction by polycyclic aromatic hydrocarbons as a result of interference with aryl hydrocarbon receptor signaling

    Science.gov (United States)

    Consumption of soy diet has been found to reduce cancer incidence in animals and is associated with reduced cancer risk in humans. Previously, we have demonstrated that female Sprague-Dawley rats fed purified AIN-93G diets with soy protein isolate (SPI) as the sole protein source had reduced CYP1A1 ...

  11. Genome Editing of the CYP1A1 Locus in iPSCs as a Platform to Map AHR Expression throughout Human Development

    Directory of Open Access Journals (Sweden)

    Brenden W. Smith

    2016-01-01

    Full Text Available The aryl hydrocarbon receptor (AHR is a ligand activated transcription factor that increases the expression of detoxifying enzymes upon ligand stimulation. Recent studies now suggest that novel endogenous roles of the AHR exist throughout development. In an effort to create an optimized model system for the study of AHR signaling in several cellular lineages, we have employed a CRISPR/CAS9 genome editing strategy in induced pluripotent stem cells (iPSCs to incorporate a reporter cassette at the transcription start site of one of its canonical targets, cytochrome P450 1A1 (CYP1A1. This cell line faithfully reports on CYP1A1 expression, with luciferase levels as its functional readout, when treated with an endogenous AHR ligand (FICZ at escalating doses. iPSC-derived fibroblast-like cells respond to acute exposure to environmental and endogenous AHR ligands, and iPSC-derived hepatocytes increase CYP1A1 in a similar manner to primary hepatocytes. This cell line is an important innovation that can be used to map AHR activity in discrete cellular subsets throughout developmental ontogeny. As further endogenous ligands are proposed, this line can be used to screen for safety and efficacy and can report on the ability of small molecules to regulate critical cellular processes by modulating the activity of the AHR.

  12. Detection and assessment of genetic effects of low and very low doses of ionizing radiations using the a1+/a1 a2+/a2 system of Tobacco

    International Nuclear Information System (INIS)

    The main problem related to the detection and assessment of biological and genetic effects of low and very low doses of ionizing radiations concerns the statistical confidence. The a1+/a1 a2+/a2 system of Tobacco (Nicotania tabacum L. variety xanthi) is particularly well suited for evaluating genetic effects in this radiobiological field. (author). 7 refs., 1 tab

  13. Association and linkage analysis of COL1A1 and AHSG gene polymorphisms with femoral neck bone geometric parameters in both Caucasian and Chinese nuclear families

    Institute of Scientific and Technical Information of China (English)

    Hui JIANG; Shu-feng LEI; Su-mei XIAO; Yuan CHEN; Xiao SUN; Fang YANG; Li-ming LI; Shun WU; Hong-wen DENC

    2007-01-01

    Aim: To simultaneously investigate the contribution of the alpha 1 chain of col-lagen type 1 (COL1A1) and alpha2-HS-glycoprotein (AHSG) genes to the varia-tion of bone geometric parameters in both Caucasians and Chinese. Methods: Six hundred and five Caucasian individuals from 157 nuclear families and 1228 Chi-nese subjects from 400 nuclear families were genotyped at the AHSG-Sacl, COL1A1-PCOL2 and Sp1 polymorphisms using polymerase chain reaction (PCR)-restric-tion fragment length polymorphism (RFLP). 5 FN bone geometric parameters were calculated based on bone mineral density and bone area of femoral neck (FN)measured by dual energy X-ray absorptiometry. Population stratification, total family association, within-family association, and linkage tests were performed by the quantitative transmission disequilibrium test program. Results: The t-test showed the significant differences of all bone geometric phenotypes (except ED)between Caucasians and Chinese in the offspring using both unadjusted and adjusted (by age, height, weight, and gender) data. In Caucasians, we found significant within-family association results between the COL1A1-Sp1 polymor-phism (rs1800012) and cross sectional area (CSA), cortical thickness (CT),endocortical diameter (ED), buckling ratio (BR) (P=0.018, 0.002, 0.023, and 0.001,respectively); the COL1A1-Sp1 polymorphism also detected significant linkage with BR (P=0.039). In the population of China, the within-family associations between the COL1A1-PCOL2 polymorphism (rs1107946) and CT, BR were signifi-cant (P=0.012 and 0.008, respectively). Furthermore, evidence of linkage were observed between the AHSG-SacI polymorphism (rs4918) and CT, BR (P--0.042 and 0.014, respectively) in Caucasians, but not in Chinese. Conclusion: Our results suggest that the COL1A1 gene may have significantly association with bone geometry in both Caucasians and Chinese, and the AHSG gene may be linked to bone geometry in Caucasians, but not in Chinese. This study

  14. CYP1A1 Gene and GSTM1 Gene Polymorphism and the Combined Effects and Risk of Lung Cancer: A meta-analysis

    Directory of Open Access Journals (Sweden)

    Cheng LI

    2011-08-01

    Full Text Available Background and objective Cytochrome P450A1 (CYP1A1 gene and glutathione S-transferase M1 (GSTM1 gene both have single nucleotide polymorphisms and effects on lung cancer. Currently, however, the risk of lung cancer due to the CYP1A1 and GSTM1 genes has no clear evidence. In this present study, we propose to research the combined effects of CYP1A1 gene and GSTM1 gene polymorphism and their risks to lung cancer. Methods We conducted the study at different research areas and using various database, including PubMed, Embase, China Biology Medicine (CBM and China National Knowledge Infrastructure (CNKI last March 31, 2011. We calculated the adjusted odds ratio (OR and 95% confidence interval (CI for lung cancer in each study. Using STATA 10, a statistical program, we summarized the calculated estimates for the adjusted ORs and performed a meta-analysis.Results The meta-analysis includes 15 research studies. The CYP1A1 IIe/Val genotype which carries a homozygous mutant type has a higher chance of risk to lung cancer than that which carries a homozygous mutant type and a heterozygous type when the GSTM1 carries a null genotype. As a result, OR was 3.18 (95%CI: 1.27-7.98, 1.45 (95%CI: 1.08-1.94, respectively. Meanwhile, the same conclusion was obtained for the CYP1A1 MspI genotype. The overall OR was 1.90 (95%CI: 1.00-3.58, 1.57 (95%CI: 1.23-2.00, respectively. Conclusion We discovered through our meta-analysis that the combined effects of CYP1A1 gene and GSTM1 gene polymorphism are significantly associated with an increased risk to lung cancer. We also found that homozygous mutant genotype of CYP1A1 has a higher chance of risk to lung cancer than the homozygous or heterozygous genotype.

  15. An A1-A1 mutant with improved binding and inhibition of β2GPI/antibody complexes in antiphospholipid syndrome.

    Science.gov (United States)

    Kolyada, Alexey; Karageorgos, Ioannis; Mahlawat, Pardeep; Beglova, Natalia

    2015-03-01

    β2 glycoprotein I (β2GPI) is the most common antigen for autoimmune antibodies in antiphospholipid syndrome (APS). Thrombosis is a clinical feature of APS. We created a molecule (A1-A1) that consists of two identical β2GPI-binding modules from ApoE receptor 2 (ApoER2). A1-A1 binds to β2GPI/antibody complexes, preventing their association with ApoER2 and anionic phospholipids, and reducing thrombus size in the mouse model of APS. Here, we describe a mutant of A1-A1 (mA1-A1ND) with improved affinity for β2GPI. mA1-A1ND inhibits the binding of β2GPI to cardiolipin in the presence of anti-β2GPI antibodies, and inhibits the binding to phospholipids in plasma samples of APS patients, affecting the clotting time. Reduction of the clotting time demonstrates the presence of soluble β2GPI/antibody complexes in patients' plasma. These complexes either already exist in patients' plasma or form rapidly in the proximity to phospholipids. All members of the low-density lipoprotein receptor family bind β2GPI. Modeling studies of A1 in a complex with domain V of β2GPI (β2GPI-DV) revealed two possible modes of interaction of a ligand-binding module from lipoprotein receptors with β2GPI-DV. In both orientations, the ligand-binding module interferes with binding of β2GPI to anionic phospholipids; however, it interacts with two different but overlapping sets of lysine residues in β2GPI-DV, depending on the orientation. PMID:25546421

  16. Skatole (3-Methylindole Is a Partial Aryl Hydrocarbon Receptor Agonist and Induces CYP1A1/2 and CYP1B1 Expression in Primary Human Hepatocytes.

    Directory of Open Access Journals (Sweden)

    Martin Krøyer Rasmussen

    Full Text Available Skatole (3-methylindole is a product of bacterial fermentation of tryptophan in the intestine. A significant amount of skatole can also be inhaled during cigarette smoking. Skatole is a pulmonary toxin that induces the expression of aryl hydrocarbon receptor (AhR regulated genes, such as cytochrome P450 1A1 (CYP1A1, in human bronchial cells. The liver has a high metabolic capacity for skatole and is the first organ encountered by the absorbed skatole; however, the effect of skatole in the liver is unknown. Therefore, we investigated the impact of skatole on hepatic AhR activity and AhR-regulated gene expression. Using reporter gene assays, we showed that skatole activates AhR and that this is accompanied by an increase of CYP1A1, CYP1A2 and CYP1B1 expression in HepG2-C3 and primary human hepatocytes. Specific AhR antagonists and siRNA-mediated AhR silencing demonstrated that skatole-induced CYP1A1 expression is dependent on AhR activation. The effect of skatole was reduced by blocking intrinsic cytochrome P450 activity and indole-3-carbinole, a known skatole metabolite, was a more potent inducer than skatole. Finally, skatole could reduce TCDD-induced CYP1A1 expression, suggesting that skatole is a partial AhR agonist. In conclusion, our findings suggest that skatole and its metabolites affect liver homeostasis by modulating the AhR pathway.

  17. Skatole (3-Methylindole) Is a Partial Aryl Hydrocarbon Receptor Agonist and Induces CYP1A1/2 and CYP1B1 Expression in Primary Human Hepatocytes.

    Science.gov (United States)

    Rasmussen, Martin Krøyer; Balaguer, Patrick; Ekstrand, Bo; Daujat-Chavanieu, Martine; Gerbal-Chaloin, Sabine

    2016-01-01

    Skatole (3-methylindole) is a product of bacterial fermentation of tryptophan in the intestine. A significant amount of skatole can also be inhaled during cigarette smoking. Skatole is a pulmonary toxin that induces the expression of aryl hydrocarbon receptor (AhR) regulated genes, such as cytochrome P450 1A1 (CYP1A1), in human bronchial cells. The liver has a high metabolic capacity for skatole and is the first organ encountered by the absorbed skatole; however, the effect of skatole in the liver is unknown. Therefore, we investigated the impact of skatole on hepatic AhR activity and AhR-regulated gene expression. Using reporter gene assays, we showed that skatole activates AhR and that this is accompanied by an increase of CYP1A1, CYP1A2 and CYP1B1 expression in HepG2-C3 and primary human hepatocytes. Specific AhR antagonists and siRNA-mediated AhR silencing demonstrated that skatole-induced CYP1A1 expression is dependent on AhR activation. The effect of skatole was reduced by blocking intrinsic cytochrome P450 activity and indole-3-carbinole, a known skatole metabolite, was a more potent inducer than skatole. Finally, skatole could reduce TCDD-induced CYP1A1 expression, suggesting that skatole is a partial AhR agonist. In conclusion, our findings suggest that skatole and its metabolites affect liver homeostasis by modulating the AhR pathway. PMID:27138278

  18. Skatole (3-Methylindole) Is a Partial Aryl Hydrocarbon Receptor Agonist and Induces CYP1A1/2 and CYP1B1 Expression in Primary Human Hepatocytes

    Science.gov (United States)

    Balaguer, Patrick; Ekstrand, Bo; Daujat-Chavanieu, Martine; Gerbal-Chaloin, Sabine

    2016-01-01

    Skatole (3-methylindole) is a product of bacterial fermentation of tryptophan in the intestine. A significant amount of skatole can also be inhaled during cigarette smoking. Skatole is a pulmonary toxin that induces the expression of aryl hydrocarbon receptor (AhR) regulated genes, such as cytochrome P450 1A1 (CYP1A1), in human bronchial cells. The liver has a high metabolic capacity for skatole and is the first organ encountered by the absorbed skatole; however, the effect of skatole in the liver is unknown. Therefore, we investigated the impact of skatole on hepatic AhR activity and AhR-regulated gene expression. Using reporter gene assays, we showed that skatole activates AhR and that this is accompanied by an increase of CYP1A1, CYP1A2 and CYP1B1 expression in HepG2-C3 and primary human hepatocytes. Specific AhR antagonists and siRNA-mediated AhR silencing demonstrated that skatole-induced CYP1A1 expression is dependent on AhR activation. The effect of skatole was reduced by blocking intrinsic cytochrome P450 activity and indole-3-carbinole, a known skatole metabolite, was a more potent inducer than skatole. Finally, skatole could reduce TCDD-induced CYP1A1 expression, suggesting that skatole is a partial AhR agonist. In conclusion, our findings suggest that skatole and its metabolites affect liver homeostasis by modulating the AhR pathway. PMID:27138278

  19. Possible involvement of sulfotransferase 1A1 in estragole-induced DNA modification and carcinogenesis in the livers of female mice.

    Science.gov (United States)

    Suzuki, Yuta; Umemura, Takashi; Ishii, Yuji; Hibi, Daisuke; Inoue, Tomoki; Jin, Meilan; Sakai, Hiroki; Kodama, Yukio; Nohmi, Takehiko; Yanai, Tokuma; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2012-12-12

    Estragole (ES), a natural organic compound, is frequently used as a flavoring in food even though it is a hepatocarcinogen in mice. Although formation of ES-specific DNA adducts following conversion from ES to the nucleophilic metabolite by sulfotransferase 1A1 (SULT1A1) has been reported, the modes of action underlying ES-induced hepatocarcinogenesis remain uncertain because conventional genotoxicity tests for ES yield negative results. In the present study, taking notice of the fact that there is a sex difference in SULT1A1 activity in the mouse liver, we assessed the frequency of micronuclei in polychromatic erythrocytes and the mutant frequency (MF) of reporter genes in female gpt delta mice treated with ES at doses of 0 (corn oil), 37.5, 75, 150 or 300mg/kg body weight (bw) by gavage for 13 weeks. Results were compared with those obtained in males. Since one female was found dead at week one, the highest dose was reduced to 250mg/kg bw in females from week two. As reported previously in C57BL/6 mice, the mRNA levels of Sult1a1 in female gpt delta mice were significantly higher than those in the males. The levels of ES-specific DNA adducts in the females were higher than those in the males at all doses except the highest dose. In addition, MFs of the gpt gene were significantly increased from doses of 75mg/kg bw of females, but the increment was observed only at the highest dose in males. There were no changes in the micronucleus test among the groups. Thus, the overall data suggest that specific DNA modifications by the SULT1A1-mediated carbocation formation and the resultant genotoxicity are key events in the early stage of ES-induced hepatocarcinogenesis of mice. PMID:22885592

  20. The synthetic retinoid AGN 193109 but not retinoic acid elevates CYP1A1 levels in mouse embryos and Hepa-1c1c7 cells.

    Science.gov (United States)

    Soprano, D R; Gambone, C J; Sheikh, S N; Gabriel, J L; Chandraratna, R A; Soprano, K J; Kochhar, D M

    2001-07-15

    The synthetic retinoid AGN 193109 is a potent pan retinoic acid receptor (RAR) antagonist. Treatment of pregnant mice with a single oral 1 mg/kg dose of this antagonist on day 8 postcoitum results in severe craniofacial (median cleft face or frontonasal deficiency) and eye malformations in virtually all exposed fetuses. Using differential display analysis, we have determined that CYP1A1 mRNA levels are elevated in mouse embryos 6 h following treatment with AGN 193109. Similarly, an elevation in CYP1A1 mRNA levels, protein levels, and aryl hydrocarbon hydoxylase activity occurs in Hepa-1c1c7 cells, with the maximal elevation observed when the cells were treated with 10(-5) M AGN 193109 for 4 to 8 h. Elevation in CYP1A1 mRNA levels in mouse embryos and Hepa-1c1c7 cells does not occur upon treatment with the natural retinoid, all-trans-retinoic acid. Finally, elevation in CYP1A1 mRNA levels was not observed when mutant Hepa-1c1c7 cells, which are defective in either the aryl hydrocarbon receptor (AhR) or aryl hydrocarbon receptor nuclear translocator (ARNT), were treated with AGN 193109. This suggests that the AhR/ARNT pathway and not the RAR/RXR pathway is mediating the elevation of CYP1A1 mRNA levels by AGN 193109, at least in the Hepa-1c1c7 cells. This is the first example of a retinoid that displays the abililty to regulate both the RAR/RXR and AhR/ARNT transcriptional regulatory pathways. PMID:11446831

  1. Gammaherpesvirus infection modulates the temporal and spatial expression of SCGB1A1 (CCSP) and BPIFA1 (SPLUNC1) in the respiratory tract.

    Science.gov (United States)

    Leeming, Gail H; Kipar, Anja; Hughes, David J; Bingle, Lynne; Bennett, Elaine; Moyo, Nathifa A; Tripp, Ralph A; Bigley, Alison L; Bingle, Colin D; Sample, Jeffery T; Stewart, James P

    2015-06-01

    Murine γ-herpesvirus 68 (MHV-68) infection of Mus musculus-derived strains of mice is an established model of γ-herpesvirus infection. We have previously developed an alternative system using a natural host, the wood mouse (Apodemus sylvaticus), and shown that the MHV-68 M3 chemokine-binding protein contributes significantly to MHV-68 pathogenesis. Here we demonstrate in A. sylvaticus using high-density micro-arrays that M3 influences the expression of genes involved in the host response including Scgb1a1 and Bpifa1 that encode potential innate defense proteins secreted into the respiratory tract. Further analysis of MHV-68-infected animals showed that the levels of both protein and RNA for SCGB1A1 and BPIFA1 were decreased at day 7 post infection (p.i.) but increased at day 14 p.i. as compared with M3-deficient and mock-infected animals. The modulation of expression was most pronounced in bronchioles but was also present in the bronchi and trachea. Double staining using RNA in situ hybridization and immunohistology demonstrated that much of the BPIFA1 expression occurs in club cells along with SCGB1A1 and that BPIFA1 is stored within granules in these cells. The increase in SCGB1A1 and BPIFA1 expression at day 14 p.i. was associated with the differentiation of club cells into mucus-secreting cells. Our data highlight the role of club cells and the potential of SCGB1A1 and BPIFA1 as innate defense mediators during respiratory virus infection. PMID:25531566

  2. Bilirubin nomograms for identification of neonatal hyperbilirubinemia in healthy term and late-preterm infants:a systematic review and meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Zhang-Bin Yu; Shu-Ping Han; Chao Chen

    2014-01-01

    Background: Hyperbilirubinemia occurs in most healthy term and late-preterm infants, and must be monitored to identify those who might develop severe hyperbilirubinemia. Total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) nomograms have been developed and validated to identify neonatal hyperbilirubinemia. This study aimed to review previously published studies and compare the TcB nomograms with the TSB nomogram, and to determine if the former has the same predictive value for signifi cant hyperbilirubinemia as TSB nomogram does. Methods: A predefined search strategy and inclusion criteria were set up. We selected studies assessing the predictive ability of TSB/TcB nomograms to identify significant hyperbilirubinemia in healthy term and latepreterm infants. Two independent reviewers assessed the quality and extracted the data from the included studies. Meta-Disc 1.4 analysis software was used to calculate the pooled sensitivity, specificity, and positive likelihood ratio of TcB/TSB nomograms. A pooled summary of the receiver operating characteristic of the TcB/TSB nomograms was created. Results: After screening 187 publications from electronic database searches and reference lists of eligible articles, we included 14 studies in the systematic review and meta-analysis. Eleven studies were of medium methodological quality. The remaining three studies were of low methodological quality. Seven studies evaluated the TcB nomograms, and seven studies assessed TSB nomograms. There were no differences between the predictive abilities of the TSB and TcB nomograms (the pooled area under curve was 0.819 vs. 0.817). Conclusions: This study showed that TcB nomograms had the same predictive value as TSB nomograms, both of which could be used to identify subsequent signifi cant hyperbilirubinemia. But this result should be interpreted cautiously because some methodological limitations of these included studies were identifi ed in this review.

  3. 新生儿小时胆红素百分位曲线图预测高胆红素血症的研究进展%Prediction of neonatal hyperbilirubinemia by the hour-specific bilirubin nomogram

    Institute of Scientific and Technical Information of China (English)

    孙小凡

    2015-01-01

    Neonatal hyperbilirubinemia,a common disease in the newborn period,account for about 8% ~ 11% in all newborns.Without getting proper controlling or being treated on time,severe hyperbilirubinemia may develop bilirubin encephalopathy leading to nerve damage and functional disability,which causes society and family problems.The hour-specific bilirubin nomogram is used to evaluate neonatal bilirubin discharge risks,intervention and follow-up.All pediatricians all over the world are focus on reducing the occurrence of bilirubin encephalopathy.In this study,we reviewed all researches about predicting the occurrence of neonatal hyperbilirubinemia after discharge using the hour-specific bilirubin nomogram which will better guide clinical diagnosis and treatment.%新生儿高胆红素血症是新生儿期的常见病,约8%~11%的新生儿发生严重的高胆红素血症.严重高胆红素血症如果没有得到及时控制和治疗,可发展为胆红素脑病,导致神经损害和功能残疾.利用小时胆红素百分位曲线图对新生儿进行出院的风险预测、干预及随访,降低胆红素脑病的发生,是国内外儿科医生关注的焦点.该文就各国制备的小时胆红素百分位曲线预测出院后高胆红素血症发生风险的研究进展作一综述,以便于小时胆红素百分位曲线更好地指导临床诊疗.

  4. CYP1A1 gene polymorphisms increase lung cancer risk in a high-incidence region of Spain: a case control study

    International Nuclear Information System (INIS)

    A rural region in south-west Spain has one of the highest lung cancer incidence rates of the country, as revealed by a previous epidemiological 10-year follow-up study. The present work was undertaken to ascertain the role of CYP1A1 gene polymorphisms and their interaction with tobacco smoking in the development of the disease in this location. One-hundred-and-three cases of lung cancer and 265 controls participated in the study. The participants were screened for the presence of four CYP1A1 polymorphisms, namely MspI, Ile462Val, T3205C, and Thr461Asn. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression models adjusting for age, sex, and smoking. The distribution of the variant CYP1A1 alleles was different from that described for other Caucasian populations, with CYP1A1*2A showing an uncommonly high frequency (p < 0.01). The CYP1A1*2B allele (carrying MspI and Ile462Val mutations) was strongly associated with high lung cancer risk (OR = 4.59, CI:1.4-12.6, p <0.01). The Ile462Val polymorphism was also shown to increase the risk for the disease (OR = 4.51, CI:1.8-11.9; p <0.01) and particularly for squamous-cell (OR = 5.01; CI: 1.6-14.3, p < 0.01) and small-cell lung carcinoma (SCLC) (OR = 6.97, CI: 1.2-81.3; p = 0.04). Moreover, the Thr461Asn polymorphism was found to be associated with SCLC in a Caucasian population for the first time to our knowledge (OR = 8.33, CI: 1.3-15.2, p = 0.04). The results suggest that CYP1A1 polymorphisms contribute to increase lung cancer susceptibility in an area with an uncommon high incidence rate

  5. Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample

    International Nuclear Information System (INIS)

    Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures >80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003–0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005–0.05 range. Very few associations with p<0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs. - Highlights: • We studied the relationship between PCBs and the genetic variation in the CYP genes. • Cross sectional data from a cohort of elderly were analysed. • The PCB levels were evaluated versus 21 SNPs in three CYP genes. • PCB 118 was related to variation in the CYP1A1 gene

  6. Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample

    Energy Technology Data Exchange (ETDEWEB)

    Lind, Lars [Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala (Sweden); Penell, Johanna [Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala (Sweden); Syvänen, Anne-Christine; Axelsson, Tomas [Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala (Sweden); Ingelsson, Erik [Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala (Sweden); Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford (United Kingdom); Morris, Andrew P.; Lindgren, Cecilia [Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford (United Kingdom); Salihovic, Samira; Bavel, Bert van [MTM Research Centre, School of Science and Technology, Örebro University, Örebro (Sweden); Lind, P. Monica, E-mail: monica.lind@medsci.uu.se [Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala (Sweden)

    2014-08-15

    Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures >80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003–0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005–0.05 range. Very few associations with p<0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs. - Highlights: • We studied the relationship between PCBs and the genetic variation in the CYP genes. • Cross sectional data from a cohort of elderly were analysed. • The PCB levels were evaluated versus 21 SNPs in three CYP genes. • PCB 118 was related to variation in the CYP1A1 gene.

  7. CYP1A1 and CYP1A2 expression: Comparing 'humanized' mouse lines and wild-type mice; comparing human and mouse hepatoma-derived cell lines

    International Nuclear Information System (INIS)

    Human and rodent cytochrome P450 (CYP) enzymes sometimes exhibit striking species-specific differences in substrate preference and rate of metabolism. Human risk assessment of CYP substrates might therefore best be evaluated in the intact mouse by replacing mouse Cyp genes with human CYP orthologs; however, how 'human-like' can human gene expression be expected in mouse tissues? Previously a bacterial-artificial-chromosome-transgenic mouse, carrying the human CYP1A1CYP1A2 locus and lacking the mouse Cyp1a1 and Cyp1a2 orthologs, was shown to express robustly human dioxin-inducible CYP1A1 and basal versus inducible CYP1A2 (mRNAs, proteins, enzyme activities) in each of nine mouse tissues examined. Chimeric mice carrying humanized liver have also been generated, by transplanting human hepatocytes into a urokinase-type plasminogen activator(+/+)severe-combined-immunodeficiency (uPA/SCID) line with most of its mouse hepatocytes ablated. Herein we compare basal and dioxin-induced CYP1A mRNA copy numbers, protein levels, and four enzymes (benzo[a]pyrene hydroxylase, ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, methoxyresorufin O-demethylase) in liver of these two humanized mouse lines versus wild-type mice; we also compare these same parameters in mouse Hepa-1c1c7 and human HepG2 hepatoma-derived established cell lines. Most strikingly, mouse liver CYP1A1-specific enzyme activities are between 38- and 170-fold higher than human CYP1A1-specific enzyme activities (per unit of mRNA), whereas mouse versus human CYP1A2 enzyme activities (per unit of mRNA) are within 2.5-fold of one another. Moreover, both the mouse and human hepatoma cell lines exhibit striking differences in CYP1A mRNA levels and enzyme activities. These findings are relevant to risk assessment involving human CYP1A1 and CYP1A2 substrates, when administered to mice as environmental toxicants or drugs.

  8. Effect of honokiol on the induction of drug-metabolizing enzymes in human hepatocytes

    Directory of Open Access Journals (Sweden)

    Cho YY

    2014-11-01

    Full Text Available Yong-Yeon Cho,1 Hyeon-Uk Jeong,1 Jeong-Han Kim,2 Hye Suk Lee1 1College of Pharmacy, The Catholic University of Korea, Bucheon, Korea; 2Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea Abstract: Honokiol, 2-(4-hydroxy-3-prop-2-enyl-phenyl-4-prop-2-enyl-phenol, an active component of Magnolia officinalis and Magnolia grandiflora, exerts various pharmacological activities such as antitumorigenic, antioxidative, anti-inflammatory, neurotrophic, and antithrombotic effects. To investigate whether honokiol acts as a perpetrator in drug interactions, messenger ribonucleic acid (mRNA levels of phase I and II drug-metabolizing enzymes, including cytochrome P450 (CYP, UDP-glucuronosyltransferase (UGT, and sulfotransferase 2A1 (SULT2A1, were analyzed by real-time reverse transcription polymerase chain reaction following 48-hour honokiol exposure in three independent cryopreserved human hepatocyte cultures. Honokiol treatment at the highest concentration tested (50 µM increased the CYP2B6 mRNA level and CYP2B6-catalyzed bupropion hydroxylase activity more than two-fold in three different hepatocyte cultures, indicating that honokiol induces CYP2B6 at higher concentrations. However, honokiol treatment (0.5–50 µM did not significantly alter the mRNA levels of phase I enzymes (CYP1A2, CYP3A4, CYP2C8, CYP2C9, and CYP2C19 or phase II enzymes (UGT1A1, UGT1A4, UGT1A9, UGT2B7, and SULT2A1 in cryopreserved human hepatocyte cultures. CYP1A2-catalyzed phenacetin O-deethylase and CYP3A4-catalyzed midazolam 1'-hydroxylase activities were not affected by 48-hour honokiol treatment in cryopreserved human hepatocytes. These results indicate that honokiol is a weak CYP2B6 inducer and is unlikely to increase the metabolism of concomitant CYP2B6 substrates and cause pharmacokinetic-based drug interactions in humans. Keywords: honokiol, human hepatocytes, drug interactions, cytochrome P450, UDP-glucuronosyltransferases

  9. Correlating alleles of genes LPH, CALCR, COL1A1, VDR with the indicators of bone tissue mineral density in female population of Eastern Kazakhstan

    Directory of Open Access Journals (Sweden)

    Ainur Akilzhanova

    2010-04-01

    Full Text Available The paper attemts to identify distribution of frequency of alleles of LPH,CALCR, COL1A1, VDR genes and correlation with indicators of bonetissue mineral density (BTMD in population of reproductive agefemales in the Eastern region of Kazakhstan.Genetic research has been conducted on 475 females exhibiting LPH,CALCR, COL1A1, VDR genes, presence of which, according to previousresearch, is due to confirmed increased risk of osteoporosis. Examinedfemales were distributed by race: 213 women were of European descent,262 -Asian (Turkic.Women of Turkic descent presented a much elevated rate of allelespertaining to the genes associated with the risk of reduced BTMD.Moreover, correlation has been established between osteopeniacsyndrome and existence of certain recessive alleles in heterozygouscases.

  10. Analysis of pharmacogenetic traits in two distinct South African populations

    Directory of Open Access Journals (Sweden)

    Ikediobi Ogechi

    2011-05-01

    Full Text Available Abstract Our knowledge of pharmacogenetic variability in diverse populations is scarce, especially in sub-Saharan Africa. To bridge this gap in knowledge, we characterised population frequencies of clinically relevant pharmacogenetic traits in two distinct South African population groups. We genotyped 211 tagging single nucleotide polymorphisms (tagSNPs in 12 genes that influence antiretroviral drug disposition, in 176 South African individuals belonging to two distinct population groups residing in the Western Cape: the Xhosa (n = 109 and Cape Mixed Ancestry (CMA (n = 67 groups. The minor allele frequencies (MAFs of eight tagSNPs in six genes (those encoding the ATP binding cassette sub-family B, member 1 [ABCB1], four members of the cytochrome P450 family [CYP2A7P1, CYP2C18, CYP3A4, CYP3A5] and UDP-glucuronosyltransferase 1 [UGT1A1] were significantly different between the Xhosa and CMA populations (Bonferroni p CYP2C18, CYP3A4, the gene encoding solute carrier family 22 member 6 [SLC22A6] and UGT1A1 between the two South African populations. Characterising the Xhosa and CMA population frequencies of variant alleles important for drug transport and metabolism can help to establish the clinical relevance of pharmacogenetic testing in these populations.

  11. Assessment of Total Suspended Sediment Distribution under Varying Tidal Conditions in Deep Bay: Initial Results from HJ-1A/1B Satellite CCD Images

    Directory of Open Access Journals (Sweden)

    Liqiao Tian

    2014-10-01

    Full Text Available Using Deep Bay in China as an example, an effective method for the retrieval of total suspended sediment (TSS concentration using HJ-1A/1B satellite images is proposed. The factors driving the variation of the TSS spatial distribution are also discussed. Two field surveys, conducted on August 29 and October 26, 2012, showed that there was a strong linear relationship (R2 = 0.9623 between field-surveyed OBS (optical backscatter measurements (5-31NTU and laboratory-analyzed TSS concentrations (9.89–35.58 mg/L. The COST image-based atmospheric correction procedure and the pseudo-invariant features (PIF method were combined to remove the atmospheric effects from the total radiance measurements obtained with different CCDs onboard the HJ-1A/1B satellites. Then, a simple and practical retrieval model was established based on the relationship between the satellite-corrected reflectance band ratio of band 3 and band 2 (Rrs3/Rrs2 and in-situ TSS measurements. The R2 of the regression relationship was 0.807, and the mean relative error (MRE was 12.78%, as determined through in-situ data validation. Finally, the influences of tide cycles, wind factors (direction and speed and other factors on the variation of the TSS spatial pattern observed from HJ-1A/1B satellite images from September through November of 2008 are discussed. The results show that HJ-1A/1B satellite CCD images can be used to estimate TSS concentrations under different tides in the study area over synoptic scales without using simultaneous in-situ atmospheric parameters and spectrum data. These findings provide strong informational support for numerical simulation studies on the combined influence of tide cycles and other associated hydrologic elements in Deep Bay.

  12. Association analysis of the COL1A1 polymorphism with bone mineral density and prevalent fractures in Polish postmenopausal women with osteoporosis

    Science.gov (United States)

    Marcinkowska, Michalina; Drwęska-Matelska, Natalia; Michalak, Michał; Horst-Sikorska, Wanda; Słomski, Ryszard

    2016-01-01

    Introduction Polymorphism in the promoter region of collagen type 1α (COL1A1) +1245G/T (Sp1, rs1800012) was in some studies shown to be relevant for bone mineral density (BMD) and low-energy fracture prediction. The aim of the study was to confirm this finding in a group of postmenopausal women diagnosed with osteoporosis. Material and methods We investigated 311 Caucasian women (mean age: 65.2 ±9.39 years) either after low-energy fractures (regardless of the location) or meeting World Health Organization (WHO) criteria for osteoporosis. All patients underwent clinical examination in order to exclude secondary osteoporosis; hip and lumbar spine DEXA was performed (Lunar). The three genotypes of Sp1 polymorphism were determined by RFLP (restriction fragment length polymorphism). Results Distribution of COL1A1 genotypes (SS/Ss/ss) agreed with Hardy-Weinberg equilibrium. No relation between COL1A1 genotypes and hip/L1-L4 BMD was found. Fractures were reported in 26.3% of women. Prevalence of low-energy fractures, regardless of the type, was 50.0% in ss genotype carriers, 26.4% in SS homozygotes and 23.7% in Ss heterozygotes. There was no statistically significant recessive or dominant effect of any Sp1 genotype on fracture prevalence (p = 0.613). Conclusions We failed to observe that COL1A1 Sp 1 genotypes contribute to BMD determination or are associated with prevalent low-energy fractures in a Polish cohort of postmenopausal osteoporotic women.

  13. Analytical potential energy function for the ground state(1A1) of hydrogen isotopic D2O molecule

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The present work is to construct the potential energy function of isotopic molecules. The so-called molecular potential energy function is the electronic energy function under Born-Oppenheimer approximation,in which the nuclear motions(translational,rotational and vibration motions) are not included,therefore,its nuclear vibration motion and isotopic effect need to be considered. Based on group theory and atomic and molecular reactive statics(AMRS),the reasonable dissociation limits of D2O(1A1)are determined,its equilibrium geometry and dissociation energy are calculated by density-functional theory(DFT) B3lyp,and then,using the many-body expansion method the potential energy function of D2O(1A1) is obtained for the first time. The potential contours are drawn,in which it is found that the reactive channel D + OD→D2O has no threshold energy,so it is a free radical reaction. But the reactive channel O + DD→D2O has a saddle point. The study of collision for D2O(1A1) is under way.

  14. Analytical potential energy function for the ground state (~X1A1) of hydrogen isotopic D2O molecule

    Institute of Scientific and Technical Information of China (English)

    RUAN Wen; LUO WenLang; ZHANG Li; ZHU ZhengHe

    2009-01-01

    The present work is to construct the potential energy function of Isotopic molecules. The so-called molecular potential energy function is the electronic energy function under Born-Oppenheimer ap-proximation, in which the nuclear motions (translational, rotational and vibration motions) are not in-cluded, therefore, its nuclear vibration motion and isotopic effect need to be considered. Based on group theory and atomic and molecular reactive statics (AMRS), the reasonable dissociation limits of D2O(~X1A1) are determined, its equilibrium geometry and dissociation energy are calculated by den-sity-functional theory (DFT) B3lyp, and then, using the many-body expansion method the potential en-ergy function of D2O (~X1A1) Is obtained for the first time. The potential contours are drawn, in which It is found that the reactive channel D + OD→D2O has no threshold energy, so it is a free radical reaction. But the reactive channel O + DD→D2P has a saddle point. The study of collision for D2O (~X1A1) is under way.

  15. Biomonitoring of detoxifying activity as measured by CYP1A1 induction in Yangtze and Jialing Rivers in Chongqing City in China.

    Science.gov (United States)

    Cui, Zhihong; Liu, Jingyi; Li, Peng; Cao, Bo; Luo, Caihong; Cao, Jia

    2009-01-01

    In order to determine the potential toxicities of organic pollutants in the river water of Chongqing City (China), chemicals were extracted from surface water of the Yangtze River and Jialing River between August 2004 and January 2005. Gas chromatography/mass spectrometry (GC/MS) analysis showed that the main compounds detected were polycyclic aromatic hydrocarbons (PAH) and phthalate acid esters (PAE). The ethoxyresorufin O-deethylase (EROD) test showed that the toxic equivalency (TEQ) values of the samples ranged from 0.9 to 13.3 x 10(-4) pg 2,3,7,8-TCDD/L river water. Incubation of H4IIE cells with organic extracts produced a time-dependent induction of cytochrome P-450 1A1 (CYP1A1) mRNA expression as determined by (1) reverse-transcription polymerase chain reaction (RT-PCR), (2) positive binding to aryl hydrocarbon receptor (AhR), and (3) activation of xenobiotic response element (XRE) by electrophoretic mobility shift assay (EMSA). Data indicated that organic extracts from the river water of Chongqing City induced CYP1A1 activity in hepatocytes in vitro. A possible mechanism underlying toxicity might involve the AhR signal pathway, but further studies are necessary. PMID:19492243

  16. Isolation of two cytochrome P450 cDNAs, CYP1A1 and CYP1A2, from harp seal (Phoca groenlandica) and grey seal (Halichoerus grypus).

    Science.gov (United States)

    Tilley, Rachel E; Kemp, Graham D; Teramitsu, Ikuko; Hall, Ailsa J

    2002-06-01

    Two cytochrome P450 (CYP), CYP1A1 and CYP1A2, cDNA sequences have been isolated and cloned from harp seal (Phoca groenlandica) and grey seal (Halichoerus grypus). EROD, a model substrate for CYP1A, and heterologous antibodies have been employed as a biomarker in marine mammals, however the CYP1A sequences have not been characterised in these two seal species. mRNA was used as the template in RT-PCR, rather than DNA as this indicates transcription of the CYP1A gene in these seal species exposed to environmental contaminants. Harp and grey seal CYP1A1 amino acid sequences exhibited >99% identity and the CYP1A2 sequences were >98% identical. Phylogenetic analyses of the two seal species with other mammalian, and avian CYP1A sequences, showed the CYP1A1 and CYP1A2 sequences clustered with corresponding sequences in other mammalian species. The closest sequences to the seal CYP1As was dog CYP1A. The CYP1A sequence information presented in this study has provided the necessary data for the future production of species-specific probes for the use as biomarkers of environmental contaminant exposure. PMID:12106895

  17. Polymorphisms in sulfotransferase 1A1 and glutathione S-transferase P1 genes in relation to colorectal cancer risk and patients' survival

    Institute of Scientific and Technical Information of China (English)

    Xiao-Feng Sun; Ahmad Ahmadi; Gunnar Arbman; (A)sa Wallin; Daniel Asklid; Hong Zhang

    2005-01-01

    AIM: To examine whether polymorphisms in SULT1A1 and GSTP1 genes contribute to colorectal cancer development and whether they are associated with clinicopathological variables are not well identified.METHODS: We examined the genotypes of 125colorectal cancer patients and 666 healthy controls in a Swedish population by using PCR-restriction fragment length polymorphism (RFLP).RESULTS: SULT1A1*2/*2 genotype (OR=2.49,95%CI=1.48-4.19, P=0.0002) and *2 allele (OR=1.56, 95%CI = 1.16-2.10, P = 0.002) had an effect on colorectal cancer susceptibility, while GSTP1 genotype was without effect. However, GSTP1 G-type predicted a worse prognosis in the patients independently of gender,age, Dukes'stage, growth pattern, and differentiation (P=0.03).CONCLUSION: Polymorphism in SULT1A1 may predispose to colorectal cancer and GSTP1 may be a biological indicator of prognosis in the patients.

  18. Optimal time of phototherapy for newborns whose total bilirubin ranges from 75 th to 95th percentile in the hour - specific serum bilirubin nomogram%对总胆红素位于小时胆红素第75-95百分位的新生儿光疗时机的研究

    Institute of Scientific and Technical Information of China (English)

    韩金粉; 彭艳松; 刘学工

    2012-01-01

    Objective To study the optimal time of phototherapy for newborns (gestational age≥36 weeks and birth weight≥2500 g) whose total bilirubin ranges from 75th to 95th percentile in the hour - specific serum bilirubin nomogram.Methods The hour - specific serum bilirubin nomogram recommended by America in 2004 was used in this study.Newborns total serum bilirubin (TSB) values from 75th to 95th percentile were divided into 2 groups based on high -risk factors of jaundice inside 72 hours after birth:the observed group with high - risk factors of jaundice and the CK group without them.The number of TSB of the newborns TSB beyond 95th percentile outside 72 h after birth was researched in the two groups.Results Before discharge,total serum bilirubin (TSB) values of 12.8% (5/39) infants were in the high risk zone ( >95th percentile) in the CK group and of 32.2% (10/31) were in that zone in the observed group.The difference was significant ( x2 =3.876,P < 0.05 ).Conclusions Phototherapy should begin inside 72 hours after birth for the newborns with high - risk factors of jaundice and (TSB) values from 75 th to 95 th percentile,and the primary diseases should be treated actively.%目的 探讨胎龄≥36周、体质量≥2500 g、总胆红素值位于小时胆红素百分位值列线图第75~95百分位的新生儿合理光疗时机.方法 利用美国2004年推荐使用的小时胆红素百分位值列线图,将生后72 h内总胆红素值位于第75 ~95百分位的新生儿,分为有黄疸高危因素的研究组及无黄疸高危因素的对照组,比较两组新生儿生后72 h后胆红素上升至第95百分位病例数的统计学差异.结果 对照组39倒,生后72 h后总胆红素上升至第95百分位5倒,发生率为12.8% (5/39);研究组31例,生后72 h后总胆红素上升至第95百分位10例,发生率为32.2%( 10/31),差异有统计学意义(x2=3.876,P< 0.05).结论 对生后72 h内总胆红素值位于小时胆

  19. 5-HT1A/1B receptors as targets for optimizing pigmentary responses in C57BL/6 mouse skin to stress.

    Directory of Open Access Journals (Sweden)

    Hua-Li Wu

    Full Text Available Stress has been reported to induce alterations of skin pigmentary response. Acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT whereas chronic stress causes a decrease. 5-HT receptors have been detected in pigment cells, indicating their role in skin pigmentation. To ascertain the precise role of 5-HT in stress-induced pigmentary responses, C57BL/6 mice were subjected to chronic restraint stress and chronic unpredictable mild stress (CRS and CUMS, two models of chronic stress for 21 days, finally resulting in abnormal pigmentary responses. Subsequently, stressed mice were characterized by the absence of a black pigment in dorsal coat. The down-regulation of tyrosinase (TYR and tyrosinase-related proteins (TRP1 and TRP2 expression in stressed skin was accompanied by reduced levels of 5-HT and decreased expression of 5-HT receptor (5-HTR system. In both murine B16F10 melanoma cells and normal human melanocytes (NHMCs, 5-HT had a stimulatory effect on melanin production, dendricity and migration. When treated with 5-HT in cultured hair follicles (HFs, the increased expression of melanogenesis-related genes and the activation of 5-HT1A, 1B and 7 receptors also occurred. The serum obtained from stressed mice showed significantly decreased tyrosinase activity in NHMCs compared to that from nonstressed mice. The decrease in tyrosinase activity was further augmented in the presence of 5-HTR1A, 1B and 7 antagonists, WAY100635, SB216641 and SB269970. In vivo, stressed mice received 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP, a member of the class of selective serotonin reuptake inhibitors (fluoxetine; FX and 5-HTR1A/1B agonists (8-OH-DPAT/CP94253, finally contributing to the normalization of pigmentary responses. Taken together, these data strongly suggest that the serotoninergic system plays an important role in the regulation of stress-induced depigmentation, which can be mediated by 5-HT1A/1B receptors. 5-HT

  20. Functional Analysis of the Dioxin Response Elements (DREs of the Murine CYP1A1 Gene Promoter: Beyond the Core DRE Sequence

    Directory of Open Access Journals (Sweden)

    Shuaizhang Li

    2014-04-01

    Full Text Available The aryl hydrocarbon receptor (AhR is a ligand-dependent transcription factor that mediates the biological and toxicological effects of halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD. When activated by dioxin, the cytosolic AhR protein complex translocates into the nucleus and dimerizes with the ARNT (Ah receptor nuclear translocator protein. The heteromeric ligand:AhR/Arnt complex then recognizes and binds to its specific DNA recognition site, the dioxin response element (DRE. DREs are located upstream of cytochrome P4501A1 (CYP1A1 and other AhR-responsive genes, and binding of the AhR complex stimulates their transcription. Although CYP1A1 expression has been used as the model system to define the biochemical and molecular mechanism of AhR action, there is still limited knowledge about the roles of each of the seven DREs located in the CYP1A1 promoter. These seven DREs are conserved in mouse, human and rat. Deletion analysis showed that a single DRE at -488 was enough to activate the transcription. Truncation analysis demonstrated that the DRE at site -981 has the highest transcriptional efficiency in response to TCDD. This result was verified by mutation analysis, suggesting that the conserved DRE at site -981 could represent a significant and universal AhR regulatory element for CYP1A1. The reversed substituted intolerant core sequence (5'-GCGTG-3' or 5'-CACGC-3' of seven DREs reduced the transcriptional efficiency, which illustrated that the adjacent sequences of DRE played a vital role in activating transcription. The core DRE sequence (5'-TNGCGTG-3' tends to show a higher transcriptional level than that of the core DRE sequence (5'-CACGCNA-3' triggered by TCDD. Furthermore, in the core DRE (5'-TNGCGTG-3' sequence, when “N” is thymine or cytosine (T or C, the transcription efficiency was stronger compared with that of the other nucleotides. The effects of DRE orientation, DRE adjacent sequences and

  1. Association of sulfotransferase SULT1A1 with breast cancer risk: a meta-analysis of case-control studies with subgroups of ethnic and menopausal statue

    Directory of Open Access Journals (Sweden)

    Shao Zhimin

    2010-07-01

    Full Text Available Abstract Background Sulfotransferase (SULT plays an important role in the formation of estrogen which is usually conferred as a risk factor for breast cancer. Polymorphism of the SULT1A1 may be closely associated with breast cancer. However, studies on the association between polymorphism and breast cancer have yielded inconsistent results. We performed a meta-analysis including ethnic subgroup and menopausal statue subgroup to investigate the association of SULT1A1 Arg213His polymorphism with breast cancer. Methods PubMed, EBSCO and Web of Science databases were searched for the correlative articles up to January 2010 (10362 breast cancer patients and 14250 controls. The risk (odds ratio, OR was used to estimate the association between SULT1A1 polymorphism and breast cancer risk. All of the data from each study use either fixed-effects or random-effects. Results We found that SULT1A1 Arg213His had no exact effect to increase the risk of breast cancer (OR = 1.07, 95% CI: 0.97-1.17, P = 0.164, but it did increase the risk of breast cancer among postmenopausal women in the dominant model (OR = 1.28, 95%CI: 1.04-1.58, P = 0.019. No similar effect was found among premenopausal breast cancer women (OR = 1.06, 95%CI: 0.88-1.27, P = 0.537. There was a significant increase in breast cancer risk among Asian women (OR = 2.03, 95% CI: 1.00-4.14, P = 0.051 but not Caucasian women in recessive model. There was publication bias among postmenopausal women subgroup (P = 0.002, however by using the trim and fill method, if the publication bias was the only source of the funnel plot asymmetry, it needed two more studies to be symmetrical. The value of Log OR did not change too much after the adjustment and the fail-safe number of missing studies that would bring the P-value changed was 17. Conclusions We concluded that the polymorphism of SULT1A1 Arg213His might be one of the high risk factors for breast cancer in Asian women and in postmenopausal women for all

  2. Association of The Common CYP1A1*2C Variant (Ile462Val Polymorphism with Chronic Myeloid Leukemia (CML in Patients Undergoing Imatinib Therapy

    Directory of Open Access Journals (Sweden)

    Samyuktha Lakkireddy

    2015-10-01

    Full Text Available Objective: Cytochrome P450 is one of the major drug metabolizing enzyme families and its role in metabolism of cancer drugs cannot be less emphasized. The association between single nucleotide polymorphisms (SNPs in CYP1A1 and pathogenesis of chronic myeloid leukemia (CML has been investigated in several studies, but the results observed vary based on varied risk factors. The objective of this study was to investigate the risk factors associated with the CYP1A1*2C [rs1048943: A>G] polymorphism in CML patients and its role in therapeutic response to imatinib mesylate (IM affecting clinico-pathological parameters, in the Indian population. Materials and Methods: In this case-control study, CYP1A1*2C was analysed in CML patients. After obtaining approval from the Ethics Committee of oncology hospital, we collected blood samples from 132 CML patients and 140 matched controls. Genomic DNA was extracted and all the samples were analysed for the presence of the CYP1A1*2C polymorphism using allele-specific polymerase chain reaction, and we examined the relationship of genotypes with risk factors such as gender, age, phase of the disease and other clinical parameters. Results: We observed a significant difference in the frequency distribution of CYP1A1*2C genotypes AA (38 vs. 16%, P=0.0001, AG (57 vs. 78%, P=0.0002 and GG (5 vs. 6%, P=0.6635 between patients and controls. In terms of response to IM therapy, significant variation was observed in the frequencies of AA vs AG in major (33 vs 67% and poor (62 vs 31% hematological responders, and AA vs AG in major (34 vs. 65% and poor (78 vs. 22% cytogenetic responders. However, the patients with the GG homozygous genotype did not show any significant therapeutic outcome. Conclusion: The higher frequency of AG in controls indicates that AG may play a protective role against developing CML. We also found that patients with the AG genotype showed favorable treatment response towards imatinib therapy, indicating

  3. Polymorphisms of estrogen metabolism-related genes ESR1 , UGT2B17 , and UGT1A1 are not associated with osteoporosis in artificial menopausal Japanese women

    Directory of Open Access Journals (Sweden)

    Megumi Yokota

    2015-09-01

    Full Text Available Introduction : Bilateral salpingo-oophorectomy (BSO is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve the quality of life for surgically menopausal patients. Material and methods : This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 ( ESR1 and UDP-glucuronosyl transferase (UGT genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated. Results : No significant association was found between osteoporosis and polymorphisms in ESR1 , UGT2B17 , or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations. Conclusions : These results suggest that the ESR1 , UGT2B17 , and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.

  4. Role of glutathione-s-transferase and CYP1A1FNx012A polymorphisms in the therapy outcome of south Indian acute lymphoblastic leukemia patients

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    K J Suneetha

    2011-01-01

    Full Text Available Background: Polymorphisms in the drug-metabolizing enzymes are found to be associated with the inter-individual variation in response to a particular drug. Glutathione S-transferases (GSTs are involved in the metabolism of several anticancer drugs, including alkylating agents, anthracyclines, and cyclophosphamides. Aim: The present study is aimed to examine the association of GST and CYP1A1FNx012A polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL and the prognostic significance. Materials and Methods: A total of 92 immunophenotyped patients and 150 cord blood controls were genotyped by PCR for GSTM1 and GSTT1, RQ-PCR allelic discrimination assay for GSTP1 and PCR-RFLP for CYP1A1FNx012A polymorphism. Results: We have previously reported the significant association of GSTM1 (null and combined GSTP1 {(Ile/Val/ (Val/Val} /GSTM1 (null genotype with the susceptibility to ALL. No significant association was observed with GSTT1 (P=0.75 and CYP1A1FNx012A (P=0.61 for +/- and P=0.86 for -/- respectively in the susceptibility to ALL. Survival analysis was performed in 50 of the 92 patients who were followed for three years. Kaplan-Meier survival analysis for three years showed significant lower event-free survival in patients harboring GSTP1 (Ile/Val and GSTP1 (Val/Val (P=0.038 and 0.0001, respectively genotype. Cox regression analysis revealed GSTP1 as an independent prognostic marker with 6-fold higher risk with Val/Val genotype (P=0.003. Conclusions: Our results show that GSTP1 (Ile/Val polymorphism has a role in the susceptibility to ALL and also influence treatment outcome.

  5. Genetic polymorphisms in CYP1A1, GSTM1, GSTP1 and GSTT1 metabolic genes and risk of lung cancer in Asturias

    International Nuclear Information System (INIS)

    Metabolic genes have been associated with the function of metabolizing and detoxifying environmental carcinogens. Polymorphisms present in these genes could lead to changes in their metabolizing and detoxifying ability and thus may contribute to individual susceptibility to different types of cancer. We investigated if the individual and/or combined modifying effects of the CYP1A1 MspI T6235C, GSTM1 present/null, GSTT1 present/null and GSTP1 Ile105Val polymorphisms are related to the risk of developing lung cancer in relation to tobacco consumption and occupation in Asturias, Northern Spain. A hospital-based case–control study (CAPUA Study) was designed including 789 lung cancer patients and 789 control subjects matched in ethnicity, age, sex, and hospital. Genotypes were determined by PCR or PCR-RFLP. Individual and combination effects were analysed using an unconditional logistic regression adjusting for age, pack-years, family history of any cancer and occupation. No statistically significant main effects were observed for the carcinogen metabolism genes in relation to lung cancer risk. In addition, the analysis did not reveal any significant gene-gene, gene-tobacco smoking or gene-occupational exposure interactions relative to lung cancer susceptibility. Lastly, no significant gene-gene combination effects were observed. These results suggest that genetic polymorphisms in the CYP1A1, GSTM1, GSTT1 and GSTP1 metabolic genes were not significantly associated with lung cancer risk in the current study. The results of the analysis of gene-gene interactions of CYP1A1 MspI T6235C, GSTM1 present/null, GSTT1 present/null and GSTP1 Ile105Val polymorphisms in lung cancer risk indicate that these genes do not interact in lung cancer development

  6. Association of CYP1A1 MspI polymorphism with oral cancer risk in Asian populations: a meta-analysis.

    Science.gov (United States)

    Xu, J L; Xia, R; Sun, L; Min, X; Sun, Z H; Liu, C; Zhang, H; Zhu, Y M

    2016-01-01

    Numerous studies regarding the association between the CYP1A1 MspI polymorphism and oral cancer risk in Asian populations have shown controversial results. To get a more precise estimation of this relationship, we conducted a comprehensive meta-analysis. PubMed, the Cochrane Library, Elsevier Science Direct, Web of Knowledge, the Chinese National Knowledge Infrastructure, VIP, and Wan Fang Med Online were searched. Pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated using fixed-effects or random-effects models. Heterogeneity among studies was assessed using the Cochran Q test and I(2) statistics. Twelve articles including 1925 oral cancer patients and 2335 controls were ultimately included in the meta-analysis. Overall, the meta-analysis showed that the CYP1A1 MspI polymorphism was associated with oral cancer risk in Asians (m1/m1 vs m2/m2: OR = 0.46, 95%CI = 0.30-070, POR = 0.000; m1/m1 vs m1/m2+m2/m2: OR = 0.70, 95%CI = 0.51-0.98, POR = 0.037; m1/m1+m1/m2 vs m2/m2: OR = 0.48, 95%CI = 0.35-0.65, POR = 0.000). Subgroup analyses showed that the control source (hospital-based or population-based), the genotyping method [polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism], the country in which the study was conducted, and Hardy-Weinberg equilibrium (Yes or No) were positively related to the association. Sensitivity analysis suggested that the overall results showed no significant change in three genetic models when any one study was removed, and publication bias was undetected by the Egger test. The CYP1A1 MspI polymorphism may be associated with oral cancer risk in Asian populations. PMID:27323067

  7. Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations - genotype-phenotype correlations and effect of bisphosphonate treatment.

    Science.gov (United States)

    Sato, Atsuko; Ouellet, Jean; Muneta, Takeshi; Glorieux, Francis H; Rauch, Frank

    2016-05-01

    Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle ≥25°) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10°) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type. PMID:26927310

  8. A study on the association of cytochrome-P450 1A1 polymorphism and breast cancer risk in north Indian women.

    Science.gov (United States)

    Singh, Virendra; Rastogi, Neeraj; Sinha, Ashima; Kumar, Abhai; Mathur, Neeraj; Singh, Mahendra Pratap

    2007-01-01

    Cytochrome P-450 1A1 (CYP1A1) is involved in the 2-hydroxylation of estrogens and mammary carcinogens into 2-hydroxy catechol metabolites. Many commonly occurring single nucleotide polymorphism (SNP) are reported in CYP1A1 in various populations that include, isoleucine to valine substitution at 462 codon in heme binding region in exon 7 (A to G transition at position 2455; M2), threonine to asparagine substitution at codon 461 (C to A transversion at position 2453; M4), T to C transition at 3801 position (M1) and T to C transition at position 3205 (M3) in 3' non-coding region. Epidemiological studies have shown inconsistent patterns between CYP1A1 polymorphism and breast cancer risk among various populations. Most of the studies have shown significant association between CYP1A1 genotype polymorphism and breast cancer risk. The present investigation was therefore undertaken to investigate the association of M1, M2, M3 and M4 polymorphisms and their subsequent contribution in premenopausal and postmenopausal women with breast cancer risk in north Indian women. Genomic DNA was isolated from case controls and breast cancer patients, specific segments of genomic DNA were amplified and restriction fragment length polymorphism (RFLP) was performed. CYP1A1 expression and catalytic activity were also assessed in premenopausal and postmenopausal case controls and patients. Polymorphism at M1, M2 and M4 alleles was detected and odds ratio for W/M1 and M1/M1 was calculated as 1.07 (95% CI, 0.59-1.87) and 0.74 (95% CI, 0.28-1.96) respectively. Odds ratio for W/M1 and M1/M1 alleles in premenopausal and postmenopausal women was 1.09 (95% CI, 0.45-2.49)/0.62 (95% CI, 0.10-2.66) and 1.60 (95% CI, 0.60-4.22)/1.06 (95% CI, 0.22-7.33) respectively. Odds ratio for W/M4 and M4/M4 allele was 1.20 (95% CI, 0.65-2.24)/4.55 (95% CI, 0.44-226.2) and 0.96 (95% CI, 0.36-2.64)/4.51 (95% CI, 0.23-273.0) respectively in total and premenopausal women. In postmenopausal women odds ratio was

  9. Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Vorrink, Sabine U. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Severson, Paul L. [Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ (United States); Kulak, Mikhail V. [Department of Surgery, The University of Iowa, Iowa City, IA (United States); Futscher, Bernard W. [Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ (United States); Domann, Frederick E., E-mail: frederick-domann@uiowa.edu [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Department of Surgery, The University of Iowa, Iowa City, IA (United States)

    2014-02-01

    The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degrees of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Exposure to 1% O{sub 2} prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity. - Highlights: • Significant crosstalk exists between AhR and HIF-1α signaling. • Hypoxia perturbs PCB 126 induced AhR function and

  10. Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver.

    Directory of Open Access Journals (Sweden)

    P Harkitis

    Full Text Available Dopaminergic systems regulate the release of several hormones including growth hormone (GH, thyroid hormones, insulin, glucocorticoids and prolactin (PRL that play significant roles in the regulation of various Cytochrome P450 (CYP enzymes. The present study investigated the role of dopamine D2-receptor-linked pathways in the regulation of CYP1A1, CYP1A2 and CYP1B1 that belong to a battery of genes controlled by the Aryl Hydrocarbon Receptor (AhR and play a crucial role in the metabolism and toxicity of numerous environmental toxicants. Inhibition of dopamine D2-receptors with sulpiride (SULP significantly repressed the constitutive and benzo[a]pyrene (B[a]P-induced CYP1A1, CYP1A2 and CYP1B expression in the rat liver. The expression of AhR, heat shock protein 90 (HSP90 and AhR nuclear translocator (ARNT was suppressed by SULP in B[a]P-treated livers, whereas the AhRR expression was increased by the drug suggesting that the SULP-mediated repression of the CYP1 inducibility is due to inactivation of the AhR regulatory system. At signal transduction level, the D2-mediated down-regulation of constitutive CYP1A1/2 and CYP1B1 expression appears to be mediated by activation of the insulin/PI3K/AKT pathway. PRL-linked pathways exerting a negative control on various CYPs, and inactivation of the glucocorticoid-linked pathways that positively control the AhR-regulated CYP1 genes, may also participate in the SULP-mediated repression of both, the constitutive and induced CYP1 expression. The present findings indicate that drugs acting as D2-dopamine receptor antagonists can modify several hormone systems that regulate the expression of CYP1A1, CYP1A2 and CYP1B1, and may affect the toxicity and carcinogenicity outcome of numerous toxicants and pre-carcinogenic substances. Therefore, these drugs could be considered as a part of the strategy to reduce the risk of exposure to environmental pollutants and pre-carcinogens.

  11. Carnosol, a Constituent of Zyflamend, Inhibits Aryl Hydrocarbon Receptor-Mediated Activation of CYP1A1 and CYP1B1 Transcription and Mutagenesis

    OpenAIRE

    Mohebati, Arash; Guttenplan, Joseph B.; Kochhar, Amit; Zhao, Zhong-Lin; Kosinska, Wieslawa; Subbaramaiah, Kotha; Dannenberg, Andrew J.

    2012-01-01

    The aryl hydrocarbon receptor (AhR), a ligand-activated member of the basic-helix-loop-helix family of transcription factors, plays a significant role in polycyclic aromatic hydrocarbon (PAH) induced carcinogenesis. In the upper aerodigestive tract of humans, tobacco smoke, a source of PAHs, activates the AhR leading to increased expression of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to genotoxic metabolites. Inhibitors of Hsp90 ATPase cause a rapid decrease in levels of AhR...

  12. Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines

    International Nuclear Information System (INIS)

    The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degrees of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Exposure to 1% O2 prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity. - Highlights: • Significant crosstalk exists between AhR and HIF-1α signaling. • Hypoxia perturbs PCB 126 induced AhR function and target

  13. MeIQx-induced DNA adduct formation and mutagenesis in DNA repair deficient CHO cells expressing human CYP1A1 and rapid or slow acetylator NAT2

    OpenAIRE

    Bendaly, Jean; Zhao, Shuang; Neale, Jason R.; Metry, Kristin J.; Doll, Mark A; States, J. Christopher; Pierce, William M.; Hein, David W.

    2007-01-01

    2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx) is one of the most potent and abundant mutagens in the western diet. Bioactivation includes N-hydroxylation catalyzed by cytochrome P450s followed by O-acetylation catalyzed by N-acetyltransferase 2 (NAT2). Nucleotide excision repair-deficient chinese hamster ovary (CHO) cells were constructed by stable transfection of human cytochrome P4501A1 (CYP1A1) and a single copy of either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alle...

  14. CYP1A1-HincⅡ和GSTT1基因遗传多态性与原发性痛经关系分析%Analysis on associations of cytochrome P450 1A1-HincⅡ and glutathion S-transferase-theta with primary dysmenorrhea

    Institute of Scientific and Technical Information of China (English)

    吴涤; 刘学; 倪佳桐; 金永堂; 陈大方; 徐希平

    2001-01-01

    目的 研究原发性痛经的遗传易感性。方法 收集某纺织厂499名新婚女工的资料,采用Logistic回归分析,评价CYP1A1-HincⅡ和GSTT1多态性与重度原发性痛经的关系。结果 在未调整环境因素时CYP1A1-HincⅡ变异基因型虽对痛经有缓解趋势,但差异无显著性(CYP1A1-HincⅡ:OR=0.64 95% CI:0.35~1.17)。而GSTT1变异基因型可增加重度原发性痛经危险性(GSTT1:OR=1.83,95% CI:1.04~3.21)。调整潜在环境影响因素后,CY1A1-HincⅡ变异基因型显示对原发性痛经有缓解趋势(CYP1A1-HincⅡ:OR=0.58,95% CI:0.31~1.08),但差异仍无显著性。而GSTT1变异基因型仍显示可增加重度原发性痛经的危险性(GSTT1:OR=2.01,95% CI:1.12~3.62)。结论 重度原发性痛经与GSTT1遗传多态性相关。%Objective To investigate the genetic susceptibility to primary dysmenorrhea.Methods Data of 499 female workers in a textile mill were collected. The associations of cytochrome P450 1A1-HincⅡ(CYP1A1-HincⅡ) and glutathion S-transferase-theta(GSTT1) polymorphisms with heavy primary dysmenorrhea were evaluated by Logistic regression, with adjustment for potential confounders.Results The result showed variant of CYP1A1-HincⅡ genotypes slightly reduced the risk of primary dysmenorrhea, but its OR value was not statistically significant (CYP1A1-HincⅡ:OR=0.64,95% CI 0.35-1.17).The GSTT1 genotype variant increased the risk of primary dysmenorrhea (GSTT1:OR=1.83,95% CI 1.04-3.21). After potential confounders were adjusted, the data showed that CYP1A1-HincⅡ variant had the trend of decreasing the risk of dysmenorrhea (CYP1A1-HincⅡ:OR=0.58,95% CI 0.31-1.08), but its decreasing scope was still not statistically significant. The GSTT1 variant genotypes showed a significantly increased risk of dysmenorrhea (GSTT1:OR=2.01, 95% CI 1.12-3.62).Conclusion The results suggested that GSTT1 polymorphism be associated with heavy

  15. Determination of Effect of Low Dose Vs Moderate Dose of Clofibrate on the Decreasing in Serum Bilirubin Level in the Term Healthy Neonate

    Directory of Open Access Journals (Sweden)

    Mohammad Ashkan Moslehi

    2007-05-01

    Full Text Available Objective: This study was performed to determine the effect of low doses (25 mg/Kg vs. moderate doses (50 mg/Kg of clofibrate in treatment of non-hemolytic hyperbilirubin¬emia in healthy term neonates. Material & Methods: A clinical randomized controlled trial was performed in three groups of healthy term neonates. One group was treated with a single low dose of clofibrate (25 mg/Kg while another group received a single moderate dose (50mg/kg both orally plus phototherapy; the results were compared with those of a control group that received only phototherapy. Findings: The mean total serum bilirubin (TSB levels of 12th and 24th hours were significantly lower in the two clofibrate-treated groups as compared with the control group (P=0.002 and P=0.003, respectively. There was no statistically significant difference between the mean of TSB levels in the two clofibrate-treated groups. Treatment with clofibrate also resulted in a shorter duration of jaundice and a decreased use of phototherapy (P=0.01. No side effects were observed. Conclusion: The present study demonstrated that there was no significant difference between a low (25mg/Kg and moderate (50mg/Kg doses of clofibrate in reducing TSB levels and also decreased need of phototherapy in healthy breastfed term newborns with marked hyperbilirubin¬emia (TSB>16 mg/dL.

  16. Electrochemistry of bilirubin oxidase and its use in preparation of a low cost enzymatic biofuel cell based on a renewable composite binder chitosan

    International Nuclear Information System (INIS)

    Graphical abstract: - Abstract: Spherical carbon nanoparticles KetjenBlack (KB) with a high sorption capacity together with conductivity increasing single walled carbon nanotubes (CNTs) were “glued” together by chitosan for the preparation of a composite. A biocathode with bilirubin oxidase (BOD) adsorbed within the composite was characterised and its composition optimised. A renewable biopolymer chitosan present in the composite offered (1) pre-concentration of BOD within the matrix via electrostatic interactions, (2) favourable orientation of BOD for a direct electron transfer (DET) between BOD and the composite, (3) electrochemical visibility of 3 redox sites present in BOD, (4) low charge transfer resistance, (5) high proton conductivity and (6) low overpotential for oxygen reduction. Electrochemical investigation of BOD revealed interesting internal redox communication within the enzyme with some novel insights provided. At least one of tyrosines present in BOD seems to be involved in electron transfer route, as well. The composite used for the biocathode was directly applied for the preparation of a bioanode with fructose dehydrogenase immobilised, working in a DET mode of operation. Finally, integration of the biocathode and the bioanode into a biofuel cell operated in a reagentless and membraneless mode offered a power density of 50 μW cm−2 at 300 mV.

  17. Validation of transcutaneous bilirubin nomogram for identifying neonatal hyperbilirubinemia in healthy Chinese term and late-preterm infants: a multicenter study

    Directory of Open Access Journals (Sweden)

    Zhangbin Yu

    2014-06-01

    Full Text Available OBJECTIVE: to prospectively validate a previously constructed transcutaneous bilirubin (TcB nomogram for identifying severe hyperbilirubinemia in healthy Chinese term and late-preterm infants. METHODS: this was a multicenter study that included 9,174 healthy term and late-preterm infants in eight hospitals of China. TcB measurements were performed using a JM-103 bilirubinometer. TcB values were plotted on a previously developed TcB nomogram, to identify the predictive ability for subsequent significant hyperbilirubinemia. RESULTS: in the present study, 972 neonates (10.6% developed significant hyperbilirubinemia. The 40th percentile of the nomogram could identify all neonates who were at risk of significant hyperbilirubinemia, but with a low positive predictive value (PPV (18.9%. Of the 453 neonates above the 95th percentile, 275 subsequently developed significant hyperbilirubinemia, with a high PPV (60.7%, but with low sensitivity (28.3%. The 75th percentile was highly specific (81.9% and moderately sensitive (79.8%. The area under the curve (AUC for the TcB nomogram was 0.875. CONCLUSIONS: this study validated the previously developed TcB nomogram, which could be used to predict subsequent significant hyperbilirubinemia in healthy Chinese term and late-preterm infants. However, combining TcB nomogram and clinical risk factors could improve the predictive accuracy for severe hyperbilirubinemia, which was not assessed in the study. Further studies are necessary to confirm this combination.

  18. Development and validation of serum bilirubin nomogram to predict the absence of risk for severe hyperbilirubinaemia before discharge: a prospective, multicenter study

    Directory of Open Access Journals (Sweden)

    Romagnoli Costantino

    2012-02-01

    Full Text Available Abstract Background Early discharge of healthy late preterm and full term newborn infants has become common practice because of the current social and economic necessities. Severe jaundice, and even kernicterus, has developed in some term infants discharged early. This study was designed to elaborate a percentile-based hour specific total serum bilirubin (TSB nomogram and to assess its ability to predict the absence of risk for subsequent non physiologic severe hyperbilirubinaemia before discharge. Methods A percentile-based hour-specific nomogram for TSB values was performed using TSB data of 1708 healthy full term neonates. The nomogram's predictive ability was then prospectively assessed in five different first level neonatal units, using a single TSB value determined before discharge. Results The 75 th percentile of hour specific TSB nomogram allows to predict newborn babies without significant hyperbilirubinemia only after the first 72 hours of life. In the first 48 hours of life the observation of false negative results did not permit a safe discharge from the hospital. Conclusion The hour-specific TSB nomogram is able to predict all neonates without risk of non physiologic hyperbilirubinemia only after 48 to 72 hours of life. The combination of TSB determination and risk factors for hyperbilirubinemia could facilitate a safe discharge from the hospital and a targeted intervention and follow-up.

  19. Regeneration of alveolar type I and II cells from Scgb1a1-expressing cells following severe pulmonary damage induced by bleomycin and influenza.

    Directory of Open Access Journals (Sweden)

    Dahai Zheng

    Full Text Available The lung comprises an extensive surface of epithelia constantly exposed to environmental insults. Maintaining the integrity of the alveolar epithelia is critical for lung function and gaseous exchange. However, following severe pulmonary damage, what progenitor cells give rise to alveolar type I and II cells during the regeneration of alveolar epithelia has not been fully determined. In this study, we have investigated this issue by using transgenic mice in which Scgb1a1-expressing cells and their progeny can be genetically labeled with EGFP. We show that following severe alveolar damage induced either by bleomycin or by infection with influenza virus, the majority of the newly generated alveolar type II cells in the damaged parenchyma were labeled with EGFP. A large proportion of EGFP-expressing type I cells were also observed among the type II cells. These findings strongly suggest that Scgb1a1-expressing cells, most likely Clara cells, are a major cell type that gives rise to alveolar type I and II cells during the regeneration of alveolar epithelia in response to severe pulmonary damage in mice.

  20. Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta.

    Science.gov (United States)

    Jacobsen, Christina M; Schwartz, Marissa A; Roberts, Heather J; Lim, Kyung-Eun; Spevak, Lyudmila; Boskey, Adele L; Zurakowski, David; Robling, Alexander G; Warman, Matthew L

    2016-09-01

    Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1(+/Mov13)) with a high bone mass (HBM) mouse (Lrp5(+/p.A214V)) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1. PMID:27297606

  1. Evaluation of primary DNA damage, cytogenetic biomarkers and genetic polymorphisms for CYP1A1 and GSTM1 in road tunnel construction workers.

    Science.gov (United States)

    Villarini, M; Moretti, M; Fatigoni, C; Agea, E; Dominici, L; Mattioli, A; Volpi, R; Pasquini, R

    2008-01-01

    In tunnel construction workers, occupational exposure to dust (alpha-quartz and other particles from blasting), gases (nitrogen dioxide, NO(2)), diesel exhausts, and oil mist has been associated with lung function decline, induction of inflammatory reactions in the lungs with release of mediators that may influence blood coagulation, and increased risk of chronic obstructive pulmonary disease. The present molecular epidemiology study was designed to evaluate whether occupational exposure to indoor pollutants during road tunnel construction might result in genotoxic effects. A study group of 39 underground workers and a reference group of 34 unexposed subjects were examined. Primary and oxidative DNA damage, sister-chromatid exchanges (SCE), and micronuclei (MN) were measured in peripheral blood cells. The possible influences of polymorphisms in gene encoding for CYP1A1 and GSTM1 xenobiotic-metabolizing enzymes were also investigated. Exposure assessment was performed with detailed interviews and questionnaires. There were no significant differences in the level of primary and oxidative DNA damage and frequency of SCE between the tunnel workers and controls, whereas the frequency of MN showed a significant increase in exposed subjects compared to controls. No effects of CYP1A1 or GSTM1 variants were observed for the analyzed biomarkers. Since MN in peripheral blood lymphocytes are recognized as a predictive biomarker of cancer risk within a population of healthy subjects, the genotoxic risk of occupational exposure to various indoor environmental pollutants during road tunnel construction cannot be excluded by this biomonitoring study. PMID:18800292

  2. UGT1A1基因启动子多态性与伊立替康化疗毒性作用的关系%Study of irinotecan-induced toxicity and its correlation to UGT1A1 gene promoter polymorphisms

    Institute of Scientific and Technical Information of China (English)

    李虎; 黄鹤; 刘继红

    2011-01-01

    目的 初步了解宫颈癌和卵巢癌患者血中尿苷二磷酸葡萄糖醛酸转移酶1A1( UGT1 A1)基因启动子的多态性情况,并研究其多态性与伊立替康化疗的毒性作用(延迟性腹泻、中性粒细胞减少)的关系.方法 收集64例使用伊立替康联合顺铂方案化疗的宫颈癌和卵巢癌患者的全血标本,提取基因组DNA,PCR扩增UGT1A1基因启动子,用毛细管电泳等位基因片段分析方法分析UGT1A1基因启动子的多态性,并与化疗毒性作用进行相关性分析.结果 64例患者中UGT1 A1基因启动子的野生纯合型(TA 6/6基因型)最为常见,共44例,占69% (44/64);其次为突变杂合型(TA 6/7基因型),共17例,占27% (17/64);突变纯合型(TA 7/7基因型)仅3例,占5%(3/64).UGT1A1基因启动子基因型是发生延迟性腹泻的独立影响因素(OR=4.228,95% CI为1.065~16.785,P=0.040),但不是中性粒细胞减少发生的独立影响因素(OR=3.659,95% CI为0.911~14.700,P=0.068);TA 6/7和TA 7/7基因型比TA 6/6基因型患者发生中性粒细胞减少、延迟性腹泻的风险高(P均=0.001).结论 在宫颈癌、卵巢癌患者中,UGT1 A1基因启动子以TA 6/6基因型较常见.UGT1A1基因启动子多态性是伊立替康所致延迟性腹泻的独立影响因素,TA 6/7和TA 7/7基因型患者发生延迟性腹泻的风险高于TA 6/6基因型.%Objectives To investigate the distribution of uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) gene promoter polymorphism and its relation to the toxicities caused by irinotecan in Chinese patients with cervical cancer and ovarian cancer.Methods Sixty-four blood samples were taken from the patients with ovarian cancer and cervical cancer.The DNA was extracted and amplified with PCR.Then,the sequences of UGT1A1 gene promoter were detected by capillary electrophoresis allele fragment analysis (size-based analysis) methods.The relationship between UGT1A1 gene promoter polymorphism and the toxicity caused

  3. The inhibitory effect of Rg1 on TCDD induced CYP1A1 in HepG2 cells%人参皂苷Rg1对TCDD致HepG2细胞CYP1A1诱导的抑制作用

    Institute of Scientific and Technical Information of China (English)

    王宇光; 陈强; 李晗; 马增春; 梁乾德; 肖成荣; 谭洪玲; 汤响林; 高月

    2013-01-01

    目的 人参对多种肿瘤具有非器官特异性的预防作用,该文对人参皂苷Rg1与 2,3,7,8-四氯代二苯并-对-二噁英(2,3,7,8-tetrachlorodibenzo-p-dioxin,TCDD)共同作用HepG2细胞,对CYP1A1在mRNA、蛋白及酶活性3个层面影响进行了研究,同时对CYP1A1转录调控子芳烃受体(AhR)表达情况亦进行了检测,旨在探索人参皂苷与TCDD共同作用时对CYP1A1影响,为干预前致癌物如TCDD等通过CYP1A1代谢活化产生致癌作用提供线索.方法 该实验分别以TCDD 5 nmol·L-1单独作用或与Rg1(1.0、10.0、100.0 μmol·L-1)共同作用于HepG2细胞24 h.溶剂对照组为二甲基亚砜(dimethyl suffoxide,DMSO).利用RT-PCR法和Western blot法检测不同药物处理后HepG2细胞中CYP1A1、AhR的mRNA和蛋白质表达水平的变化,同时采用EROD法测定不同处理组细胞CYP1A1酶活性.结果 与溶剂对照组比较,TCDD能使CYP1A1基因、蛋白表达上调及酶活性水平上升;与TCDD单独处理细胞组比较,Rg1与TCDD共处理组CYP1A1、AhR在mRNA和蛋白质表达水平均较TCDD单独处理组明显降低(P<0.01);同时CYP1A1酶活性也较单独TCDD处理组明显降低(P<0.01).结论 人参皂苷Rg1对TCDD致HepG2细胞CYP1A1诱导在mRNA、蛋白表达及酶活性3个层面均具有抑制作用,为深入研究人参皂苷Rg1 对TCDD 致肝脏损伤的保护作用提供线索.

  4. 吸附于银胶颗粒表面的胆红素及胆绿素分子吸附取向研究%The Study of Orientations of Bilirubin and Biliverdin by Surface-enhanced Raman Spectroscopy

    Institute of Scientific and Technical Information of China (English)

    胡军; 方清; 盛蓉生; 徐知三; 曾云鹗

    2001-01-01

    胆红素、胆绿素作为重要的生物小分子被广泛研究。本文采用表面增强拉曼光谱技术获得了胆红素和胆绿素分子吸附于银胶颗粒表面的拉曼光谱。通过对其谱带的指认分析,表明胆红素形成了三对内氢键,并以其两个吡咯亚甲基酮环沿银胶颗粒表面切向方向镶嵌在银胶颗粒上,而胆绿素则以顺式-顺式-顺式构型平躺吸附于银胶颗粒表面。%The surface-enhanced Raman spectra of bilirubin and biliverdin were obtained.By the bands analysis of the spectra,the orientation of bilirubin and biliverdin on the surface of silver colloid was discussed.In such case,the bilirubin was adsorbed on the silver colloid particle with the two planar pyrromethenone groups intercalated into the globe silver colloid particle,however,the biliverdin might lie flat on the surface of silver colloid with syn-synsyn conformation.

  5. CYP1A1和CYP2D6基因多态性对白血病发生的影响%Genetic polymorphisms of CYP1A1 and CYP2D6 and their impact on leukemia morbidity

    Institute of Scientific and Technical Information of China (English)

    李文凯; 刘清霞; 陈放知; 骆亚萍; 陈慧娟; 夏嘉志; 陈汉春

    2008-01-01

    目的 分析细胞色素P450 CYP1A1和CYP2D6的多态性基因型在湖南地区白血病患者和健康人群中的分布及其对白血病发生的影响.方法 采用PCR及PCR-RFLP技术分析多态性基因型频率.结果 CYP1A1和CYP2D6基因的野生型、杂合突变型及纯合突变型的分布频率在急性淋巴细胞性白血病、急性非淋巴细胞性白血病、慢性粒细胞性白血病患者组与健康对照组之间无显著性差异;携带一个突变等位基因型的个体患白血病的风险与相应野生型携带者比较均无显著性差异;急性非淋巴细胞性白血病患者组的CYP1A1杂合突变型与CYP2D6杂合突变型的联合基因型频率高于健康对照组.结论 单独的CYP1A1或CYP2D6基因的多态性变异与白血病易感性不相关;CYP1A1杂合突变与CYP2D6杂合突变的联合基因型增加患急性非淋巴细胞性白血病的风险.

  6. GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high-risk population.

    Science.gov (United States)

    Hung, Rayjean J; Boffetta, Paolo; Brennan, Paul; Malaveille, Christian; Hautefeuille, Agnès; Donato, Francesco; Gelatti, Umberto; Spaliviero, Massimiliano; Placidi, Donatella; Carta, Angela; Scotto di Carlo, Antonio; Porru, Stefano

    2004-07-01

    Tobacco smoking and occupation are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. Glutathione S-transferase (GST) M1, T1 and P1 are involved in the detoxification of PAH reactive metabolites. Two N-acetyltransferase isozymes, NAT2 and NAT1, have major roles in catalyzing the N-acetylation and O-acetylation of aromatic amines. Cytochrome p450 1B1 (CYP1B1) and sulfotransferase 1A1 (SULT1A1) are also involved in the metabolism of PAHs and aromatic amines. It is hypothesized that the genetic polymorphisms of these metabolic enzymes have an effect on the individual susceptibility to bladder cancer in particular by interacting with relevant environmental exposures. A hospital-based case-control study among men in Brescia, Northern Italy recruited 201 incidence cases and 214 controls from 1997-2000. Occupational exposures were blindly coded by occupational physicians. Genotyping of polymorphisms were carried out with PCR-RFLP method. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk. Effect modifications by age of onset, smoking and occupational exposures to PAHs and aromatic amines were evaluated. We also conducted an analysis of interaction between genetic factors. GSTM1 and GSTT1 null genotype were associated with an increased risk of bladder cancer with an odds ratio (OR) of 1.69 (95% confidence interval [CI] = 1.11-2.56) and 1.74 (95% CI = 1.02-2.95), respectively. The effect of GSTM1 null was seen particularly in heavy smokers, and there was a combined effect with occupational exposure of aromatic amines (OR = 2.77, 95% CI = 1.08-7.10). We observed a trend (p-value < 0.01) of increasing cancer risk comparing subjects with normal GSTM1 and T1 activity to subjects with one (OR = 1.82, 95% CI = 1.16-2.85) or both null genotypes (OR = 2.58, 95% CI = 1.27-5.23). NAT2 slow acetylator was associated with marginally

  7. A full CI treatment of the 1A1, 1B1, and 3B1 states of SiH2

    Science.gov (United States)

    Bauschlicher, Charles W., Jr.; Taylor, Peter R.

    1987-01-01

    Full CI calculations are presented for the 1A1, 3B1, and 1B1 states of SiH2 at their respective equilibrium geometries and at geometries with the SiH bonds stretched. These results are compared with those obtained from single-reference and multireference CI calculations. The computed Te values agree well with the full CI results, provided that the effects of higher-than-double excitations are accounted for either by the Davidson correction or by a multireference approach. When the SiH bonds are stretched, the single-reference methods are not sufficiently flexible, and only CASSCF/MRCI achieves chemical accuracy (i.e., agrees with the full CI to 1 kcal/mol). Overall, the accuracy of the various approximate methods is very similar to that found for H2O, NH2, and CH2.

  8. Systems biology approach identifies the kinase Csnk1a1 as a regulator of the DNA damage response in embryonic stem cells

    DEFF Research Database (Denmark)

    Carreras Puigvert, Jordi; von Stechow, Louise; Siddappa, Ramakrishnaiah;

    2013-01-01

    In pluripotent stem cells, DNA damage triggers loss of pluripotency and apoptosis as a safeguard to exclude damaged DNA from the lineage. An intricate DNA damage response (DDR) signaling network ensures that the response is proportional to the severity of the damage. We combined an RNA interference...... screen targeting all kinases, phosphatases, and transcription factors with global transcriptomics and phosphoproteomics to map the DDR in mouse embryonic stem cells treated with the DNA cross-linker cisplatin. Networks derived from canonical pathways shared in all three data sets were implicated in DNA....... Instead, this response occurred through reduced abundance of Csnk1a1 (CK1α), a kinase that inhibits β-catenin. Together, our findings reveal a balance between p53-mediated elimination of stem cells (through loss of pluripotency and apoptosis) and Wnt signaling that attenuates this response to tune the...

  9. Rats fed soy protein isolate (SPI) have impaired hepatic CYP1A1 induction by polycyclic aromatic hydrocarbons as a result of interference with aryl hydrocarbon receptor signaling

    International Nuclear Information System (INIS)

    Consumption of soy diets has been found to reduce cancer incidence in animals and is associated with reduced cancer risk in humans. Previously, we have demonstrated that female Sprague-Dawley rats fed purified AIN-93G diets with soy protein isolate (SPI) as the sole protein source had reduced CYP1A1 induction and basal aryl hydrocarbon receptor (AhR) levels relative to those fed the same diet containing casein (CAS). In the present study, the molecular mechanisms underlying reduced AhR expression have been studied. The SPI-effect on AhR was not observed after feeding diets containing the purified soy isoflavones genistein or daidzein. Rat hepatoma FGC-4 cells were treated with the serum obtained from rats fed CAS- or SPI-containing diets. Reduced AhR levels (P < 0.05) were observed after 24 h exposure to SPI-serum without any changes in the overall expression of chaperone proteins-HSP90 and XAP2. SPI-serum-stimulated AhR degradation was inhibited by treating the cells with the proteasome inhibitor, MG132, and was observed to be preceded by ubiquitination of the receptor. A reduced association of XAP2 with the immunoprecipitated AhR complex was observed. SPI-serum-mediated AhR degradation was preceded by nuclear translocation of the receptor. However, the translocated receptor was found to be unable to heterodimerize with ARNT or to bind to XRE elements on the CYP1A1 enhancer. These data suggest that feeding SPI-containing diets antagonizes AhR signaling by a novel mechanism which differs from those established for known AhR antagonists

  10. Evaluación del modelo 1 a 1 en Iberoamérica: efectos del uso de computadoras portátiles en el aula

    Directory of Open Access Journals (Sweden)

    Raúl Choque-Larrauri

    2011-10-01

    Full Text Available En Iberoamérica alrededor de dos millones de estudiantes usan laptops en el modelo 1 a 1 (una computadora por cada estudiante en la educación básica. Se proyecta que en 2015 treinta millones de estudiantes en esa región estarán usando computadoras. Actualmente, un tercio de la población en Iberoamérica es internauta y hay un crecimiento sostenido de la población que tiene acceso al Internet. Se han realizado una serie de evaluaciones sobre los efectos del modelo 1 a 1 en la educación. Los efectos primarios están referidos al incremento del desempeño académico de los estudiantes, principalmente en matemática, lenguaje y ciencias. Los resultados de las evaluaciones al respecto no son claros y contundentes, por lo cual el debate está abierto. Por su parte, los efectos secundarios aluden a aspectos sociales, psicológicos y tecnológicos; en este rubro, los resultados de las evaluaciones son claros y concluyentes. Hay un efecto en la mejora del capital social, la comunicación, el trabajo en equipo, la autoestima, la creatividad, el pensamiento y razonamiento abstracto, la resolución de problemas, la motivación para ir a la escuela, el desarrollo de habilidades TIC, la reducción de la brecha digital y la mayor interacción de los padres e hijos.

  11. Co-expression of human cytochrome P4501A1 (CYP1A1) variants and human NADPH-cytochrome P450 reductase in the baculovirus/insect cell system.

    Science.gov (United States)

    Schwarz, D; Kisselev, P; Honeck, H; Cascorbi, I; Schunck, W H; Roots, I

    2001-06-01

    1. Three human cytochrome P4501A1 (CYP1A1) variants, wild-type (CYP1A1.1), CYP1A1.2 (1462V) and CYP1A1.4 (T461N), were co-expressed with human NADPH-P450 reductase (OR) in Spodoptera frugiperda (Sf9) insect cells by baculovirus co-infection to elaborate a suitable system for studying the role of CYPA1 polymorphism in the metabolism of exogenous and endogenous substrates. 2. A wide range of conditions was examined to optimize co-expression with regard to such parameters as relative multiplicity of infection (MOI), time of harvest, haem precursor supplementation and post-translational stabilization. tinder optimized conditions, almost identical expression levels and molar OR/CYP1A1 ratios (20:1) were attained for all CYP1A1 variants. 3. Microsomes isolated from co-infected cells demonstrated ethoxyresorufin deethlylase activities (nmol/min(-1) nmol(-1) CYP1A1) of 16.0 (CYP1A1.1), 20.5 (CYP1A1.2) and 22.5 (CYP1A1.4). Pentoxyresorufin was dealkylated approximately 10-20 times slower with all enzyme variants. 4. All three CYP1A1 variants were active in metabolizing the precarcinogen benzo[a]pyrene (B[a]P), with wild-type enzyme showing the highest activity, followed by CYP1A1.4 (60%) and CYP1A1.2 (40%). Each variant produced all major metabolites including B[a]P-7,8-dihydrodiol, the precursor of the ultimate carcinogenic species. 5. These studies demonstrate that the baculovirus-mediated co-expression-by-co-infection approach all CYP1A1 variants yields functionally active enzyme systems with similar molar OR/CYP1A1 ratios, thus providing suitable preconditions to examine the metabolism of and environmental chemicals by the different CY1A1 variants. PMID:11513247

  12. Membraneless enzymatic ethanol/O2 fuel cell: Transitioning from an air-breathing Pt-based cathode to a bilirubin oxidase-based biocathode

    Science.gov (United States)

    Aquino Neto, Sidney; Milton, Ross D.; Hickey, David P.; De Andrade, Adalgisa R.; Minteer, Shelley D.

    2016-08-01

    The bioelectrooxidation of ethanol was investigated in a fully enzymatic membraneless ethanol/O2 biofuel cell assembly using hybrid bioanodes containing multi-walled carbon nanotube (MWCNT)-decorated gold metallic nanoparticles with either a pyrroloquinoline quinone (PQQ)-dependent alcohol dehydrogenase (ADH) enzyme or a nicotinamide adenine dinucleotide (NAD+)-dependent ADH enzyme. The biofuel cell anode was prepared with the PQQ-dependent enzyme and designed using either a direct electron transfer (DET) architecture or via a mediated electron transfer (MET) configuration through a redox polymer, 1,1‧-dimethylferrocene-modified linear polyethyleneimine (FcMe2-C3-LPEI). In the case of the bioanode containing the NAD+-dependent enzyme, only the mediated electron transfer mechanism was employed using an electropolymerized methylene green film to regenerate the NAD+ cofactor. Regardless of the enzyme being employed at the anode, a bilirubin oxidase-based biocathode prepared within a DET architecture afforded efficient electrocatalytic oxygen reduction in an ethanol/O2 biofuel cell. The power curves showed that DET-based bioanodes via the PQQ-dependent ADH still lack high current densities, whereas the MET architecture furnished maximum power density values as high as 226 ± 21 μW cm-2. Considering the complete membraneless enzymatic biofuel cell with the NAD+-dependent ADH-based bioanode, power densities as high as 111 ± 14 μW cm-2 were obtained. This shows the advantage of PQQ-dependent ADH for membraneless ethanol/O2 biofuel cell applications.

  13. High baseline bilirubin and low albumin predict liver decompensation and serious adverse events in HCV-infected patients treated with sofosbuvir-containing regimens.

    Science.gov (United States)

    Perumalswami, P V; Patel, N; Bichoupan, K; Ku, L; Yalamanchili, R; Harty, A; Motamed, D; Khaitova, V; Chang, C; Grewal, P; Liu, L; Schiano, T D; Woodward, M; Dieterich, D T; Branch, A D

    2016-09-01

    To conduct surveillance and determine the safety profile of new hepatitis C virus treatments in real-world clinical practice. Hepatic decompensation and other serious adverse events were investigated in an observational cohort study of 511 patients treated with regimens containing sofosbuvir, December 2013-June 2014. Among 499 previously stable patients (no history of hepatic decompensation during the previous 12 months), a nested case-control study was performed to identify predictors of decompensation/serious adverse event. Cases and controls were matched 1:5 based on treatment regimen and duration. Matched conditional logistic regression was used for analysis. Providers scored the likelihood that events were treatment-related (scale = 0-4). The cumulative incidence of decompensation/events was 6.4% for the total cohort. Among 499 previously stable patients, the incidence of decompensation/events was 4.5%; the mortality rate was 0.6%. Sixteen of the 499 experienced one or more serious complications considered to be at least potentially treatment-related, and the sustained virological response rate was 7/16 (44%). Two cases, both on sofosbuvir/simeprevir (without interferon or ribavirin), had complications consistent with autoimmune events (score 3, 'likely treatment-related'), and one experienced a flare of autoimmune hepatitis. Compared to controls, cases had higher baseline median model for end-stage liver disease scores (14 vs 8, P < 0.01). Decompensation/events was independently associated with lower baseline albumin (OR = 0.12/g/dL, P = 0.01) and higher total bilirubin (OR = 4.31/mg/dL, P = 0.01). Reduced hepatic function at baseline increased the risk of liver decompensation/events. PMID:26989855

  14. Metastable and equilibrium phase diagrams of unconjugated bilirubin IXα as functions of pH in model bile systems: Implications for pigment gallstone formation.

    Science.gov (United States)

    Berman, Marvin D; Carey, Martin C

    2015-01-01

    Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment gallstone formation. Also, UCB is a molecule of considerable biomedical importance because it is a potent antioxidant and an inhibitor of atherogenesis. We employed principally a titrimetric approach to obtain metastable and equilibrium UCB solubilities in model bile systems composed of taurine-conjugated bile salts, egg yolk lecithin (mixed long-chain phosphatidylcholines), and cholesterol as functions of total lipid concentration, biliary pH values, and CaCl2 plus NaCl concentrations. Metastable and equilibrium precipitation pH values were obtained, and average pKa values of the two carboxyl groups of UCB were calculated. Added lecithin and increased temperature decreased UCB solubility markedly, whereas increases in bile salt concentrations and molar levels of urea augmented solubility. A wide range of NaCl and cholesterol concentrations resulted in no specific effects, whereas added CaCl2 produced large decreases in UCB solubilities at alkaline pH values only. UV-visible absorption spectra were consistent with both hydrophobic and hydrophilic interactions between UCB and bile salts that were strongly influenced by pH. Reliable literature values for UCB compositions of native gallbladder biles revealed that biles from hemolytic mice and humans with black pigment gallstones are markedly supersaturated with UCB and exhibit more acidic pH values, whereas biles from nonstone control animals and patients with cholesterol gallstone are unsaturated with UCB. PMID:25359538

  15. Review: Bilirubin pKa studies; new models and theories indicate high pKa values in water, dimethylformamide and DMSO

    Directory of Open Access Journals (Sweden)

    Ostrow J

    2010-03-01

    Full Text Available Abstract Background Correct aqueous pKa values of unconjugated bilirubin (UCB, a poorly-soluble, unstable substance, are essential for understanding its functions. Our prior solvent partition studies, of unlabeled and [14C] UCB, indicated pKa values above 8.0. These high values were attributed to effects of internal H-bonding in UCB. Many earlier and subsequent studies have reported lower pKa values, some even below 5.0, which are often used to describe the behavior of UCB. We here review 18 published studies that assessed aqueous pKa values of UCB, critically evaluating their methodologies in relation to essential preconditions for valid pKa measurements (short-duration experiments with purified UCB below saturation and accounting for self-association of UCB. Results These re-assessments identified major deficiencies that invalidate the results of all but our partition studies. New theoretical modeling of UCB titrations shows remarkable, unexpected effects of self-association, yielding falsely low pKa estimates, and provides some rationalization of the titration anomalies. The titration behavior reported for a soluble thioether conjugate of UCB at high aqueous concentrations is shown to be highly anomalous. Theoretical re-interpretations of data in DMSO and dimethylformamide show that those indirectly-derived aqueous pKa values are unacceptable, and indicate new, high average pKa values for UCB in non-aqueous media (>11 in DMSO and, probably, >10 in dimethylformamide. Conclusions No reliable aqueous pKa values of UCB are available for comparison with our partition-derived results. A companion paper shows that only the high pKa values can explain the pH-dependence of UCB binding to phospholipids, cyclodextrins, and alkyl-glycoside and bile salt micelles.

  16. 酶抑制剂对V79-hCYP2E1-SULT1A1细胞酶依赖性化学诱变的影响%Effects of enzyme inhibitors on enzyme-dependent and chemical-induced mutagenesis in V79-hCYP2E1-hSULT1A1 cells

    Institute of Scientific and Technical Information of China (English)

    刘云岗; 胡克歧

    2011-01-01

    0bjective: V79-hCYP2E1-hSULT1A1 ,a genetically engineered Chinese hamster V79 cell line expressing human CYP2E1 and human sulfotransferase(SULT) 1A1 ,demonstrates mutagenic response to promutagens requiring metabolic activation by either expressed enzyme. For the purpose of investigating the effect of either enzyme alone, it is highly necessary to establish a test model wherein either of the enzymes is specifically inhibited. Methods:Using the forward mutation at Hprt locus as the end point to observe, N-nitrosodimethylamine (NDMA) and 2-nitropropane (2-NP) as CYP2E1- and SULT1A1-dependent promutagen.the effects of CYP inhibitors,trans-1,2-dichloroethylene (DCE) and 1-aminobenzotriazole (ABT),and that of SULT1 inhibitors,quercetin and pentachlorophenol (PCP) on each promutagen-induced mutagenic response were observed. Results:ABT prohibited NDMA-induced mutagenic activity by 99% with the action of 2-NP unaffected,while DCE reduced it only by 55% and simultaneously potentiated 2-NP-induced cytotoxicity. Quercetin and PCP reduced 2-NP-induced mutagenic activity by 63% and 98%, with the action of NDMA unaffected. Conclusion:Specifically and completely, ABT and PCP are capable of prohibiting CYP2El-and SULT1A1 -dependent mutagenic response, respectively, which is a test model of reliable value for investigating metabolic activation of genotoxicants.%目的:V79-hCYP2E1-hSULT1A1是一个表达人细胞色素P450(CYP)2E1和硫酸基转移酶(Sulfotransferase,SULT) 1A1的重组中国地鼠V79[Chinese hamster lung (V79)cells]细胞系,它对于需有关代谢酶活化的间接诱变剂有基因突变反应;为观察单个酶的作用,需要建立对细胞中任一酶特异抑制的模型.方法:以细胞Hprt位点的正向突变为试验终点,N-二甲基亚硝胺(N-Nitrosodimethylamine,NDMA)和2-硝基丙烷(2-Nitropropane,2-NP)为依赖CYP2E1和SULT1A1的间接诱变剂,观察CYP抑制剂反式二氯乙烯(Trans-1,2-dichloroethylene,DCE)和1-氨基苯并三唑(1

  17. Correlation of CYP1A1 Msp Ⅰ polymorphism with the susceptibility of the uterine leiomyoma%CYP1A1基因MspⅠ位点多态性与子宫肌瘤易感性的研究

    Institute of Scientific and Technical Information of China (English)

    周超; 林林; 南芳芳; 徐天和; 张磊磊; 张英姿

    2011-01-01

    Objective : To study of the relationship between CYP1 A1 genetic polymorphism and uterine leiomyoma in Northem QiLu,about Han people. Methods : Msp Ⅰ genotypes of CYP1A1 gene were detected with the methods of PCR-RFLP a case-control study,including 123 cases of uterine leiomyoma and 123 cases as controls. Multivariate logistic regression analysis was used to estimate uterine leiomyoma risk associated with environmental exposures by SULT1A1 genotype. Results : ( 1) There was no significant correlation between uterine leiomyoma group and control group in Msp Ⅰ polymorphism(P=O. 927) . (2) Contrast with T/T genotype,T/C and C /C , the difference between the case and control group all were no significant ( P = 0. 738 , P= 0. 947 , respectively ) . ( 3) Contrast with T/T genotype , merging T/C and C /C ,the difference between the case and control group was no significant ( P=O. 925 ) . Condusions :The results do not imply that CYP1A1 polymorphism of Msp Ⅰ is associated with susceptibility of uterine leiomyoma,in Northem QiLu , about Han people.%目的:探讨细胞色素P450(cytochrome P450,CYP)1A1基因Msp Ⅰ位点多态性与鲁北地区汉族女性子宫肌瘤的关系.方法:以病例-对照的研究方法,采用PCR-RFLP 方法检测了123例子宫肌瘤患者和123例匹配对照者的CYP1A1基因Msp Ⅰ位点的基因多态性.应用Logistic回归等方法分析基因多态性与子宫肌瘤的关系.结果:(1)CYP1A1基因Msp Ⅰ位点的基因型在子宫肌瘤组与对照组中分布的差异无统计学意义(P=0.927);(2)杂合型(T/C)和突变型(C/C)与野生型(T/T)在子宫肌瘤组与对照组的分布差异均无统计学意义(P=0.738,P=0.947);(3)合并杂合型(T/C)和突变型(C/C)与野生型(T/T)比较,在子宫肌瘤组与对照组分布的差异无统计学意义(P=0.925).结论:CYP1A1 Msp Ⅰ等位基因多态性与鲁北地区汉族女性子宫肌瘤的易感性无显著相关性.

  18. Spatio-temporal prediction of leaf area index of rubber plantation using HJ-1A/1B CCD images and recurrent neural network

    Science.gov (United States)

    Chen, Bangqian; Wu, Zhixiang; Wang, Jikun; Dong, Jinwei; Guan, Liming; Chen, Junming; Yang, Kai; Xie, Guishui

    2015-04-01

    Rubber (Hevea brasiliensis) plantations are one of the most important economic forest in tropical area. Retrieving leaf area index (LAI) and its dynamics by remote sensing is of great significance in ecological study and production management, such as yield prediction and post-hurricane damage evaluation. Thirteen HJ-1A/1B CCD images, which possess the spatial advantage of Landsat TM/ETM+ and 2-days temporal resolution of MODIS, were introduced to predict the spatial-temporal LAI of rubber plantation on Hainan Island by Nonlinear AutoRegressive networks with eXogenous inputs (NARX) model. Monthly measured LAIs at 30 stands by LAI-2000 between 2012 and 2013 were used to explore the LAI dynamics and their relationship with spectral bands and seven vegetation indices, and to develop and validate model. The NARX model, which was built base on input variables of day of year (DOY), four spectral bands and weight difference vegetation index (WDVI), possessed good accuracies during the model building for the data set of training (N = 202, R2 = 0.98, RMSE = 0.13), validation (N = 43, R2 = 0.93, RMSE = 0.24) and testing (N = 43, R2 = 0.87, RMSE = 0.31), respectively. The model performed well during field validation (N = 24, R2 = 0.88, RMSE = 0.24) and most of its mapping results showed better agreement (R2 = 0.54-0.58, RMSE = 0.47-0.71) with the field data than the results of corresponding stepwise regression models (R2 = 0.43-0.51, RMSE = 0.52-0.82). Besides, the LAI statistical values from the spatio-temporal LAI maps and their dynamics, which increased dramatically from late March (2.36 ± 0.59) to early May (3.22 ± 0.64) and then gradually slow down until reached the maximum value in early October (4.21 ± 0.87), were quite consistent with the statistical results of the field data. The study demonstrates the feasibility and reliability of retrieving spatio-temporal LAI of rubber plantations by an artificial neural network (ANN) approach, and provides some insight on the

  19. The relationship between transcutaneous bilirubin changes after surgery and the prognosis in biliary atresia%测定胆道闭锁术后皮肤胆红素动态变化与预后的关系

    Institute of Scientific and Technical Information of China (English)

    王文晓; 李龙; 张金山; 刘树立; 谢华伟; 明安晓; 崔龙; 周峻

    2011-01-01

    Objective To study the relationship between the post-op transcutaneous bilirubin changes after Surgery and the prognosis in children with biliary atresia. Methods Between July 2009to December 2009,52 children( 19 males and 33 female, age: 36 d~304 d, the mean age 83d, including 5cholestasis and 47 biliary atresia)with jaundice and 59 non-jaundiced children's (28 males and 31 females,aged 26 d~200 d and the mean age 119 d) were recruited for the study. The transcutaneous bilirubin and total serum bilirubin of children with jaundice and non-jaundice were measured at the same time. Twenty-three children with biliary atresia (8 males and 15 females, aged 36 d~ 127 d and the mean age 63 d) underwent Kasai operation. The children were divided into good or poor prognosis groups according to the serum bilirubin levels of 20 μmol/L three months after operation. Measurements were compared between the two groups during hospital stay. Results Linear regression oftranscutaneous bilirubin (x) correlated with that of serum bilirubin (y) (y = 0. 945x - 46. 273, P<0. 05). The 95% confidence interval of transcutaneous bilirubin in normal children was 33. 14~96. 14μmol/L. The transcutaneous bilirubin of children with good prognosis was significantly lower than that of children with poor prognosis on postoperative day 11 ( 159 μmol/L vs 205 μmol/L,P<0. 05) and 12(151 μmol/L vs 210μmol/L,P<0. 05). Postoperative average daily decline of transcutaneous bilirubin in children with good prognosis was faster (5. 04 μmol/L vs 2. 33 μmol/L, P<0. 05). Conclusions Transcutaneous bilirubin measurement is a safe and reliable method of monitoring the decline of jaundice of children with biliary atresia.%目的 初步探讨胆道闭锁患儿术后测定皮肤胆红素动态变化与黄疸消退及预后的关系.方法 2009年7月至12月,收治黄疸患儿52例,男19例,女33例,年龄36 d~304 d,平均年龄83 d,包括胆汁淤积5例,胆道闭锁47例,采血测血清胆

  20. COL1A1 and COL1A2 sequencing results in cohort of patients undergoing evaluation for potential child abuse.

    Science.gov (United States)

    Zarate, Yuri A; Clingenpeel, Rachel; Sellars, Elizabeth A; Tang, Xinyu; Kaylor, Julie A; Bosanko, Katherine; Linam, Leann E; Byers, Peter H

    2016-07-01

    Child abuse is a major public health concern that can explain a proportion of fractures in children. Osteogenesis imperfecta (OI) is the most common inherited syndrome that predisposes to skeletal fractures. We conducted a retrospective analysis of data from clinical, laboratory, and radiographic information from children evaluated for child abuse in which molecular testing for COL1A1 and COL1A2 genes was conducted. A total of 43 patients underwent molecular testing for OI. Pathogenic variants predicted to result in a mild form of OI were found in two patients (5%), both clinically suspected to have this diagnosis. None of the cases in whom OI molecular testing was ordered when maltreatment concerns were thought to be more likely (0/35) were identified to have pathogenic variants. After reviewing each individual case, the final diagnosis was child abuse for 34 cases (77%), and additional radiographic and laboratory studies did not identify any with inherited metabolic predisposition to fracture or rickets. We conclude that routine testing for OI in the setting of child abuse when no other suggestive clinical findings are present has a low yield. A careful review of the medical history and a detailed clinical evaluation help identify those at risk for genetic alterations. © 2016 Wiley Periodicals, Inc. PMID:27090748

  1. Partial antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cyp1a1 gene expression by α-naphthoflavone

    International Nuclear Information System (INIS)

    Treatment of rat hepatoma H-4-II E cells with TCDD (10-9 M) causes a time-dependent induction of ethoxyresorufin O-deethylase activity in which maximal induction occurs within 24 hours. In contrast ∝-naphthoflavone (∝-NF) at concentrations from 10-9 to 10-6 M was inactive as an inducer of EROD activity. Cotreatment of the cells with TCDD (10-9 M) and ∝-NF (10-6 M) resulted in significant antagonism of TCDD-mediated induction of EROD activity. In a parallel time-course study, the interactive effects of ∝-NF and [3H]-TCDD on the accumulation of nuclear [3H]-TCDD-Ah receptor complexes were also determined. The results showed the ∝-NF inhibited the accumulation of transcriptionally active nuclear receptor complexes in rat hepatoma H-4-II E cells. These results coupled with the effects of ∝-NF on TCDD-induced CYP1A1 m-RNA levels will be discussed in terms of the mechanism of ∝-NF as a partial TCDD antagonist (ES-03843)

  2. Comparison of PCR-based mutation detection methods and application for identification of mouse Sult1a1 mutant embryonic stem cell clones using pooled templates.

    Science.gov (United States)

    Greber, Boris; Tandara, Helena; Lehrach, Hans; Himmelbauer, Heinz

    2005-05-01

    Reverse genetic approaches to generate mutants of model species are useful tools to assess functions of unknown genes. Recent work has demonstrated the feasibility of such strategies in several organisms, exploiting the power of chemical mutagenesis to disrupt genes randomly throughout the genome. To increase the throughput of gene-driven mutant identification, efficient mutation screening protocols are needed. Given the availability of sequence information for large numbers of unknown genes in many species, mutation detection protocols are preferably based on PCR. Using a set of defined mutations in the Hprt1 gene of mouse embryonic stem (ES) cells, we have systematically compared several PCR-based point mutation and deletion detection methods available for their ability to identify lesions in pooled samples, which is a major criterion for an efficient large-scale mutation screening assay. Results indicate that point mutations are most effectively identified by heteroduplex cleavage using CEL I endonuclease. Small deletions can most effectively be detected employing the recently described "poison" primer PCR technique. Further, we employed the CEL I assay followed by conventional agarose gel electrophoresis analysis for screening a library of chemically mutagenized ES cell clones. This resulted in the isolation of several clones harboring mutations in the mouse Sult1a1 locus, demonstrating the high-throughput compatibility of this approach using simple and inexpensive laboratory equipment. PMID:15832303

  3. Ab Initio Multiple Spawning Method for Intersystem Crossing Dynamics: Spin-Forbidden Transitions between (3)B1 and (1)A1 States of GeH2.

    Science.gov (United States)

    Fedorov, Dmitry A; Pruitt, Spencer R; Keipert, Kristopher; Gordon, Mark S; Varganov, Sergey A

    2016-05-12

    Dynamics at intersystem crossings are fundamental to many processes in chemistry, physics, and biology. The ab initio multiple spawning (AIMS) method was originally developed to describe internal conversion dynamics at conical intersections where derivative coupling is responsible for nonadiabatic transitions between electronic states with the same spin multiplicity. Here, the applicability of the AIMS method is extended to intersystem crossing dynamics in which transitions between electronic states with different spin multiplicities are mediated by relativistic spin-orbit coupling. In the direct AIMS dynamics, the nuclear wave function is expanded in the basis of frozen multidimensional Gaussians propagating on the coupled electronic potential energy surfaces calculated on the fly. The AIMS method for intersystem crossing is used to describe the nonadiabatic transitions between the (3)B1 and (1)A1 states of GeH2. The potential energies and gradients were obtained at the CASSCF(6,6)/6-31G(d) level of theory. The spin-orbit coupling matrix elements were calculated with the configuration interaction method using the two-electron Breit-Pauli Hamiltonian. The excited (3)B1 state lifetime and intersystem crossing rate constants were estimated by fitting the AIMS state population with the first-order kinetics equation for a reversible unimolecular reaction. The obtained rate constants are compared with the values predicted by the statistical nonadiabatic transition state theory with transition probabilities calculated using the Landau-Zener and weak coupling formulas. PMID:27064356

  4. CYP1A1, mEH, and GSTM1 Polymophisms and Risk of Oral and Pharyngeal Cancer: A Spanish Case-Control Study.

    Science.gov (United States)

    Varela-Lema, L; Ruano-Ravina, A; Juiz Crespo, M A; Kelsey, K T; Loidi, L; Barros-Dios, J M

    2008-01-01

    Background. Genetic polymorphisms of drug metabolizing enzymes involved in the detoxification pathways of carcinogenic substances may influence cancer risk. Methods. Case-control study that investigates the relationship between CYP1A1 Ile/Val, exon 4 mEH, and GSTM1 null genetic polymorphism and the risk of oral and pharyngeal cancer examining the interaction between these genes, tobacco, and alcohol. 92 incident cases and 130 consecutive hospital-based controls have been included. Results. No significant associations were found for any of the genotypes assessed. The estimated risk was slightly elevated in subjects with the wild type of the mEH gene and the null GSTM1 genotype. For exon 4 mEH heterozygous polymorphism, the risk was slightly lower for heavy smokers than for light smokers. The inverse association was observed for the GSTM1 null genotype. Conclusions. The results suggest that exon 4 mEH and GSTM1 null polymorphisms might influence oral and pharyngeal cancer. PMID:19259333

  5. CYP1A1, mEH, and GSTM1 Polymophisms and Risk of Oral and Pharyngeal Cancer: A Spanish Case-Control Study

    Directory of Open Access Journals (Sweden)

    L. Varela-Lema

    2008-01-01

    Full Text Available Background. Genetic polymorphisms of drug metabolizing enzymes involved in the detoxification pathways of carcinogenic substances may influence cancer risk. Methods. Case-control study that investigates the relationship between CYP1A1 Ile/Val, exon 4 mEH, and GSTM1 null genetic polymorphism and the risk of oral and pharyngeal cancer examining the interaction between these genes, tobacco, and alcohol. 92 incident cases and 130 consecutive hospital-based controls have been included. Results. No significant associations were found for any of the genotypes assessed. The estimated risk was slightly elevated in subjects with the wild type of the mEH gene and the null GSTM1 genotype. For exon 4 mEH heterozygous polymorphism, the risk was slightly lower for heavy smokers than for light smokers. The inverse association was observed for the GSTM1 null genotype. Conclusions. The results suggest that exon 4 mEH and GSTM1 null polymorphisms might influence oral and pharyngeal cancer.

  6. Differential expression of P-type ATPases in intestinal epithelial cells: Identification of putative new atp1a1 splice-variant

    International Nuclear Information System (INIS)

    P-type ATPases are membrane proteins that couple ATP hydrolysis with cation transport across the membrane. Ten different subtypes have been described. In mammalia, 15 genes of P-type ATPases from subtypes II-A, II-B and II-C, that transport low-atomic-weight cations (Ca2+, Na+, K+ and H+), have been reported. They include reticulum and plasma-membrane Ca2+-ATPases, Na+/K+-ATPase and H+/K+-ATPases. Enterocytes and colonocytes show functional differences, which seem to be partially due to the differential expression of P-type ATPases. These enzymes have 9 structural motifs, being the phosphorylation (E) and the Mg2+ATP-binding (H) motifs the most preserved. These structural characteristics permitted developing a Multiplex-Nested-PCR (MN-PCR) for the simultaneous identification of different P-type ATPases. Thus, using MN-PCR, seven different cDNAs were cloned from enterocytes and colonocytes, including SERCA3, SERCA2, Na+/K+-ATPase α1-isoform, H+/K+-ATPase α2-isoform, PMCA1, PMCA4 and a cDNA-fragment that seems to be a new cassette-type splice-variant of the atp1a1 gen. PMCA4 in enterocytes and H+/K+-ATPase α2-isoform in colonocytes were differentially expressed. This cell-specific expression pattern is related with the distinctive enterocyte and colonocyte functions.

  7. Pegvisomant-Induced Cholestatic Hepatitis in an Acromegalic Patient with UGT1A1 ​⁎ 28 Mutation

    Directory of Open Access Journals (Sweden)

    Maria Susana Mallea-Gil

    2016-01-01

    Full Text Available Pegvisomant (PEGv is a growth hormone receptor antagonist approved for the treatment of acromegaly; one of its documented adverse effects is reversible elevation of hepatic enzymes. We report a 39-year-old male acromegalic patient with a pituitary macroadenoma who underwent transsphenoidal surgery. The patient’s condition improved but GH and IGF-I levels did not normalize; as a consequence, we first administered dopamine agonists and then somatostatin receptor ligands (SRLs with poor response. PEGv 15 mg every other day was added to lanreotide 120 mg monthly. The patient developed a severe hepatitis five months after starting the combination therapy. Elevated ferritin, iron, and transferrin saturation suggested probable hepatitis due to haemochromatosis. We performed a liver biopsy which showed an acute cholestatic hepatitis consistent with toxic etiology. A heterozygous genotype UGT1A1​⁎28 polymorphism associated with Gilbert’s syndrome was also found in this Argentine patient. The predominant clinical presentation resembled an acute cholestatic hepatitis associated with severe hemosiderosis, a different and new pattern of PEGv hepatotoxicity.

  8. Analysis and Treatment of Related Risk Factors of Neonatal Bilirubin Encephalopathy%新生儿胆红素脑病相关危险因素的分析与处理

    Institute of Scientific and Technical Information of China (English)

    张超雁

    2016-01-01

    目的:进一步探索新生儿胆红素脑病的相关危险因素及处理方法。方法对我院新生儿科自2008年6月~2015年8月收治的76例新生儿胆红素脑病患儿病历进行回顾性分析。结果患儿自身因素造成的新生儿胆红素性脑病前3位的危险因素包括感染因素、围产期因素和G-6-PD缺乏症,所占比率分别达到了48.68%、32.89%和10.53%。患儿自身以外因素造成新生儿胆红素性脑病最主要的因素是产妇产后住院时间不足3 d、在家自行用药和未按医生要求进行及时随访,所占比率分别为47.36%、38.16%、51.32%。结论临床上造成新生儿胆红素性脑病的危险因素是多方面的,加强围产期保健工作、做好患儿生后护理、及时发现并治疗新生儿黄疸是防止新生儿胆红素性脑病发生的关键。%Objective To explore the related risk factors and treatment methods of neonatal bilirubin encephalopathy.Methods In our new pediatric since June 2008 to August 2015 treated 76 cases of neonatal bilirubin encephalopathy patients medical records were retrospectively analyzed.ResultsIts own factors of neonatal bilirubin encephalopathy in children with risk factors for the three factors including infection,perinatal factors and G-6-PD deficiency,proportion reached 48.68%,32.89% and 48.68% respectively. The outside factors of the patients is the most important factors of neonatal bilirubin encephalopathy maternal postpartum hospitalization time less than 3 days,take medicines at home and not timely folow-up required by doctors,proportion of 47.36%,38.16% and 51.32% respectively.Conclusion Clinical risk factors of the neonatal bilirubin encephalopathy is various, strengthening perinatal health care work,completes the child postpartum nursing,timely detection and timely treatment of neonatal jaundice is the key to prevention of neonatal bilirubin encephalopathy.

  9. 中国北方汉族人细胞色素P450 1A1基因MspⅠ多态性与早发性帕金森病关系的研究%Genetic polymorphisms of cytochrome P450 1A1 and susceptibility of early-onset Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    刘平; 刘振华; 邵明; 陈彪

    2001-01-01

    目的 探讨中国北方汉族人细胞色素P450 1A1基因Msp Ⅰ多态性与早发性帕金森病的易感性的关系。方法 用聚合酶链反应-限制性片段长度多态性技术,分析了126例早发性帕金森病患者(发病年龄<50岁)和172名正常健康成人CYP1A1基因3′端限制性内切酶MspⅠ位点的3种基因型(A、B、C)的分布频率。结果 MspⅠ基因型C在病例组和对照组中各占15.1%和13.4%,基因型A在两组中分别占41.3%和34.9%,基因型B在两组中分别占43.6%和51.7%,各基因型在两组中相比较,差异无显著性(P>0.05)。C基因型在病例组和对照组分别占36.9%和39.2%,两者差异无显著性(P>0.05)。结论提示解毒酶CYP1A1基因MspⅠ多态性的单独存在可能与早发性帕金森病的易患性无关。

  10. Clinical research of Irinotecan-Induced adverse reactions and UGT1A1*28 Polymorphism%伊立替康所致不良反应与 UGT1A1*28基因多态性的临床研究

    Institute of Scientific and Technical Information of China (English)

    许春伟; 田玉旺; 张立英; 满秋红; 邵云; 吴永芳; 王怀涛; 宋业颖; 张博; 李晓兵

    2015-01-01

    目的:检测恶性肿瘤患者UGT1A1*28基因多态性的分布情况,探讨其与伊立替康所致不良反应的关系。方法对63例恶性肿瘤外周血标本采用PCR扩增和基因测序的方法检测 UGT1A1*28的基因型 TA(6)/TA(6)纯合子、TA(6)/TA(7)杂合子、TA(7)/TA(7)纯合子。结果迟发性腹泻的发生上一般临床特征如患者的年龄、性别、ECOG评分、复发转移灶、合并疾病史、剂量强度差异均无统计学意义(P>0.05);而在中性粒细胞减少的发生上,剂量强度是危险因素(P<0.05),余各项特征差异无统计学意义(P>0.05);TA(6)/TA(6)正常野生型48例(76.19% ),TA(6)/TA(7)杂合基因型15例(23.81% ),TA(7)/TA(7)纯合突变型0例;基因TA(6)/TA(6)野生型与TA(6)/TA(7)杂合型在患者的性别、年龄、ECOG评分、合并疾病、原发灶的部位与复发转移灶临床特征之间差异均无统计学意义(P>0.05)。结论 UGT1A1*28基因TA(6)/TA(6)野生型最为常见,TA(6)/TA(7)杂合型次之;迟发性腹泻的发生与剂量强度无明显相关性,UGT1A1*28基因多态性是腹泻危险因素,TA(6)/TA(7)型基因患者迟发性腹泻的发生率增加;中性粒细胞减少的发生与剂量强度呈正相关,剂量强度越大的患者可能越易发生中性粒细胞的减少。%Objective To detect UGT1A1* 28 gene polymorphism in patients with malignant tumor and explore its relationship between UGT1A1*28 gene polymorphism and irinotecan-induced adverse reactions .Method 63 ca‐ses of malignant tumors were detected by PCR amplification and sequencing of UGT1A1*28 gene ,including homo‐zygous TA(6)/TA(6) ,heterozygotes TA(6)/TA(7) ,homozygous TA(7)/TA(7) .Result General clinical features in delayed diarrhea occurred such as age ,gender ,ECOG score ,recurrence transfer stove ,merged

  11. Structure and function of uridine diphosphate glucuronosyltransferases.

    Science.gov (United States)

    Meech, R; Mackenzie, P I

    1997-12-01

    1. The uridine diphosphate (UDP)-glucuronosyltransferases (UGT) are a family of enzymes that catalyse the covalent addition of glucuronic acid to a wide range of lipophilic chemicals. They play a major role in the detoxification of many exogenous and endogenous compounds by generating products that are more polar and, thus, more readily excreted in bile or urine. 2. Inherited deficiencies in UGT forms are deleterious, as exemplified by the debilitating effects of hyperbilirubinaemia and neurotoxicity in subjects with mutations in the enzyme that converts bilirubin to its more polar glucuronide. 3. The UGT protein can be conceptually divided into two domains with the amino-terminal half of the protein demonstrating greater sequence divergence between isoforms. This region apparently determines aglycone specificity. The aglycone binding site is presumed to be a 'loose' fit, as many structurally diverse substrates can be bound by the same UGT isoform. The carboxyl-terminal half, which is more conserved in sequence between different isoforms, is believed to contain a binding site for the cosubstrate UDP glucuronic acid (UDPGA). 4. Uridine diphosphate glucuronosyltransferase is localized to the endoplasmic reticulum (ER) and spans the membrane with a type I topology. The putative transmembrane domain is located near the carboxyl terminus of the protein such that only a small portion of the protein resides in the cytosol. This cytosolic tail is believed to contain an ER-targeting signal. The major portion of the protein is located in the ER lumen, including the proposed substrate-binding domains and the catalytic site. 5. The microsomal membrane impedes the access of UDPGA to the active site, resulting in latency of UGT activity in intact ER-derived microsomes. Active transport of UDPGA is believed to occur in hepatocytes, but the transport system has not been fully characterized. Uridine diphosphate glucuronosyltransferase activity is also highly lipid dependent and the

  12. Endothelial cells derived from the blood-brain barrier and islets of Langerhans differ in their response to the effects of bilirubin on oxidative stress under hyperglycemic conditions

    Directory of Open Access Journals (Sweden)

    JaimeKapitulnik

    2012-07-01

    Full Text Available Unconjugated bilirubin (UCB is a neurotoxic degradation product of heme. Its toxic effects include induction of apoptosis, and ultimately neuronal cell death. However, at low concentrations, UCB is a potent antioxidant that may protect cells and tissues against oxidative stress by neutralizing toxic metabolites such as reactive oxygen species (ROS. High glucose levels (hyperglycemia generate reactive metabolites. Endothelial cell dysfunction, an early vascular complication in diabetes, has been associated with hyperglycemia-induced oxidative stress. Both glucose and UCB are substrates for transport proteins in microvascular endothelial cells of the blood-brain barrier (BBB. In the current study we show that UCB (1-40 M induces apoptosis and reduces survival of bEnd3 cells, a mouse brain endothelial cell line which serves as an in vitro model of the BBB. These deleterious effects of UCB were enhanced in the presence of high glucose (25 mM levels. Interestingly, the bEnd3 cells exhibited an increased sensitivity to the apoptotic effects of UCB when compared to the MS1 microcapillary endothelial cell line. MS1 cells originate from murine pancreatic islets of Langherans, and are devoid of the barrier characteristics of BBB-derived endothelial cells. ROS production was increased in both bEnd3 and MS1 cells exposed to high glucose, as compared with cells exposed to normal (5.5 mM glucose levels. While UCB (0.1-40 M did not alter ROS production in cells exposed to normal glucose, relatively low ('physiological' UCB concentrations (0.1-5 M attenuated ROS generation in both cell lines exposed to high glucose levels. Most strikingly, higher UCB concentrations (20-40 M increased ROS generation in bEnd3 cells exposed to high glucose, but not in similarly treated MS1 cells. These results may be of critical importance for understanding the vulnerability of the BBB endothelium upon exposure to increasing UCB levels under hyperglycemic conditions.

  13. Study on extraction of chenodeoxycholic acid and bilirubin fromgoose gallbladder%鹅胆汁中鹅脱氧胆酸和胆红素提取工艺研究

    Institute of Scientific and Technical Information of China (English)

    贾霖; 黄国清; 王宝维; 肖军霞

    2012-01-01

    Both chenodeoxycholic acid and bilirubin are the main active components of goose gallbladder.The chenodeoxycholic acid and bilirubin were isolated and extracted from the goose gallbladder in the same time through the steps of saponification,neutralization,delamination and so on.The effect of saponification temperature,time and sodium hydroxide concentration were determined through the single factor and orthogonal tests.The results showed that the optimum conditions were as follows:saponification temperature 90℃,1h,sodium hydroxide concentration 8%.Under these conditions,the yield of chenodeoxycholic acid reached 0.9mg/g,the yield of bilirubin reached 0.46mg/g.%鹅脱氧胆酸(CDCA)和胆红素均是鹅胆中的主要活性成分。将鹅胆通过皂化、中和、分层等步骤,同时从中分离提取出鹅脱氧胆酸和胆红素。通过单因素实验和正交实验确定了皂化温度、皂化时间和NaOH浓度的最佳条件。实验结果表明,当皂化温度为90℃,皂化时间为1h,NaOH浓度为8%时,CDCA的提取量为0.9mg/g,胆红素的提取量为0.46mg/g。

  14. Self-assembly of aqueous bilirubin ditaurate, a natural conjugated bile pigment, to contraposing enantiomeric dimers and M(-) and P(+) tetramers and their selective hydrophilic disaggregation by monomers and micelles of bile salts.

    Science.gov (United States)

    Neubrand, Michael W; Carey, Martin C; Laue, Thomas M

    2015-02-24

    The solution behavior of bilirubin ditaurate (BDT), the first naturally occurring conjugated bile pigment to be physically and chemically characterized, was assessed in aqueous solution and in monomeric and micellar solutions of common taurine-conjugated bile salts (BS). Analytical ultracentrifugation revealed that BDT self-associates in monomer-dimer equilibria between 1 and 500 μM, forming limiting tetramers at low millimolar concentrations. Self-association was enthalpically driven with ΔG values of ≈5 kcal/mol, suggesting strong hydrophobic interactions. Added NaCl and decreases in temperature shifted the oligomerization to lower BDT concentrations. On the basis of circular dichroism spectra and the limiting size of the self-aggregates, we infer that the tetramers are composed of 2P(+) and 2M(-) enantiomeric BDT pairs in "ridge-tile" conformations interacting in a "double-bookend" structure. With added monomeric BS, blue shifts in the UV-vis spectra and tight isosbestic points revealed that BDT/BS heterodimers form, followed by BDT "decorating" BS micelles mostly via hydrophilic interactions. Conformational enantiomerism, fluorescence intensities, and anisotropy, as well as resistance of the hybrid particles to disaggregation in 6 M urea, suggested that two or three hydrogen-bonding sites bound BDT monomers to the hydroxyl groups of BS, possibly via pyrrole-π-orbital-OH interactions. BDT stabilized these interactions by enveloping the BS in its "ridge-tile" pincers with variable strain that maximized van der Waals interactions. Possibly because the BDT molecule becomes highly strained with BS subtending a 7β-hydroxyl group, BDT became totally resistant to oxidation in air. This work predicts that, because of BS dissolution of the BDT self-aggregates, BS/bilirubin hybrid particles, which are stabilized hydrophilically, are likely to be the dominant mode of transport for all conjugated bilirubins in bile. PMID:25671490

  15. Analysis the Risk Factor of Bilirubin Encephalopathy of Neonatal Hyperbilirubinemia%新生儿高胆红素血症胆红素脑病的危险性因素分析

    Institute of Scientific and Technical Information of China (English)

    陈思远; 覃睿; 黄国坚; 叶军; 陈媚; 周江; 周转智

    2015-01-01

    Objective Analysis the risk factor of bilirubin encephalopathy of Neonatal .And provides the measurement to decrease hy-perbilirubinemia bilirubin encephalopathy incidence.Methods Retrospective analysis 209 neonatal hyperbilirubinemia patients′clinical data.Definite bind the score 7-9 points as acute bilirubin encephalopathy (ABE).the children ABE as the observation group (n=40 pa-tients), the rest patients as the control group (n=169 patients).Related factors that may affect the incidence of hyperbilirubinemia ABE were univariate and multivariate Logistic regression analysis, the Related factors include gender, neonatal gestational age, birth weight, mode of delivery, fetal membranes early break, feeding patterns, gestational diabetes, gestational hypertension, asphyxia or fetal distress,the peak total bilirubin, jaundice family history, RH hemolytic disease and ABO hemolytic disease.Results It was found that birth weight (OR=3.739,95%CI:1.240 -11.880), total bilirubin peak (OR=6.475,95%CI:1.724 -17.419), RH hemolytic disease(OR=11.473,95%CI:2.708-33.697)and ABO hemolytic disease (OR=9.143,95%CI:2.492-28.513)were the risk factors for neonatal hy-perbilirubinemia bilirubin encephalopathy after multivariate Logistic regression analysis, P<0.05.Conclusion Birth weight, total biliru-bin peak, RH hemolytic disease and ABO hemolytic disease are related to bilirubin encephalopathy, clinicians should strengthen Screening and treat the very low birth weight, high total bilirubin peak, accompanied by RH hemolytic disease and ABO hemolytic patients.%目的:分析新生儿高胆红素血症胆红素脑病的危险性因素,为预防高胆红素血症胆红素脑病提供思路。方法回顾性分析我院收治的209例新生儿高胆红素血症患儿临床资料,将胆红素脑病致使神经功能系统障碍( bilirubin-induced neurologic dysfunction,Bind)评分为7~9分的患儿定义为急性胆红素脑病(ABE)患儿

  16. Composição do liquido cefalorrraqueano do recem-nascido normal: citometria, proteinorraquia e bilirrubinorraquia em 79 casos Cerebrospinal fluid composition of normal newborn children: cytology, proteins, and bilirubin

    Directory of Open Access Journals (Sweden)

    Berta R. Luz

    1975-09-01

    Full Text Available Estudo do LCR de recém-nascidos a termo e de parto normal, sem intercorrências perinatais, para verificar o quanto a xantocromia é devida à bilirrubinorraquia. Foi verificado que a bilirrubinorraquia é constante na primeira semana de vida e que sua concentração: não guarda relação com a concentração proteica total do LCR e/ou com os níveis de bilirrubina no soro; não sofre influência do número de hemácias e/ou de leucócitos presente na amostra. Os valores encontrados no LCR quanto ao número de leucócitos e de hemácias e às concentrações de proteínas totais e de bilirrubina são analisados na caracterização do LCR do recém-nascido normal na primeira semana de vida.The study was made in order to verify if the bilirubin content of the cerebrospinal fluid (CSF is constant during the first week of life, and their relations to: the concentrations of total proteins in the CSF and bilirubin in the blood serum; the red blood cells and leucocytes present in the CSF sample. The study was made in 79 normal newborns without perinatal problems or obstetrical abnormalities. The gestational ages were stablished through maternal anamnesis and the clinical evaluation of the newborn was made according to the patterns established by Usher & col., Lubchenko & col. and Lubchenko. All the pregnancies were over 37 weeks. The vital conditions of the newborn immediately after the delivery were calculated according to the patterns proposed by Apgar and Apgar & James. The first complete clinical examination was made in the first twelve hours of life. The cranial sizes were situated within the limits accepted as normal. The deliveries were head-first (only two were breech presentation. The cry was immediate after birth, the breathing well established in the first minute of life and the cut of the umbelical cord was made after the first respiratory movement. The deliveries were made in delivery rooms or surgical rooms always assisted by an

  17. CYP1A1, CYP2E1 Y RIESGO A CÁNCER GÁSTRICO EN UNA POBLACIÓN COLOMBIANA DE ALTA INCIDENCIA CYP1A1, CYP2E1 AND GASTRIC CANCER RISK IN A HIGH-INCIDENCE COLOMBIAN POPULATION

    Directory of Open Access Journals (Sweden)

    Eduardo Castaño-Molina

    Full Text Available El objetivo fue probar la hipótesis de que en casos y controles, de una población colombiana con alta incidencia de cáncer gástrico, muestran diferencias significativas entre las frecuencias de los polimorfismos genéticos CYP1A1*2A y CYP2E1*5A; y a la vez, probar si hay diferencias entre el hábito del tabaquismo, el consumo de alcohol y el estrato socioeconómico; así como también sus posibles interacciones. Durante dos años consecutivos se diagnosticaron y confirmaron ochenta y siete casos nuevos de pacientes afectados por cáncer gástrico y se colectaron igual número de controles pareados por edad y del mismo grupo poblacional, pertenecientes a la comunidad “paisa” del departamento de Caldas. Se genotipificaron por medio de PCR-RFLPs para los polimorfismos CYP1A1*2A y CYP2E1*5A. Además, se tuvo en cuenta las variables socioeconómicas y el estilo de vida, con respecto al tabaquismo y al consumo de alcohol. Los resultados encontrados sugieren que los portadores del alelo CYP2E1-c2, asociado con mayor actividad metabólica, tienen mayor riesgo a desarrollar cáncer gástrico (OR=3,6 CI95% 1,6-8,1/p=0,002. En contraste, la frecuencia del alelo CYP1A1-m2, también asociado con mayor actividad enzimática, mostró similar frecuencia entre los dos grupos. El tabaquismo y el estrato socioeconómico bajo, también mostraron diferencias significativas. En conclusión, se evidencia una interacción significativa entre gen-ambiente, particularmente entre el tabaquismo y los alelos bioactiavantes CYP2E1-c2 y CYP1A1-m2, que pueden alterar la susceptibilidad a cáncer gástrico en esta región Andina del noroeste de Sur América caracterizada por alta incidencia de esta neoplasiaThe aim was to test the hypothesis that some cases and controls, in a Colombian population with a high incidence of gastric cancer, show significant differences among the frequencies of CYP1A1*2A, CYP2E1*5A gene polymorphisms and simultaneously to test the

  18. A Combined Experimental and Theoretical Study on the Formation of the 2-Methyl-1-silacycloprop-2-enylidene Molecule via the Crossed Beam Reactions of the Silylidyne Radical (SiH; X(2)Π) with Methylacetylene (CH3CCH; X(1)A1) and D4-Methylacetylene (CD3CCD; X(1)A1).

    Science.gov (United States)

    Yang, Tao; Dangi, Beni B; Kaiser, Ralf I; Bertels, Luke W; Head-Gordon, Martin

    2016-07-14

    The bimolecular gas-phase reactions of the ground-state silylidyne radical (SiH; X(2)Π) with methylacetylene (CH3CCH; X(1)A1) and D4-methylacetylene (CD3CCD; X(1)A1) were explored at collision energies of 30 kJ mol(-1) under single-collision conditions exploiting the crossed molecular beam technique and complemented by electronic structure calculations. These studies reveal that the reactions follow indirect scattering dynamics, have no entrance barriers, and are initiated by the addition of the silylidyne radical to the carbon-carbon triple bond of the methylacetylene molecule either to one carbon atom (C1; [i1]/[i2]) or to both carbon atoms concurrently (C1-C2; [i3]). The collision complexes [i1]/[i2] eventually isomerize via ring-closure to the c-SiC3H5 doublet radical intermediate [i3], which is identified as the decomposing reaction intermediate. The hydrogen atom is emitted almost perpendicularly to the rotational plane of the fragmenting complex resulting in a sideways scattering dynamics with the reaction being overall exoergic by -12 ± 11 kJ mol(-1) (experimental) and -1 ± 3 kJ mol(-1) (computational) to form the cyclic 2-methyl-1-silacycloprop-2-enylidene molecule (c-SiC3H4; p1). In line with computational data, experiments of silylidyne with D4-methylacetylene (CD3CCD; X(1)A1) depict that the hydrogen is emitted solely from the silylidyne moiety but not from methylacetylene. The dynamics are compared to those of the related D1-silylidyne (SiD; X(2)Π)-acetylene (HCCH; X(1)Σg(+)) reaction studied previously in our group, and from there, we discovered that the methyl group acts primarily as a spectator in the title reaction. The formation of 2-methyl-1-silacycloprop-2-enylidene under single-collision conditions via a bimolecular gas-phase reaction augments our knowledge of the hitherto poorly understood silylidyne (SiH; X(2)Π) radical reactions with small hydrocarbon molecules leading to the synthesis of organosilicon molecules in cold molecular

  19. CYP1A1, GSTM1 and GSTT1 genetic polymorphisms and gastric cancer risk among Japanese: A nested case-control study within a large-scale population-based prospective study.

    Science.gov (United States)

    Hidaka, Akihisa; Sasazuki, Shizuka; Matsuo, Keitaro; Ito, Hidemi; Charvat, Hadrien; Sawada, Norie; Shimazu, Taichi; Yamaji, Taiki; Iwasaki, Motoki; Inoue, Manami; Tsugane, Shoichiro

    2016-08-15

    Cytochrome P450 (CYP) 1A1 and glutathione S-transferases (GST) M1 and T1 are major enzymes in the carcinogen metabolizing pathway. We examined the association between single nucleotide polymorphisms (SNPs) of CYP1A1 (rs4646421, rs4646422 and rs1048943), GSTM1 and GSTT1 and gastric cancer risk in Japan. This is a nested case-control study (457 cases and 457 matched controls) of our population-based cohort involving 36,745 subjects who answered a baseline questionnaire and supplied blood samples. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression models. We found that CYP1A1 (rs4646422) variant allele was associated with a statistically significant increased risk of gastric cancer compared with the homozygous wild-type genotype (OR = 1.65; 95% CI = 1.17-2.32). GSTM1 null, GSTT1 null and GSTM1/T1 both or either null genotypes were associated with increased risk, but not statistically significantly. Combination of the CYP1A1 (rs4646422) variant allele and GSTM1/T1 both or either null genotypes was associated with a statistically significant increased risk compared with the combination of the CYP1A1 homozygous wild-type genotype and the GSTM1/T1 both active genotypes. In addition, compared with CYP1A1 (rs4646422) homozygous wild-type genotypes in those who were never-smokers, CYP1A1 variant alleles in those who smoked ≥30 pack-years were associated with an increased risk; neither gene-gene nor gene-environment interactions were significant. The CYP1A1 (rs4646422) polymorphism might be involved in gastric carcinogenesis among the Japanese population. PMID:27062139

  20. Relationship between serum bilirubin and diabetic retinopathy in patients with type 2 diabetes%2型糖尿病增殖期视网膜病变与血清胆红素水平关系的研究

    Institute of Scientific and Technical Information of China (English)

    冯伟; 杨金奎

    2012-01-01

    Objective To investigate the difference of serum bilirubin between non-diabetic retinopathy( NDR) in long-standing type-2 diabetes mellitus and proliferative diabetic retinopathy( PDR) . Methods Type-2 diabetic patients who were out-patient or who attended the department of endocrinology at Capital Medical University affiliated Tongren Hospital between March 2010 and December 2011 were recruited. Of all the patients, 253 had diabetic duration longer than 10 years and non-diabetic retinopathy( NDR) (male female ratio: 136/117) , and 218 had proliferative diabetic retinopathy( PDR) and diabetic duration was not restricted( male female ratio: 98/120). Comparing the level of serum bilibubin between the two groups and the significant parameters were taken to the logistic regression formula. Results Both total bilirubin and indirect bilirubin were not significantly different between the two groups(P>0. 05) , however, patients with NDR had higher direct bilirubin than those with PDR(P<0. 05). Concerning sex, male patients in NDR group had higher direct bilirubin than those with PDR. But in female patients, no significant diffenence was found. In the logistic regression analysis about diabetic retinopathy risk factors, age and direct bilirubin were protective factors; and systolic blood pressure, HbAlc were risk factors. Conclusion The level of direct bilirubin between the NDR group with diabetic duration longer than 10 years and PDR was different. Bilirubin is a natural anti-oxidant, and can play a protective role in the onset and development of diabetic retinopathy.%目的 研究2型糖尿病长病程的无糖尿病视网膜病变患者(病程≥10年)与增殖期糖尿病视网膜病变患者之间胆红素水平的差异.方法 2010年3月至2011年12月于首都医科大学附属北京同仁医院内分泌科门诊或住院治疗的2型糖尿病患者.其中病程≥10年且无糖尿病视网膜病变(non-diabetic retinopathy,NDR)的患者253例(男女比例为136

  1. Characterization of mutants of the vitamin-D-binding protein/group specific component: GC aborigine (1A1) from Australian aborigines and South African blacks, and 2A9 from south Germany.

    Science.gov (United States)

    Kofler, A; Braun, A; Jenkins, T; Serjeantson, S W; Cleve, H

    1995-01-01

    The structure and organization of the human vitamin-D-binding protein gene (DBP, group-specific component, GC) have recently been determined. Each exon may now be amplified by the PCR method using oligonucleotide primers deduced from the intron sequences near their 5' ends and 3' ends. In this study we examined the anodal GC variants 1A1 and 2A9. Genomic DNA of the variant 1A1 was obtained from Australian Aborigines and from South African Bantu-speaking Blacks. Amplification and sequencing of exon 11 of 1A1 revealed a point mutation in codon 429 at the second position. It is remarkable that this mutation was found in the Australian 1A1 variant and in the African 1A1 variant, and raises the question whether the mutation in these two ethnic groups has a common origin. Genomic DNA of the 2A variant called 2A9 was obtained from South Germany and a point mutation also concerning position 429 in exon 11 was found. The nucleotide exchange in this case, however, was at the first position of the codon. The widely distributed genetic polymorphism of DBP/GC is located in exon 11 and is characterized by substitution at amino acid positions 416 and 420. Variant 1A1 is due to a second site mutation of the allele GC*1F; variant 2A9 is due to a mutation in the GC*2 allele. PMID:7725672

  2. 利用免疫共沉淀技术验证SET与eEF1A1在人肝细胞内的相互作用(摘要)(英文)

    Institute of Scientific and Technical Information of China (English)

    杨亮; 杨细飞; 张毅; 刘建军; 李杰

    2010-01-01

    [目的]探讨SET与eEF1A1在人肝细胞内是否存在相互作用。[方法]以人L-02肝细胞为材料,在非变性条件下提取总蛋白,将鼠抗人SET、兔抗人eEF1A1抗体分别加到总蛋白提取物中,用偶联了琼脂糖珠的ProteinA/G分离抗原抗体复合物,最后分别用兔抗人eEF1A1、鼠抗人SET抗体进行Western blotting检测。[结果]在用SET抗体免疫共沉淀下来的蛋白复合物中检测到eEF1A1,同时在用eEF1A1抗体免疫共沉淀下来的蛋白复合物中也检测到SET。[结论]SET与eEF1A1在人肝细胞内存在相互作用。

  3. Cytochrome b5 and epoxide hydrolase contribute to benzo[a]pyrene-DNA adduct formation catalyzed by cytochrome P450 1A1 under low NADPH:P450 oxidoreductase conditions

    International Nuclear Information System (INIS)

    In previous studies we had administered benzo[a]pyrene (BaP) to genetically engineered mice (HRN) which do not express NADPH:cytochrome P450 oxidoreductase (POR) in hepatocytes and observed higher DNA adduct levels in livers of these mice than in wild-type mice. To elucidate the reason for this unexpected finding we have used two different settings for in vitro incubations; hepatic microsomes from control and BaP-pretreated HRN mice and reconstituted systems with cytochrome P450 1A1 (CYP1A1), POR, cytochrome b5, and epoxide hydrolase (mEH) in different ratios. In microsomes from BaP-pretreated mice, in which Cyp1a1 was induced, higher levels of BaP metabolites were formed, mainly of BaP-7,8-dihydrodiol. At a low POR:CYP1A1 ratio of 0.05:1 in the reconstituted system, the amounts of BaP diones and BaP-9-ol formed were essentially the same as at an equimolar ratio, but formation of BaP-3-ol was ∼1.6-fold higher. Only after addition of mEH were BaP dihydrodiols found. Two BaP-DNA adducts were formed in the presence of mEH, but only one when CYP1A1 and POR were present alone. At a ratio of POR:CYP1A1 of 0.05:1, addition of cytochrome b5 increased CYP1A1-mediated BaP oxidation to most of its metabolites indicating that cytochrome b5 participates in the electron transfer from NADPH to CYP1A1 required for enzyme activity of this CYP. BaP-9-ol was formed even by CYP1A1 reconstituted with cytochrome b5 without POR. Our results suggest that in livers of HRN mice Cyp1a1, cytochrome b5 and mEH can effectively activate BaP to DNA binding species, even in the presence of very low amounts of POR

  4. MG-132 inhibits the TCDD-mediated induction of Cyp1a1 at the catalytic activity but not the mRNA or protein levels in Hepa 1c1c7 cells.

    Science.gov (United States)

    Anwar-Mohamed, Anwar; Elbekai, Reem H; El-Kadi, Ayman O S

    2008-11-10

    Previous studies have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced degradation of aryl hydrocarbon receptor (AhR) is inhibited by MG-132, a potent inhibitor of the 26S proteasome. Therefore, the current study aims to address the effect of MG-132 on the AhR-regulated gene, cytochrome P450 1a1 (Cyp1a1), using murine hepatoma Hepa 1c1c7 cells. Our results showed that MG-132 at the highest concentration tested, 10 microM significantly increased the Cyp1a1 at mRNA, protein and catalytic activity levels through a transcriptional mechanism. On the other hand, MG-132 further potentiated the TCDD-mediated induction of Cyp1a1 at mRNA but not at protein level. In contrast, MG-132 significantly inhibited the TCDD-mediated induction of Cyp1a1 catalytic activity. In addition, we showed that the decrease in Cyp1a1 catalytic activity is not Cyp specific, as MG-132 significantly inhibited Cyp2b1 and total cytochrome P450 catalytic activities. These results prompted us to examine the effect of MG-132 on total cellular heme content and heme oxygenase-1 (HO-1) mRNA, a rate limiting enzyme of heme degradation. Our results showed that MG-132 significantly induced HO-1 mRNA in a concentration-dependent manner. Furthermore, MG-132 potentiated the induction of HO-1 mRNA by TCDD in a concentration-dependent manner. The induction of HO-1 mRNA level coincided with a decrease in total cellular heme content. In conclusion, the present study demonstrates for the first time that MG-132, despite of increasing Cyp1a1 mRNA expression, it decreases its activity probably through decreasing its heme content. PMID:18835339

  5. Sulforaphane induces CYP1A1 mRNA, protein, and catalytic activity levels via an AhR-dependent pathway in murine hepatoma Hepa 1c1c7 and human HepG2 cells.

    Science.gov (United States)

    Anwar-Mohamed, Anwar; El-Kadi, Ayman O S

    2009-03-01

    Recent reports have proposed that some naturally occurring phytochemicals can function as anticancer agents mainly through inducing phase II drug detoxification enzymes. Of these phytochemicals, isothiocyanates sulforaphane (SUL), present in broccoli, is by far the most extensively studied. In spite of its positive effect on phase II drug metabolizing enzymes, its effect on the phase I bioactivating enzyme cytochrome P450 1a1 (Cyp1a1) is still a matter of debate. As a first step to investigate this effect, Hepa 1c1c7 and HepG2 cells were treated with various concentration of SUL. Our results showed that SUL-induced CYP1A1 mRNA in a dose- and time-dependent manner. Furthermore, this induction was further reflected on the protein and catalytic activity levels. Investigating the effect of SUL at the transcriptional level revealed that SUL increases the Cyp1a1 mRNA as early as 1h. The RNA polymerase inhibitor actinomycin D (Act-D) completely abolished the SUL-induced Cyp1a1 mRNA. Furthermore, SUL successfully activated AhR transformation and its subsequent binding to the XRE. At the post-transcriptional level, SUL did not affect the levels of existing Cyp1a1 mRNA transcripts. This is the first demonstration that the broccoli-derived SUL can directly induce Cyp1a1 gene expression in an AhR-dependent manner and represents a novel mechanism by which SUL induces this enzyme. PMID:19013013

  6. Regulation of COL1A1 expression in type I collagen producing tissues: identification of a 49 base pair region which is required for transgene expression in bone of transgenic mice

    Science.gov (United States)

    Bedalov, A.; Salvatori, R.; Dodig, M.; Kronenberg, M. S.; Kapural, B.; Bogdanovic, Z.; Kream, B. E.; Woody, C. O.; Clark, S. H.; Mack, K.; Rowe, D. W. (Principal Investigator)

    1995-01-01

    Previous deletion studies using a series of COL1A1-CAT fusion genes have indicated that the 625 bp region of the COL1A1 upstream promoter between -2295 and -1670 bp is required for high levels of expression in bone, tendon, and skin of transgenic mice. To further define the important sequences within this region, a new series of deletion constructs extending to -1997, -1794, -1763, and -1719 bp has been analyzed in transgenic mice. Transgene activity, determined by measuring CAT activity in tissue extracts of 6- to 8-day-old transgenic mouse calvariae, remains high for all the new deletion constructs and drops to undetectable levels in calvariae containing the -1670 bp construct. These results indicate that the 49 bp region of the COL1A1 promoter between -1719 and -1670 bp is required for high COL1A1 expression in bone. Although deletion of the same region caused a substantial reduction of promoter activity in tail tendon, the construct extending to -1670 bp is still expressed in this tissue. However, further deletion of the promoter to -944 bp abolished activity in tendon. Gel mobility shift studies identified a protein in calvarial nuclear extracts that is not found in tendon nuclear extracts, which binds within this 49 bp region. Our study has delineated sequences in the COL1A1 promoter required for expression of the COL1A1 gene in high type I collagen-producing tissues, and suggests that different cis elements control expression of the COL1A1 gene in bone and tendon.

  7. Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, Noriko; Yonemoto, Junzo [National Institute for Environmental Studies, Endocrine Disruptors and Dioxin Research Project, Tsukuba (Japan); Miyabara, Yuichi [Shinshu University, Research and Education Center for Inlandwater Environment, Nagano (Japan); Fujii-Kuriyama, Yoshiaki [University of Tsukuba, Center for Tsukuba Advanced Research Alliance, Tsukuba (Japan); Tohyama, Chiharu [National Institute for Environmental Studies, Environmental Health Sciences Division, Tsukuba (Japan)

    2005-05-01

    To determine whether the disruption of thyroid hormone and retinoid homeostasis that occurs after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can be mediated by the arylhydrocarbon receptor (AhR), pregnant AhR-heterozygous (AhR+/-) mice were administered a single oral dose of 10 {mu}g kg{sup -1} TCDD at gestation day 12.5. Serum and liver were collected on postnatal day 21 from vehicle-treated control or TCDD-treated AhR+/- and AhR-null (AhR-/-) mouse pups. Whereas TCDD exposure resulted in a marked reduction of total thyroxin (TT4) and free T4 (FT4) levels in the serum of AhR+/- mice, TCDD had no effects on AhR-/- mice. Gene expression of UDP-glucuronosyltransferase (UGT)1A6, cytochrome P450 (CYP)1A1, and CYP1A2 in the liver was induced markedly by TCDD in AhR+/- but not AhR-/- mice. Induction of CYP1A1 in response to TCDD was confirmed by immunohistochemical evidence in that CYP1A1 protein was conspicuously localized in the cytoplasm of hepatocytes in the centrilobular region. Levels of retinyl palmitate were greatly reduced in the liver of TCDD-exposed AhR+/- mice, but not in vehicle-treated AhR+/- mice. No effects of TCDD on retinoid levels in the liver were found in AhR-/- mice. We conclude that disruption of thyroid hormone and retinoid homeostasis is mediated entirely via AhR. Induction of UGT1A6 is thought to be responsible at least partly for reduced serum thyroid hormone levels in TCDD-exposed mice. (orig.)

  8. Combined Experimental and Theoretical Study on the Formation of the Elusive 2-Methyl-1-silacycloprop-2-enylidene Molecule under Single Collision Conditions via Reactions of the Silylidyne Radical (SiH; X(2)Π) with Allene (H2CCCH2; X(1)A1) and D4-Allene (D2CCCD2; X(1)A1).

    Science.gov (United States)

    Yang, Tao; Dangi, Beni B; Maksyutenko, Pavlo; Kaiser, Ralf I; Bertels, Luke W; Head-Gordon, Martin

    2015-12-17

    The crossed molecular beam reactions of the ground-state silylidyne radical (SiH; X(2)Π) with allene (H2CCCH2; X(1)A1) and D4-allene (D2CCCD2; X(1)A1) were carried out at collision energies of 30 kJ mol(-1). Electronic structure calculations propose that the reaction of silylidyne with allene has no entrance barrier and is initiated by silylidyne addition to the π electron density of allene either to one carbon atom (C1/C2) or to both carbon atoms simultaneously via indirect (complex forming) reaction dynamics. The initially formed addition complexes isomerize via two distinct reaction pathways, both leading eventually to a cyclic SiC3H5 intermediate. The latter decomposes through a loose exit transition state via an atomic hydrogen loss perpendicularly to the plane of the decomposing complex (sideways scattering) in an overall exoergic reaction (experimentally: -19 ± 13 kJ mol(-1); computationally: -5 ± 3 kJ mol(-1)). This hydrogen loss yields the hitherto elusive 2-methyl-1-silacycloprop-2-enylidene molecule (c-SiC3H4), which can be derived from the closed-shell cyclopropenylidene molecule (c-C3H2) by replacing a hydrogen atom with a methyl group and the carbene carbon atom by the isovalent silicon atom. The synthesis of the 2-methyl-1-silacycloprop-2-enylidene molecule in the bimolecular gas-phase reaction of silylidyne with allene enriches our understanding toward the formation of organosilicon species in the gas phase of the interstellar medium in particular via exoergic reactions of no entrance barrier. This facile route to 2-methyl-1-silacycloprop-2-enylidene via a silylidyne radical reaction with allene opens up a versatile approach to form hitherto poorly characterized silicon-bearing species in extraterrestrial environments; this reaction class might represent the missing link, leading from silicon-bearing radicals via organosilicon chemistry eventually to silicon-carbon-rich interstellar grains even in cold molecular clouds where temperatures are as

  9. Biotransformation enzyme-dependent formation of micronucleus and multinuclei in cell line V79-hCYP2E1-hSULT1A1 by 2-nitropropane and N-nitrosodimethylamine.

    Science.gov (United States)

    Deng, Hong; Gao, Hai; Liu, Yungang

    2011-11-27

    V79-hCYP2E1-hSULT1A1, a V79-derived cell line co-expressing both human CYP2E1 and SULT1A1, has been constructed and efficiently used in detection of the mutagenic activities of a number of promutagens. 2-Nitropropane (2-NP) and N-nitrosodimethylamine (NDMA), both being hepatocarcinogenic to animals but inactive in standard genotoxicity assays in vitro, are activated to mutagenic metabolites by human SULT1A1 and CYP2E1, respectively. Nevertheless, little is known about the chromosomal effects of these two carcinogens. In the present study, we investigated the effects of 2-NP and NDMA on frequencies of micronucleated (F(mi)) and multinucleated cells (F(mu)) in V79-hCYP2E1-hSULT1A1 cells. The results showed induction of both F(mi) and F(mu) by 2-NP and NDMA individually, and this effect was completely suppressed by relatively specific inhibitor of SULT1A1 and CYP2E1, i.e., pentachlorophenol and 1-aminobenzotriazole, respectively. The F(mu)/F(mi) ratio in 2-NP groups was significantly higher than NDMA groups, probably indicating an aneugenic activity of 2-NP based on proposed F(mu)/F(mi) ratio as a simple index to discriminate aneugens from clastogens. The present study has established biotransformation enzyme-dependent formation of multinuclei and micronuclei induced by 2-NP and NDMA. PMID:21903177

  10. All-trans retinoic acid inhibits the recruitment of ARNT to DNA, resulting in the decrease of CYP1A1 mRNA expression in HepG2 cells

    International Nuclear Information System (INIS)

    Highlights: ► AHR and ARNT transcriptionally regulate genes related to metabolisms such as CYP1A1. ► We investigated the effect of retinoic acid (RA) on the function of AHR/ARNT. ► RA inhibited the recruitment of ARNT, not AHR, to the regulatory region of CYP1A1. ► It resulted in a reduction of constitutive expression of CYP1A1 to less than half. -- Abstract: Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) are well-conserved transcription factors among species. However, there are a very limited number of reports on the physiological function of AHR, particularly on the regulation of AHR by endogenous compounds. We hence investigated the effects of all-trans retinoic acid (atRA) on cytochrome P450 (CYP) 1A1 gene transcription as a model of AHR-regulated transcription mechanisms in HepG2 cells, a human hepatoma cell line. Treatment with atRA significantly reduced transactivation and expression of CYP1A1 mRNA to less than half of its control value, and this inhibitory effect was mediated by RARα. The result of chromatin immunoprecipitation assay indicated that treatment with atRA at 1–100 nM drastically inhibited the recruitment of ARNT to DNA regions containing xenobiotic responsive elements. In conclusion, atRA at physiological concentrations could reduce AHR-mediated gene transcription via the inhibition of recruitment of ARNT to relevant DNA regions.

  11. Comparing the glucuronidation capacity of the feline liver with substrate-specific glucuronidation in dogs

    NARCIS (Netherlands)

    van Beusekom, C D; Fink-Gremmels, J; Schrickx, J A

    2014-01-01

    This study aimed to assess the overall glucuronidation capacity of cats, using prototypic substrates identified for human UDP-glucuronosyltransferases (UGTs). To this end, Michaelis-Menten kinetics were established for the substrates using feline hepatic microsomal fractions, and results were compar

  12. The kinetic basis for age-associated changes in quercetin and genistein glucuronidation by rat liver microsomes

    Science.gov (United States)

    The dietary bioavailability of the isoflavone genistein is decreased in older rats compared to young adults. Since flavonoids are metabolized extensively by the UDP-glucuronosyltransferases (UGTs), we hypothesized that UGT flavonoid conjugating activity changes with age. The effect of age on flavono...

  13. Methoxychlor suppresses the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible CYP1A1 expression in murine Hepa-1c1c7 cells.