Uses and limits of radiotracers in the study of drugs and xenobiotics metabolism

International Nuclear Information System (INIS)

Cohen, Y.

1980-01-01

This review deals with scientific papers issued in 1977-1978, on labelling of drugs and xenobiotics and their metabolism. It is divided in five parts: site of label; in vivo metabolism in animals and human beings; in vitro metabolism on tissue slices, cells culture, microsomes, membrane receptors; metabolism of xenobiotics: nutrients, food additives, detergents, plastics and fabrics; discussion. Metabolic studies, nowadays, associate radiotracers, stable isotopes with high performing procedures for analytical separation [fr

Hepatocyte-based flow analytical bioreactor for xenobiotics metabolism bioprediction

Directory of Open Access Journals (Sweden)

M Helvenstein

2017-04-01

Full Text Available The research for new in vitro screening tools for predictive metabolic profiling of drug candidates is of major interest in the pharmaceutical field. The main motivation is to avoid late rejection in drug development and to deliver safer drugs to the market. Thanks to the superparamagnetic properties of iron oxide nanoparticles, a flow bioreactor has been developed which is able to perform xenobiotic metabolism studies. The selected cell line (HepaRG maintained its metabolic competencies once iron oxide nanoparticles were internalized. Based on magnetically trapped cells in a homemade immobilization chamber, through which a flow of circulating phase was injected to transport nutrients and/or the studied xenobiotic, off-line and online (when coupled to a high-performance liquid chromatography chain metabolic assays were developed using diclofenac as a reference compound. The diclofenac demonstrated a similar metabolization profile chromatogram, both with the newly developed setup and with the control situation. Highly versatile, this pioneering and innovative instrumental design paves the way for a new approach in predictive metabolism studies.

Comparative liver accumulation of dioxin-like compounds in sheep and cattle: Possible role of AhR-mediated xenobiotic metabolizing enzymes.

Science.gov (United States)

Girolami, F; Spalenza, V; Benedetto, A; Manzini, L; Badino, P; Abete, M C; Nebbia, C

2016-11-15

PCDDs, PCDFs, and PCBs are persistent organic pollutants (POPs) that accumulate in animal products and may pose serious health problems. Those able to bind the aryl hydrocarbon receptor (AhR), eliciting a plethora of toxic responses, are defined dioxin-like (DL) compounds, while the remainders are called non-DL (NDL). An EFSA opinion has highlighted the tendency of ovine liver to specifically accumulate DL-compounds to a greater extent than any other farmed ruminant species. To examine the possible role in such an accumulation of xenobiotic metabolizing enzymes (XME) involved in DL-compound biotransformation, liver samples were collected from ewes and cows reared in an area known for low dioxin contamination. A related paper reported that sheep livers had about 5-fold higher DL-compound concentrations than cattle livers, while the content of the six marker NDL-PCBs did not differ between species. Specimens from the same animals were subjected to gene expression analysis for AhR, AhR nuclear translocator (ARNT) and AhR-dependent oxidative and conjugative pathways; XME protein expression and activities were also investigated. Both AhR and ARNT mRNA levels were about 2-fold lower in ovine samples and the same occurred for CYP1A1 and CYP1A2, being approximately 3- and 9-fold less expressed in sheep compared to cattle, while CYP1B1 could be detectable in cattle only. The results of the immunoblotting and catalytic activity (most notably EROD) measurements of the CYP1A family enzymes were in line with the gene expression data. By contrast, phase II enzyme expression and activities in sheep were higher (UGT1A) or similar (GSTA1, NQO1) to those recorded in cattle. The overall low expression of CYP1 family enzymes in the sheep is in line with the observed liver accumulation of DL-compounds and is expected to affect the kinetics and the dynamics of other POPs such as many polycyclic aromatic hydrocarbons, as well as of toxins (e.g. aflatoxins) or drugs (e.g. benzimidazole

Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers.

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Rezen, Tadeja; Tamasi, Viola; Lövgren-Sandblom, Anita; Björkhem, Ingemar; Meyer, Urs A; Rozman, Damjana

2009-08-19

Detoxification in the liver involves activation of nuclear receptors, such as the constitutive androstane receptor (CAR), which regulate downstream genes of xenobiotic metabolism. Frequently, the metabolism of endobiotics is also modulated, resulting in potentially harmful effects. We therefore used 1,4-Bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) to study the effect of CAR activation on mouse hepatic transcriptome and lipid metabolome under conditions of diet-induced hyperlipidemia. Using gene expression profiling with a dedicated microarray, we show that xenobiotic metabolism, PPARalpha and adipocytokine signaling, and steroid synthesis are the pathways most affected by TCPOBOP in normal and hyperlipidemic mice. TCPOBOP-induced CAR activation prevented the increased hepatic and serum cholesterol caused by feeding mice a diet containing 1% cholesterol. We show that this is due to increased bile acid metabolism and up-regulated removal of LDL, even though TCPOBOP increased cholesterol synthesis under conditions of hyperlipidemia. Up-regulation of cholesterol synthesis was not accompanied by an increase in mature SREBP2 protein. As determined by studies in CAR -/- mice, up-regulation of cholesterol synthesis is however CAR-dependent; and no obvious CAR binding sites were detected in promoters of cholesterogenic genes. TCPOBOP also affected serum glucose and triglyceride levels and other metabolic processes in the liver, irrespective of the diet. Our data show that CAR activation modulates hepatic metabolism by lowering cholesterol and glucose levels, through effects on PPARalpha and adiponectin signaling pathways, and by compromising liver adaptations to hyperlipidemia.

Organ slices as an in vitro test system for drug metabolism in human liver, lung and kidney

NARCIS (Netherlands)

Olinga, Peter; de Jager, M.H; Meijer, D.K F; Groothuis, Geny; Merema, M.T.

1999-01-01

Metabolism of xenobiotics occurs mainly in the liver, but in addition, the lungs and kidneys may contribute considerably. The choice of the animal species during drug development as a predictive model for the human condition is often inadequate due to large interspecies differences. Therefore, a

Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure.

Science.gov (United States)

Rouas, Caroline; Souidi, Maâmar; Grandcolas, Line; Grison, Stephane; Baudelin, Cedric; Gourmelon, Patrick; Pallardy, Marc; Gueguen, Yann

2009-11-01

The extensive use of uranium in civilian and military applications increases the risk of human chronic exposure. Uranium is a slightly radioactive heavy metal with a predominantly chemical toxicity, especially in kidney but also in liver. Few studies have previously shown some effects of uranium on xenobiotic-metabolizing enzymes (XME) that might disturb drug pharmacokinetic. The aim of this study was to determine whether a chronic (9 months) non-nephrotoxic low dose exposure to depleted uranium (DU, 1mg/rat/day) could modify the liver XME, using a single non-hepatotoxic acetaminophen (APAP) treatment (50mg/kg). Most of XME analysed were induced by APAP treatment at the gene expression level but at the protein level only CYP3A2 was significantly increased 3h after APAP treatment in DU-exposed rats whereas it remained at a basal level in unexposed rats. In conclusion, these results showed that a chronic non-nephrotoxic DU exposure specially modify CYP3A2 after a single therapeutic APAP treatment. Copyright © 2009 Elsevier B.V. All rights reserved.

Applications of NMR spectroscopy to xenobiotic metabolism

International Nuclear Information System (INIS)

Harris, T.M.

1989-01-01

Recent years have seen high field NMR spectrometers become commonplace in research laboratories. At the same time, major advances in methodology for structural analysis have occurred, particularly notable among these being the development of two-dimensional spectroscopic techniques. Many applications have been made of NMR spectroscopy in the study of xenobiotic metabolic processes. This deals with two specific applications which have been made in the author's laboratory and involve mechanistic studies of the reactions of the carcinogens ethylene dibromide and aflatoxin with DNA

Time-course comparison of xenobiotic activators of CAR and PPARα in mouse liver

International Nuclear Information System (INIS)

Ross, Pamela K.; Woods, Courtney G.; Bradford, Blair U.; Kosyk, Oksana; Gatti, Daniel M.; Cunningham, Michael L.; Rusyn, Ivan

2009-01-01

Constitutive androstane receptor (CAR) and peroxisome proliferator activated receptor (PPAR)α are transcription factors known to be primary mediators of liver effects, including carcinogenesis, by phenobarbital-like compounds and peroxisome proliferators, respectively, in rodents. Many similarities exist in the phenotypes elicited by these two classes of agents in rodent liver, and we hypothesized that the initial transcriptional responses to the xenobiotic activators of CAR and PPARα will exhibit distinct patterns, but at later time-points these biological pathways will converge. In order to capture the global transcriptional changes that result from activation of these nuclear receptors over a time-course in the mouse liver, microarray technology was used. First, differences in basal expression of liver genes between C57Bl/6J wild-type and Car-null mice were examined and 14 significantly differentially expressed genes were identified. Next, mice were treated with phenobarbital (100 mg/kg by gavage for 24 h, or 0.085% w/w diet for 7 or 28 days), and liver gene expression changes with regards to both time and treatment were identified. While several pathways related to cellular proliferation and metabolism were affected by phenobarbital in wild-type mice, no significant changes in gene expression were found over time in the Car-nulls. Next, we determined commonalities and differences in the temporal response to phenobarbital and WY-14,643, a prototypical activator of PPAR α. Gene expression signatures from livers of wild-type mice C57Bl6/J mice treated with PB or WY-14,643 were compared. Similar pathways were affected by both compounds; however, considerable time-related differences were present. This study establishes common gene expression fingerprints of exposure to activators of CAR and PPARα in rodent liver and demonstrates that despite similar phenotypic changes, molecular pathways differ between classes of chemical carcinogens

Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery.

Science.gov (United States)

Naritomi, Yoichi; Sanoh, Seigo; Ohta, Shigeru

2018-02-01

Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans; therefore, these mice are useful for predicting human drug metabolism and PK. In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats

International Nuclear Information System (INIS)

Zheng, Ruijin; Dragomir, Ana-Cristina; Mishin, Vladimir; Richardson, Jason R.; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

2014-01-01

The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress. - Highlights: • Lipid peroxidation generates 4-hydroxynonenal, a highly reactive aldehyde. • Rodent liver, but not lung or brain, is efficient in degrading 4-hydroxynonenal. • 4-hydroxynonenal persists in tissues with low metabolism, causing tissue damage

Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats

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Zheng, Ruijin; Dragomir, Ana-Cristina; Mishin, Vladimir [Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ (United States); Richardson, Jason R. [Environmental and Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ (United States); Heck, Diane E. [Environmental Science, School of Health Sciences and Practice, New York Medical College, Valhalla, NY (United States); Laskin, Debra L. [Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Environmental and Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ (United States)

2014-08-15

The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress. - Highlights: • Lipid peroxidation generates 4-hydroxynonenal, a highly reactive aldehyde. • Rodent liver, but not lung or brain, is efficient in degrading 4-hydroxynonenal. • 4-hydroxynonenal persists in tissues with low metabolism, causing tissue damage.

Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days

NARCIS (Netherlands)

Starokozhko, Viktoriia; Vatakuti, Suresh; Schievink, Bauke; Merema, Marjolijn T.; Asplund, Annika; Synnergren, Jane; Aspegren, Anders; Groothuis, Geny M. M.

Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and

Retrofit Strategies for Incorporating Xenobiotic Metabolism into High Throughput Screening Assays (EMGS)

Science.gov (United States)

The US EPA’s ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to a mischaracterization...

LC-MS-BASED METABOLOMICS OF XENOBIOTIC-INDUCED TOXICITIES

Directory of Open Access Journals (Sweden)

Chi Chen

2013-01-01

Full Text Available Xenobiotic exposure, especially high-dose or repeated exposure of xenobiotics, can elicit detrimental effects on biological systems through diverse mechanisms. Changes in metabolic systems, including formation of reactive metabolites and disruption of endogenous metabolism, are not only the common consequences of toxic xenobiotic exposure, but in many cases are the major causes behind development of xenobiotic-induced toxicities (XIT. Therefore, examining the metabolic events associated with XIT generates mechanistic insights into the initiation and progression of XIT, and provides guidance for prevention and treatment. Traditional bioanalytical platforms that target only a few suspected metabolites are capable of validating the expected outcomes of xenobiotic exposure. However, these approaches lack the capacity to define global changes and to identify unexpected events in the metabolic system. Recent developments in high-throughput metabolomics have dramatically expanded the scope and potential of metabolite analysis. Among all analytical techniques adopted for metabolomics, liquid chromatography-mass spectrometry (LC-MS has been most widely used for metabolomic investigations of XIT due to its versatility and sensitivity in metabolite analysis. In this review, technical platform of LC-MS-based metabolomics, including experimental model, sample preparation, instrumentation, and data analysis, are discussed. Applications of LC-MS-based metabolomics in exploratory and hypothesis-driven investigations of XIT are illustrated by case studies of xenobiotic metabolism and endogenous metabolism associated with xenobiotic exposure.

Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models

Energy Technology Data Exchange (ETDEWEB)

Van der Hauwaert, Cynthia; Savary, Grégoire [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Buob, David [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Leroy, Xavier; Aubert, Sébastien [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); Flamand, Vincent [Service d' Urologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Hennino, Marie-Flore [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Service de Néphrologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Perrais, Michaël [Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); and others

2014-09-15

Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies. - Highlights: • Renal proximal tubular (PT) cells are highly sensitive to xenobiotics. • Expression of genes involved in xenobiotic disposition was measured. • PT cells exhibited the highest similarities with renal tissue.

Nuclear receptors and nonalcoholic fatty liver disease1

Science.gov (United States)

Cave, Matthew C.; Clair, Heather B.; Hardesty, Josiah E.; Falkner, K. Cameron; Feng, Wenke; Clark, Barbara J.; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A.; McClain, Craig J.; Prough, Russell A.

2016-01-01

Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic

Xenobiotics and the Glucocorticoid Receptor

International Nuclear Information System (INIS)

Gulliver, Linda S M

2017-01-01

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

Xenobiotics and the Glucocorticoid Receptor

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Gulliver, Linda S M, E-mail: linda.gulliver@otago.ac.nz

2017-03-15

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

Microbial transformation of xenobiotics for environmental ...

African Journals Online (AJOL)

Microbial transformation of xenobiotics for environmental bioremediation. ... anaerobic and reductive biotransformation by co-metabolic processes and an overview of ... of xenobiotic compounds in context to the modern day biotechnology.

Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha.

Directory of Open Access Journals (Sweden)

Mei-Fei Yueh

Full Text Available Triclocarban (3,4,4'-trichlorocarbanilide, TCC is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs. To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR and estrogen receptor alpha (ERα activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR because no induction occurred in hUGT1Car(-/- mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for

Nrf2 the rescue: Effects of the antioxidative/electrophilic response on the liver

International Nuclear Information System (INIS)

Klaassen, Curtis D.; Reisman, Scott A.

2010-01-01

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes. These gene products include proteins that catalyze reduction reactions (NAD(P)H:quinone oxidoreductase 1, Nqo1), conjugation reactions (glutathione-S-transferases, Gsts and UDP-glucuronosyltransferases, Ugts), as well as the efflux of potentially toxic xenobiotics and xenobiotic conjugates (multidrug resistance-associated proteins, Mrps). The significance of Nrf2 in the liver has been established, as livers of Nrf2-null mice are more susceptible to various oxidative/electrophilic stress-induced pathologies than wild-type mice. In contrast, both pharmacological and genetic models of hepatic Nrf2 activation are protective against oxidative/electrophilic stress. Furthermore, because certain Nrf2-target genes in the liver could affect the distribution, metabolism, and excretion of xenobiotics, the effects of Nrf2 on the kinetics of drugs and other xenobiotics should also be considered, with a special emphasis on metabolism and excretion. Therefore, this review highlights the research that has contributed to the understanding of the importance of Nrf2 in toxicodynamics and toxicokinetics, especially that which pertains to the liver.

Xenobiotic Metabolizing Gene Variants and Renal Cell Cancer: A Multicenter Study

International Nuclear Information System (INIS)

Heck, Julia E.; Moore, Lee E.; Lee, Yuan-Chin A.; McKay, James D.; Hung, Rayjean J.; Karami, Sara; Gaborieau, Valérie; Szeszenia-Dabrowska, Neonila; Zaridze, David G.; Mukeriya, Anush; Mates, Dana; Foretova, Lenka; Janout, Vladimir; Kollárová, Helena; Bencko, Vladimir; Rothman, Nathaniel; Brennan, Paul; Chow, Wong-Ho; Boffetta, Paolo

2012-01-01

Background: The countries of Central and Eastern Europe have among the highest worldwide rates of renal cell cancer (RCC). Few studies have examined whether genetic variation in xenobiotic metabolic pathway genes may modify risk for this cancer. Methods: The Central and Eastern Europe Renal Cell Cancer study was a hospital-based case–control study conducted between 1998 and 2003 across seven centers in Central and Eastern Europe. Detailed data were collected from 874 cases and 2053 controls on demographics, work history, and occupational exposure to chemical agents. Genes [cytochrome P-450 family, N-acetyltransferases, NAD(P)H:quinone oxidoreductase I (NQO1), microsomal epoxide hydrolase (mEH), catechol-O-methyltransferase (COMT), uridine diphosphate-glucuronosyltransferase (UGT)] were selected for the present analysis based on their putative role in xenobiotic metabolism. Haplotypes were calculated using fastPhase. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for country of residence, age, sex, smoking, alcohol intake, obesity, and hypertension. Results: We observed an increased risk of RCC with one SNP. After adjustment for multiple comparisons it did not remain significant. Neither NAT1 nor NAT2 slow acetylation was associated with disease. Conclusion: We observed no association between this pathway and renal cell cancer.

Xenobiotic Metabolizing Gene Variants and Renal Cell Cancer: A Multicenter Study

Energy Technology Data Exchange (ETDEWEB)

Heck, Julia E. [International Agency for Research on Cancer, Lyon (France); Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, CA (United States); Moore, Lee E. [Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (United States); Lee, Yuan-Chin A. [International Agency for Research on Cancer, Lyon (France); Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, CA (United States); McKay, James D. [International Agency for Research on Cancer, Lyon (France); Hung, Rayjean J. [Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, ON (Canada); Karami, Sara [Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (United States); Gaborieau, Valérie [International Agency for Research on Cancer, Lyon (France); Szeszenia-Dabrowska, Neonila [Department of Epidemiology, Institute of Occupational Medicine, Lodz (Poland); Zaridze, David G. [Cancer Research Centre, Institute of Carcinogenesis, Moscow (Russian Federation); Mukeriya, Anush [Cancer Research Centre, Department of Epidemiology, Moscow (Russian Federation); Mates, Dana [Institute of Public Health, Bucharest (Romania); Foretova, Lenka [Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno (Czech Republic); Janout, Vladimir; Kollárová, Helena [Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc (Czech Republic); Bencko, Vladimir [First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague, Prague, Czech Republic (Czech Republic); Rothman, Nathaniel [Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (United States); Brennan, Paul [International Agency for Research on Cancer, Lyon (France); Chow, Wong-Ho [Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (United States); Boffetta, Paolo, E-mail: paolo.boffetta@mssm.edu [International Prevention Research Institute, Lyon (France); Tisch Cancer Institute, Mt. Sinai School of Medicine, New York, NY (United States)

2012-02-20

Background: The countries of Central and Eastern Europe have among the highest worldwide rates of renal cell cancer (RCC). Few studies have examined whether genetic variation in xenobiotic metabolic pathway genes may modify risk for this cancer. Methods: The Central and Eastern Europe Renal Cell Cancer study was a hospital-based case–control study conducted between 1998 and 2003 across seven centers in Central and Eastern Europe. Detailed data were collected from 874 cases and 2053 controls on demographics, work history, and occupational exposure to chemical agents. Genes [cytochrome P-450 family, N-acetyltransferases, NAD(P)H:quinone oxidoreductase I (NQO1), microsomal epoxide hydrolase (mEH), catechol-O-methyltransferase (COMT), uridine diphosphate-glucuronosyltransferase (UGT)] were selected for the present analysis based on their putative role in xenobiotic metabolism. Haplotypes were calculated using fastPhase. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for country of residence, age, sex, smoking, alcohol intake, obesity, and hypertension. Results: We observed an increased risk of RCC with one SNP. After adjustment for multiple comparisons it did not remain significant. Neither NAT1 nor NAT2 slow acetylation was associated with disease. Conclusion: We observed no association between this pathway and renal cell cancer.

Transcriptional expression analysis of ABC efflux transporters and xenobiotic-metabolizing enzymes in the Chinese rare minnow.

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Yuan, Lilai; Lv, Biping; Zha, Jinmiao; Wang, Zijian

2014-05-01

In the present study, the cDNA fragments of five ABC transporter genes (ABCB1, ABCB11, ABCC1, ABCC2, and ABCG2) in the rare minnow were cloned, and their tissue-specific expression patterns were evaluated across eight rare minnow tissues (liver, gill, intestine, kidney, spleen, brain, skin, and muscle). Furthermore, the transcriptional effects on these ABC transporter genes and five xenobiotic-metabolizing enzyme genes (CYP1A, GSTm, GSTp1, GCLC, and UGT1a) were determined in the rare minnow liver after 12 days of pyrene exposure. Basal expression analysis showed that the tissues with high expression of the ABC transporters included the liver, kidney, and intestine. Moreover, the most highly expressed of the ABC genes were ABCB1 and ABCC2 in all eight of the tissues tested. The ABCB11 gene was almost exclusively expressed in the liver of the rare minnow, whereas ABCC1 and ABCG2 showed weak expression in all eight tissues compared to ABCB1 and ABCC2. Our results provide the first thorough examination of the expression patterns of toxicologically relevant ABC transporters in the rare minnow and serve as a necessary basis for further studies of these ABC transporters in fish. Furthermore, synergistic up-regulation of CYP1A, GSTp1, GCLC, UGT1a, and ABCC2 was observed in the rare minnow liver following pyrene exposure, while GSTm, ABCB1, ABCB11, ABCC1, and ABCG2 were not significantly affected (p ABC transporters by pyrene suggests a possible involvement and cooperation of these genes in the detoxification process in rare minnows. Copyright © 2014 Elsevier B.V. All rights reserved.

Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma

International Nuclear Information System (INIS)

Bièche, Ivan; Girault, Igor; Urbain, Estelle; Tozlu, Sengül; Lidereau, Rosette

2004-01-01

Little is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability. To test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes (12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast (and liver) tissues, and in estrogen receptor alpha (ERα)-negative and ERα-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERα-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone. Seven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes (CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERα-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERα-positive breast tumors than in ERα-negative breast tumors. In the 97 ERα-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERα-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis (P = 0.0013). Taken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an

Extent of cutaneous metabolism during percutaneous absorption of xenobiotics.

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Bronaugh, R L; Stewart, R F; Storm, J E

1989-07-01

In vitro percutaneous absorption studies generally do not determine whether biotransformation occurs during passage of a substance through the skin. Since it has recently been demonstrated that several chemicals are metabolized during skin permeation, we investigated the metabolism of five additional compounds (14C-labeled) after application to fuzzy rat skin: caffeine, p,p'-DDT, butylated hydroxytoluene (BHT), salicylic acid, and acetyl ethyl tetramethyltetralin (AETT). The viability of skin was maintained with a tissue culture medium. Radioactivity of each substrate and any metabolites in skin and receptor fluid was measured so that the absorption and metabolism of water-insoluble compounds would be accurately determined. Percutaneous absorption ranged from a low of 13% of the applied dose for BHT to a high of 49% for DDT. BHT was metabolized in skin to 4-hydroxy-BHT and an unknown metabolite. Of the absorbed radioisotope, 6.6% was isolated in biotransformed products found mainly in the receptor fluid. AETT was also metabolized during absorption, with 1.9% of the absorbed radioisotope found in two unknown peaks. Caffeine, DDT, and salicylic acid were not metabolized during skin permeation. Skin and liver microsomal metabolism was measured for all compounds except DDT. Metabolism in skin was observed only for the compounds also biotransformed in the diffusion cell; BHT and AETT were metabolized at 113 and 2.5 pmol/min/mg protein, respectively. In this study, as in others, skin metabolism was substantially less than the corresponding metabolism in liver. Therefore, a low rate of liver metabolism such as that found for caffeine, salicylic acid, and DDT might often be predictive of the absence of measurable metabolism during skin permeation. It seems likely that for many compounds, the biotransformations in skin will be small in terms of the percentage of absorbed material that is metabolized. Nevertheless, with potent compounds, even small quantities of a metabolite

Energy Metabolism in the Liver

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Rui, Liangyou

2014-01-01

The liver is an essential metabolic organ, and its metabolic activity is tightly controlled by insulin and other metabolic hormones. Glucose is metabolized into pyruvate through glycolysis in the cytoplasm, and pyruvate is completely oxidized to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and cholesterol esters in hepatocytes, and these complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as VLDL particles. In the fasted state, the liver secretes glucose through both breakdown of glycogen (glycogenolysis) and de novo glucose synthesis (gluconeogenesis). During pronged fasting, hepatic gluconeogenesis is the primary source of endogenous glucose production. Fasting also promotes lipolysis in adipose tissue to release nonesterified fatty acids which are converted into ketone bodies in the liver though mitochondrial β oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver metabolic processes are tightly regulated by neuronal and hormonal systems. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis, but suppresses gluconeogenesis; glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze the rate-limiting steps of liver metabolic processes, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases (NAFLD). PMID:24692138

Clonal xenobiotic resistance during pollution-induced toxic injury and hepatocellular carcinogenesis in liver of female flounder (Platichthys flesus (L.))

NARCIS (Netherlands)

Koehler, Angela; Alpermann, Tilmann; Lauritzen, Bjarne; van Noorden, Cornelis J. F.

2004-01-01

Juvenile and adult female flounder (Platichthys flesus (L.)) were caught either in the estuary of the most polluted European river, the Elbe, or as controls in a reference site to study pollution-induced xenobiotic resistance in their livers in relation to pathological alterations. In juvenile fish,

Molecular, cellular, and tissue impact of depleted uranium on xenobiotic-metabolizing enzymes.

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Gueguen, Yann; Rouas, Caroline; Monin, Audrey; Manens, Line; Stefani, Johanna; Delissen, Olivia; Grison, Stéphane; Dublineau, Isabelle

2014-02-01

Enzymes that metabolize xenobiotics (XME) are well recognized in experimental models as representative indicators of organ detoxification functions and of exposure to toxicants. As several in vivo studies have shown, uranium can alter XME in the rat liver or kidneys after either acute or chronic exposure. To determine how length or level of exposure affects these changes in XME, we continued our investigation of chronic rat exposure to depleted uranium (DU, uranyl nitrate). The first study examined the effect of duration (1-18 months) of chronic exposure to DU, the second evaluated dose dependence, from a level close to that found in the environment near mining sites (0.2 mg/L) to a supra-environmental dose (120 mg/L, 10 times the highest level naturally found in the environment), and the third was an in vitro assessment of whether DU exposure directly affects XME and, in particular, CYP3A. The experimental in vivo models used here demonstrated that CYP3A is the enzyme modified to the greatest extent: high gene expression changed after 6 and 9 months. The most substantial effects were observed in the liver of rats after 9 months of exposure to 120 mg/L of DU: CYP3A gene and protein expression and enzyme activity all decreased by more than 40 %. Nonetheless, no direct effect of DU by itself was observed after in vitro exposure of rat microsomal preparations, HepG2 cells, or human primary hepatocytes. Overall, these results probably indicate the occurrence of regulatory or adaptive mechanisms that could explain the indirect effect observed in vivo after chronic exposure.

Application of chimeric mice with humanized liver for study of human-specific drug metabolism.

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Bateman, Thomas J; Reddy, Vijay G B; Kakuni, Masakazu; Morikawa, Yoshio; Kumar, Sanjeev

2014-06-01

Human-specific or disproportionately abundant human metabolites of drug candidates that are not adequately formed and qualified in preclinical safety assessment species pose an important drug development challenge. Furthermore, the overall metabolic profile of drug candidates in humans is an important determinant of their drug-drug interaction susceptibility. These risks can be effectively assessed and/or mitigated if human metabolic profile of the drug candidate could reliably be determined in early development. However, currently available in vitro human models (e.g., liver microsomes, hepatocytes) are often inadequate in this regard. Furthermore, the conduct of definitive radiolabeled human ADME studies is an expensive and time-consuming endeavor that is more suited for later in development when the risk of failure has been reduced. We evaluated a recently developed chimeric mouse model with humanized liver on uPA/SCID background for its ability to predict human disposition of four model drugs (lamotrigine, diclofenac, MRK-A, and propafenone) that are known to exhibit human-specific metabolism. The results from these studies demonstrate that chimeric mice were able to reproduce the human-specific metabolite profile for lamotrigine, diclofenac, and MRK-A. In the case of propafenone, however, the human-specific metabolism was not detected as a predominant pathway, and the metabolite profiles in native and humanized mice were similar; this was attributed to the presence of residual highly active propafenone-metabolizing mouse enzymes in chimeric mice. Overall, the data indicate that the chimeric mice with humanized liver have the potential to be a useful tool for the prediction of human-specific metabolism of xenobiotics and warrant further investigation.

Functioning of Microsomal Cytochrome P450s: Murburn Concept Explains the Metabolism of Xenobiotics in Hepatocytes.

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Manoj, Kelath Murali; Parashar, Abhinav; Gade, Sudeep K; Venkatachalam, Avanthika

2016-01-01

murburn as the operative concept. The mechanism of uncoupling (peroxide/water formation) was found to be dependent on multiple one and two electron equilibriums amongst the reaction components. The investigation explains the evolutionary implications of xenobiotic metabolism, confirms the obligatory role of diffusible reactive species in routine redox metabolism within liver microsomes and establishes that a redox enzyme like CYP enhances reaction rates (achieves catalysis) via a novel (hitherto unknown) modality.

Phase 0 and phase III transport in various organs: combined concept of phases in xenobiotic transport and metabolism.

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Döring, Barbara; Petzinger, Ernst

2014-08-01

The historical phasing concept of drug metabolism and elimination was introduced to comprise the two phases of metabolism: phase I metabolism for oxidations, reductions and hydrolyses, and phase II metabolism for synthesis. With this concept, biological membrane barriers obstructing the accessibility of metabolism sites in the cells for drugs were not considered. The concept of two phases was extended to a concept of four phases when drug transporters were detected that guided drugs and drug metabolites in and out of the cells. In particular, water soluble or charged drugs are virtually not able to overcome the phospholipid membrane barrier. Drug transporters belong to two main clusters of transporter families: the solute carrier (SLC) families and the ATP binding cassette (ABC) carriers. The ABC transporters comprise seven families with about 20 carriers involved in drug transport. All of them operate as pumps at the expense of ATP splitting. Embedded in the former phase concept, the term "phase III" was introduced by Ishikawa in 1992 for drug export by ABC efflux pumps. SLC comprise 52 families, from which many carriers are drug uptake transporters. Later on, this uptake process was referred to as the "phase 0 transport" of drugs. Transporters for xenobiotics in man and animal are most expressed in liver, but they are also present in extra-hepatic tissues such as in the kidney, the adrenal gland and lung. This review deals with the function of drug carriers in various organs and their impact on drug metabolism and elimination.

Effects of tin-protoporphyrin administration on hepatic xenobiotic metabolizing enzymes in the juvenile rat

International Nuclear Information System (INIS)

Stout, D.L.; Becker, F.F.

1988-01-01

The heme analogue tin-protoporphyrin IX (SnP) is a potent inhibitor of microsomal heme oxygenase. Administration of SnP to neonatal rats can prevent hyperbilirubinemia by blocking the postnatal increase of heme oxygenase activity. Apparently innocuous at therapeutic doses, it is of potential clinical value for chemoprevention of neonatal jaundice. We found that when 50-g male Sprague-Dawley rats were treated daily with 50 mumol of SnP/kg sc for 6 days, hepatic microsomal cytochromes b5 and P-450 were significantly diminished. Cytochrome P-450 reductase, two P-450-dependent monooxygenases, aminopyrine demethylase and benzo(a)pyrene hydroxylase, and catalase, a peroxisomal hemoprotein, were also significantly diminished. These results suggested that SnP might significantly affect the metabolism of other xenobiotics. This possibility was confirmed by the finding that hexobarbital-induced sleep lasted 4 times longer in SnP-treated rats than in controls. Inhibition of protein synthesis by SnP was ruled out as the cause of hemoprotein loss when administration of [ 3 H]leucine to SnP-treated and control rats demonstrated that proteins of the microsomal, cytosolic, and plasma membrane fractions of the livers from both groups incorporated similar levels of leucine. When 55 FeCl 3 and [2- 14 C]glycine were administered to measure heme synthesis, heme extract from the livers of SnP-treated rats contained 4 times more label from iron and glycine than did heme from control livers. Despite the apparent increased rate of heme synthesis in SnP-treated rats, each of the three cell fractions demonstrated a significant loss of heme but contained sizable amounts of SnP. These findings suggest that SnP causes a decrease of functional hemoprotein and partial loss of enzymic activity by displacing intracellular heme

Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas.

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Fairchild, C R; Ivy, S P; Rushmore, T; Lee, G; Koo, P; Goldsmith, M E; Myers, C E; Farber, E; Cowan, K H

1987-11-01

We have previously reported the isolation of a human breast cancer cell line resistant to doxorubicin (adriamycin; AdrR MCF-7 cells) that has also developed the phenotype of multidrug resistance (MDR). MDR in this cell line is associated with increased expression of mdr (P glycoprotein) gene sequences. The development of MDR in AdrR MCF-7 cells is also associated with changes in the expression of several phase I and phase II drug-detoxifying enzymes. These changes are remarkably similar to those associated with development of xenobiotic resistance in rat hyperplastic liver nodules, a well-studied model system of chemical carcinogenesis. Using an mdr-encoded cDNA sequence isolated from AdrR MCF-7 cells, we have examined the expression of mdr sequences in rat livers under a variety of experimental conditions. The expression of mdr increased 3-fold in regenerating liver. It was also elevated (3- to 12-fold) in several different samples of rat hyperplastic nodules and in four of five hepatomas that developed in this system. This suggests that overexpression of mdr, a gene previously associated with resistance to antineoplastic agents, may also be involved in the development of resistance to xenobiotics in rat hyperplastic nodules. In addition, although the acute administration of 2-acetylaminofluorene induced an 8-fold increase in hepatic mdr-encoded RNA, performance of a partial hepatectomy either before or after administration of 2-acetylaminofluorene resulted in a greater than 80-fold increase in mdr gene expression over that in normal untreated livers. This represents an important in vivo model system in which to study the acute regulation of this drug resistance gene.

Energy metabolism in the liver.

Science.gov (United States)

Rui, Liangyou

2014-01-01

The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones. Glucose is converted into pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and/or cholesterol esters in hepatocytes. These complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as very low-density lipoprotein particles. In the fasted state, the liver secretes glucose through both glycogenolysis and gluconeogenesis. During pronged fasting, hepatic gluconeogenesis is the primary source for endogenous glucose production. Fasting also promotes lipolysis in adipose tissue, resulting in release of nonesterified fatty acids which are converted into ketone bodies in hepatic mitochondria though β-oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver energy metabolism is tightly regulated by neuronal and hormonal signals. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis but suppresses gluconeogenesis, and glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze key steps of metabolic pathways, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases. © 2014 American Physiological Society.

Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: Role of male sex hormone

International Nuclear Information System (INIS)

Kim, Young C.; Yim, Hye K.; Jung, Young S.; Park, Jae H.; Kim, Sung Y.

2007-01-01

Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomy also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards

Med1 subunit of the mediator complex in nuclear receptor-regulated energy metabolism, liver regeneration, and hepatocarcinogenesis.

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Jia, Yuzhi; Viswakarma, Navin; Reddy, Janardan K

2014-01-01

Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARα-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARα activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARα, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARα, PPARγ, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARα activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic

Avian cytochrome P450 (CYP 1-3 family genes: isoforms, evolutionary relationships, and mRNA expression in chicken liver.

Directory of Open Access Journals (Sweden)

Kensuke P Watanabe

Full Text Available Cytochrome P450 (CYP of chicken and other avian species have been studied primarily with microsomes or characterized by cloning and protein expression. However, the overall existing isoforms in avian CYP1-3 families or dominant isoforms in avian xenobiotic metabolism have not yet been elucidated. In this study, we aimed to clarify and classify all of the existing isoforms of CYP1-3 in avian species using available genome assemblies for chicken, zebra finch, and turkey. Furthermore, we performed qRT-PCR assay to identify dominant CYP genes in chicken liver. Our results suggested that avian xenobiotic-metabolizing CYP genes have undergone unique evolution such as CYP2C and CYP3A genes, which have undergone avian-specific gene duplications. qRT-PCR experiments showed that CYP2C45 was the most highly expressed isoform in chicken liver, while CYP2C23b was the most highly induced gene by phenobarbital. Considering together with the result of further enzymatic characterization, CYP2C45 may have a dominant role in chicken xenobiotic metabolism due to the constitutive high expression levels, while CYP2C23a and CYP2C23b can be greatly induced by chicken xenobiotic receptor (CXR activators. These findings will provide not only novel insights into avian xenobiotic metabolism, but also a basis for the further characterization of each CYP gene.

The liver in regulation of iron homeostasis.

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Rishi, Gautam; Subramaniam, V Nathan

2017-09-01

The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the body's metabolism. This hepatic iron-regulatory function can be attributed to the expression of many liver-specific or liver-enriched proteins, all of which play an important role in the regulation of iron homeostasis. This review focuses on these proteins and their known roles in the regulation of body iron metabolism. Copyright © 2017 the American Physiological Society.

Xenobiotic-metabolizing enzymes in plants and their role in uptake and biotransformation of veterinary drugs in the environment.

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Bártíková, Hana; Skálová, Lenka; Stuchlíková, Lucie; Vokřál, Ivan; Vaněk, Tomáš; Podlipná, Radka

2015-08-01

Many various xenobiotics permanently enter plants and represent potential danger for their organism. For that reason, plants have evolved extremely sophisticated detoxification systems including a battery of xenobiotic-metabolizing enzymes. Some of them are similar to those in humans and animals, but there are several plant-specific ones. This review briefly introduces xenobiotic-metabolizing enzymes in plants and summarizes present information about their action toward veterinary drugs. Veterinary drugs are used worldwide to treat diseases and protect animal health. However, veterinary drugs are also unwantedly introduced into environment mostly via animal excrements, they persist in the environment for a long time and may impact on the non-target organisms. Plants are able to uptake, transform the veterinary drugs to non- or less-toxic compounds and store them in the vacuoles and cell walls. This ability may protect not only plant themselves but also other organisms, predominantly invertebrates and wild herbivores. The aim of this review is to emphasize the importance of plants in detoxification of veterinary drugs in the environment. The results of studies, which dealt with transport and biotransformation of veterinary drugs in plants, are summarized and evaluated. In conclusion, the risks and consequences of veterinary drugs in the environment and the possibilities of phytoremediation technologies are considered and future perspectives are outlined.

Bile Acid Metabolism and Signaling

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Chiang, John Y. L.

2015-01-01

Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans. PMID:23897684

Bile Acid Metabolism in Liver Pathobiology

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Chiang, John Y. L.; Ferrell, Jessica M.

2018-01-01

Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders. PMID:29325602

Apoptosis (programmed cell death) as an indicator of xenobiotic toxicity

International Nuclear Information System (INIS)

Bond, G.P.

1989-01-01

Xenobiotics alter the frequency and pattern of apoptosis (programmed cell death). Preliminary studies identified the mouse liver, with normally low levels of apoptosis, as a preferable test system to the chicken embryo limb, with normally high levels of apoptosis. The major purposes of these investigations, using the apoptogen and necrogen 1,1-dichloroethylene (DCE), were to determine if increases in apoptosis, (1) could be quantified as a direct result of treatment, (2) were dose- and time-dependent, (3) were independent of necrosis, (4) were associated with mitosis in the control of cell numbers and (5) were limited to specific areas of the liver. To these ends, food-deprived female, CF-1 mice were administered DCE ip under varying experimental conditions. Increased apoptosis occurred in a dose- and time-dependent manner after treatment with 12.5, 40, and 125 mg/kg for 0.5, 1, 2, 4 and 8 hr. Peak effects were observed at 4 hr. Apoptosis occurred only in the midzonal/pericentral areas of the liver. At 12.5 mg/kg, there were no effects on biochemical (alanine transaminase) and morphological indices of necrosis, establishing apoptosis as a separate phenomenon from necrosis. Increased 3 H-thymidine incorporation (DNA synthesis), mitosis and the percentage of octaploid hepatocytes occurred from 24-48 hr after treatment with the apoptotic but non-necrotic dose of 40 mg/kg. Apoptosis only occurred in the midzonal/pericentral areas of the liver after multiple doses with DCE, indicating the zonal selectivity of the response. In conclusion, apoptosis, a normally occurring homeostatic process associated with mitosis in the control of cell numbers, is affected by selected xenobiotics in a dose-dependent manner. Xenobiotic-induced apoptosis in the liver occurs at low doses of xenobiotics which cause no other effects on tissue structure or function

Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.

Science.gov (United States)

Wahlang, Banrida; Prough, Russell A; Falkner, K Cameron; Hardesty, Josiah E; Song, Ming; Clair, Heather B; Clark, Barbara J; States, J Christopher; Arteel, Gavin E; Cave, Matthew C

2016-02-01

Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

Monocrotophos induces the expression and activity of xenobiotic metabolizing enzymes in pre-sensitized cultured human brain cells.

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Vinay K Tripathi

Full Text Available The expression and metabolic profile of cytochrome P450s (CYPs is largely missing in human brain due to non-availability of brain tissue. We attempted to address the issue by using human brain neuronal (SH-SY5Y and glial (U373-MG cells. The expression and activity of CYP1A1, 2B6 and 2E1 were carried out in the cells exposed to CYP inducers viz., 3-methylcholanthrene (3-MC, cyclophosphamide (CPA, ethanol and known neurotoxicant- monocrotophos (MCP, a widely used organophosphorous pesticide. Both the cells show significant induction in the expression and CYP-specific activity against classical inducers and MCP. The induction level of CYPs was comparatively lower in MCP exposed cells than cells exposed to classical inducers. Pre-exposure (12 h of cells to classical inducers significantly added the MCP induced CYPs expression and activity. The findings were concurrent with protein ligand docking studies, which show a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR, PXR and AHR. Similarly, the known CYP inducers- 3-MC, CPA and ethanol have also shown significantly high docking scores with all the three studied CYP regulators. The expression of CYPs in neuronal and glial cells has suggested their possible association with the endogenous physiology of the brain. The findings also suggest the xenobiotic metabolizing capabilities of these cells against MCP, if received a pre-sensitization to trigger the xenobiotic metabolizing machinery. MCP induced CYP-specific activity in neuronal cells could help in explaining its effect on neurotransmission, as these CYPs are known to involve in the synthesis/transport of the neurotransmitters. The induction of CYPs in glial cells is also of significance as these cells are thought to be involved in protecting the neurons from environmental insults and safeguard them from toxicity. The data provide better understanding of the metabolizing capability of the human brain cells against

High-throughput metagenomic analysis of petroleum-contaminated soil microbiome reveals the versatility in xenobiotic aromatics metabolism.

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Bao, Yun-Juan; Xu, Zixiang; Li, Yang; Yao, Zhi; Sun, Jibin; Song, Hui

2017-06-01

The soil with petroleum contamination is one of the most studied soil ecosystems due to its rich microorganisms for hydrocarbon degradation and broad applications in bioremediation. However, our understanding of the genomic properties and functional traits of the soil microbiome is limited. In this study, we used high-throughput metagenomic sequencing to comprehensively study the microbial community from petroleum-contaminated soils near Tianjin Dagang oilfield in eastern China. The analysis reveals that the soil metagenome is characterized by high level of community diversity and metabolic versatility. The metageome community is predominated by γ-Proteobacteria and α-Proteobacteria, which are key players for petroleum hydrocarbon degradation. The functional study demonstrates over-represented enzyme groups and pathways involved in degradation of a broad set of xenobiotic aromatic compounds, including toluene, xylene, chlorobenzoate, aminobenzoate, DDT, methylnaphthalene, and bisphenol. A composite metabolic network is proposed for the identified pathways, thus consolidating our identification of the pathways. The overall data demonstrated the great potential of the studied soil microbiome in the xenobiotic aromatics degradation. The results not only establish a rich reservoir for novel enzyme discovery but also provide putative applications in bioremediation. Copyright © 2016. Published by Elsevier B.V.

Structural changes in the liver in metabolic syndrome

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D. V. Vasendin

2015-01-01

Full Text Available Scientifically proven close relationship of nonalcoholic fatty liver disease with development of metabolic syndrome and its individual components involves the conclusion that the target organ in metabolic symptom, even regardless of the severity of obesity, the liver occupies a dominant position, as the body undergoes the first characteristic of non-alcoholic fatty liver disease changes, involving violation of metabolism in the body. Dislipoproteinemia plays an important role in the formation of metabolic syndrome in obesity and other obesity-associated diseases. Altered liver function are the root cause of violations of processes of lipid metabolism and, consequently, abnormal functioning of the liver may be a separate, additional and independent risk factor for development of dyslipidemia and obesity as the main component of the metabolic syndrome.

Purification and characterization of akr1b10 from human liver: role in carbonyl reduction of xenobiotics.

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Martin, Hans-Jörg; Breyer-Pfaff, Ursula; Wsol, Vladimir; Venz, Simone; Block, Simone; Maser, Edmund

2006-03-01

Members of the aldo-keto reductase (AKR) superfamily have a broad substrate specificity in catalyzing the reduction of carbonyl group-containing xenobiotics. In the present investigation, a member of the aldose reductase subfamily, AKR1B10, was purified from human liver cytosol. This is the first time AKR1B10 has been purified in its native form. AKR1B10 showed a molecular mass of 35 kDa upon gel filtration and SDS-polyacrylamide gel electrophoresis. Kinetic parameters for the NADPH-dependent reduction of the antiemetic 5-HT3 receptor antagonist dolasetron, the antitumor drugs daunorubicin and oracin, and the carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) to the corresponding alcohols have been determined by HPLC. Km values ranged between 0.06 mM for dolasetron and 1.1 mM for daunorubicin. Enzymatic efficiencies calculated as kcat/Km were more than 100 mM-1 min-1 for dolasetron and 1.3, 0.43, and 0.47 mM-1 min-1 for daunorubicin, oracin, and NNK, respectively. Thus, AKR1B10 is one of the most significant reductases in the activation of dolasetron. In addition to its reducing activity, AKR1B10 catalyzed the NADP+-dependent oxidation of the secondary alcohol (S)-1-indanol to 1-indanone with high enzymatic efficiency (kcat/Km=112 mM-1 min-1). The gene encoding AKR1B10 was cloned from a human liver cDNA library and the recombinant enzyme was purified. Kinetic studies revealed lower activity of the recombinant compared with the native form. Immunoblot studies indicated large interindividual variations in the expression of AKR1B10 in human liver. Since carbonyl reduction of xenobiotics often leads to their inactivation, AKR1B10 may play a role in the occurrence of chemoresistance of tumors toward carbonyl group-bearing cytostatic drugs.

The time point of β-catenin knockout in hepatocytes determines their response to xenobiotic activation of the constitutive androstane receptor

International Nuclear Information System (INIS)

Ganzenberg, Katrin; Singh, Yasmin; Braeuning, Albert

2013-01-01

The constitutive androstane receptor (CAR) controls the expression of drug-metabolizing enzymes and regulates hepatocyte proliferation. Studies with transgenic mice with an early postnatal conditional hepatocyte-specific knockout of the β-catenin gene Ctnnb1 revealed that β-catenin deficiency decreases the magnitude of induction of drug-metabolizing enzymes by CAR activators, abrogates zonal differences in the hepatocytes’ susceptibility to these compounds, and impacts on hepatocyte proliferation. These data, however, do not allow distinguishing between effects caused by β-catenin deficiency during postnatal liver development and acute effects of β-catenin deficiency in the adult animal at the time point of CAR activation. Therefore, CAR activation was now studied in a different mouse model allowing for the hepatocyte-specific knockout of β-catenin in adult mice. Treatment of these mice with 3 mg/kg body weight of the model CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) confirmed previous findings related to the coordinate regulation of drug metabolism by β-catenin and CAR. More importantly, the present study clarified that the impact of β-catenin signaling on CAR-mediated enzyme induction in the liver is not merely due to developmental defects caused by a postnatal lack of β-catenin, but depends on the presence of β-catenin at the time point of xenobiotic treatment. The study also revealed interesting differences between the two mouse models: hepatic zonation of TCPOBOP-dependent induction of drug-metabolizing enzymes was restored in mice with late knockout of β-catenin, and the strong proliferative response of female mice was exclusively abolished when using animals with a late β-catenin knockout. This suggests a β-catenin-dependent postnatal priming of hepatocytes during postnatal liver development, later affecting the proliferative response of adult animals to CAR-activating xenobiotics

Effect of thiabendazole on some rat hepatic xenobiotic metabolising enzymes

NARCIS (Netherlands)

Price, R.J.; Scott, M.P.; Walters, D.G.; Stierum, R.H.; Groten, J.P.; Meredith, C.; Lake, B.G.

2004-01-01

The effect of thiabendazole (TB) on some rat hepatic xenobiotic metabolising enzymes has been investigated. Male Sprague-Dawley rats were fed control diet or diets containing 102-5188 ppm TB for 28 days. As a positive control for induction of hepatic xenobiotic metabolism, rats were also fed diets

The role of IL6 in liver cancer linked to metabolic liver disease ...

International Development Research Centre (IDRC) Digital Library (Canada)

The role of IL6 in liver cancer linked to metabolic liver disease. Liver cancer is highly fatal, it has very few treatment options, and it is one of the few cancers whose incidence is rising worldwide. One poorly understood risk factor for liver cancer is obesity/metabolic disease (such as diabetes and fatty liver disease).

Drug and xenobiotic biotransformation in the blood-brain barrier: A neglected issue.

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José A.G. Agúndez

2014-10-01

Full Text Available Drug biotransformation is a crucial mechanism for facilitating the elimination of chemicals from the organism and for decreasing their pharmacological activity. Published evidence suggests that brain drug metabolism may play a role in the development of adverse drug reactions and in the clinical response to drugs and xenobiotics. The blood-brain barrier (BBB has been regarded mainly as a physical barrier for drugs and xenobiotics, and little attention has been paid to BBB as a drug-metabolizing barrier. The presence of drug metabolizing enzymes in the BBB is likely to have functional implications because local metabolism may inactivate drugs or may modify the drug's ability to cross the BBB, thus modifying the drug response and the risk of developing adverse drug reactions. In this perspective paper, we discuss the expression of relevant xenobiotic metabolizing enzymes in the brain and in the BBB, and we cover current advances and future directions on the potential role of these BBB drug-metabolizing enzymes as modifiers of drug response.

Influence of frequently used industrial solvents and monomers of plastics on xenobiotic metabolism

Energy Technology Data Exchange (ETDEWEB)

Gut, I. (Institut Hygieny a Epidemiologie, Prague (Czechoslovakia))

1983-11-01

In male Wistar rats, inhalation of benzene, toluene, or styrene induced a dose-dependent increase of the in vitro hepatic microsomal metabolism of benzene, but toluene metabolism and microsomal cytochrome P-450 level were little affected. In phenobarbital pretreated rats the solvents induced increased biotransformation of benzene metabolism toluene, but relatively less than in controls, and benzene and toluene inhalation actually caused an apparent destruction of cytochrome P-450. In vivo rates of metabolism of toluene and styrene were in good agreement with the in vitro hepatic microsomal biotransformation of benzene or toluene, but benzene metabolism not due to inhibition of benzene metabolism in vivo caused by benzene metabolites. In simultaneously administered two solvents, toluene, styrene or xylene markedly inhibited metabolism of benzene-/sup 14/C, but toluene-/sup 14/C metabolsim was little affected by coadministered benzene, styrene or xylene. Various industrial solvents inhibited metabolism of acrylonitrile along the oxidative pathway leading to thiocyanate, but actually increased the rate of the conjugative pathway beginning with cyanoethylation of glutathion and the final products. Various derivatives of benzene had low inhibiting effect on antipyrine metabolism and clinical significance of such effect is of little significance. Inhibition of benzene metabolism by toluene followed in significantly decreased myelotoxicity of benzene, but the modification of acrylonitrile metabolism and pharmacokinetics by organic solvents given at low doses markedly increased lethal effects of acrylonitrile. The prediction of in vivo rates of metabolism based on the in vitro rates of hepatic microsomal metabolism is therefore possible, provided the inhibiting potency of the xenobiotic and/or its metabolites, self-induction of their metabolism, as well as differences in their pharmacokinetics are considered.

In vitro metabolism of [14C]-toluene by human and rat liver microsomes and liver slices

International Nuclear Information System (INIS)

Chapman, D.E.; Moore, T.J.; Michener, S.R.; Powis, G.

1990-01-01

Toluene metabolites produced by liver microsomes from six human donors included benzylalcohol (Balc), benzaldehyde (Bald) and benzoic acid (Bacid). Microsomes from only one human donor metabolized toluene to p-cresol and o-cresol. Human liver microsomes also metabolized Balc to Bald. Balc metabolism required NADPH, was inhibited by carbon monoxide, and was decreased at a buffer pH of 10. Balc metabolism was not inhibited by ADP-ribose or sodium azide. These results suggest that cytochrome P450 is responsible for the in vitro metabolism of Balc by human liver microsomes. Toluene metabolites formed by human liver slices and released into the incubation media included hippuric acid, and Bacid. Cresols or cresol-conjugates were not detected in liver slice incubation media from any human donor. Toluene metabolism by human liver was compared to metabolism by comparable liver preparations from male Fischer F344 rats. Rates of toluene metabolism by human liver microsomes and liver slices were 9-fold and 1.3-fold greater than for rat liver, respectively. Covalent binding of toluene to human liver microsomes and liver slices was 21-fold and 4-fold greater than for comparable rat liver preparations. Covalent binding of toluene to human microsomes required NADPH, was significantly decreased by coincubation with 4 mM cysteine or 4 mM glutathione, and radioactivity associated with microsomes was decreased by subsequent digestion of microsomes with protease. These results suggest that toluene metabolism and covalent binding of toluene are underestimated if the male Fischer 344 rat is used as a model for human toluene metabolism

Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics

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Francesco Gatto

2016-07-01

Full Text Available Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network.

Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice

International Nuclear Information System (INIS)

Fu, Zidong Donna; Klaassen, Curtis D.

2014-01-01

Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. - Highlights: • Utilized a graded CR model in male mice • The mRNA profiles of xenobiotic processing genes (XPGs) in liver were investigated. • CR up-regulates many phase-II enzymes. • CR tends to feminize the mRNA profiles of XPGs

Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice

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Fu, Zidong Donna [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

2014-01-01

Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. - Highlights: • Utilized a graded CR model in male mice • The mRNA profiles of xenobiotic processing genes (XPGs) in liver were investigated. • CR up-regulates many phase-II enzymes. • CR tends to feminize the mRNA profiles of XPGs.

Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism.

Science.gov (United States)

Ayyar, Vivaswath S; Almon, Richard R; DuBois, Debra C; Sukumaran, Siddharth; Qu, Jun; Jusko, William J

2017-05-08

Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66h in rat liver following a single dose of methylprednisolone (MPL). Data mining identified 451 differentially regulated proteins. These proteins were analyzed on the basis of temporal regulation, cellular localization, and literature-mined functional information. Of the 451 proteins, 378 were clustered into six functional groups based on major clinically-relevant effects of CS in liver. MPL-responsive proteins were highly localized in the mitochondria (20%) and cytosol (24%). Interestingly, several proteins were related to hepatic stress and signaling processes, which appear to be involved in secondary signaling cascades and in protecting the liver from CS-induced oxidative damage. Consistent with known adverse metabolic effects of CS, several rate-controlling enzymes involved in amino acid metabolism, gluconeogenesis, and fatty-acid metabolism were altered by MPL. In addition, proteins involved in the metabolism of endogenous compounds, xenobiotics, and therapeutic drugs including cytochrome P450 and Phase-II enzymes were differentially regulated. Proteins related to the inflammatory acute-phase response were up-regulated in response to MPL. Functionally-similar proteins showed large diversity in their temporal profiles, indicating complex mechanisms of regulation by CS. Clinical use of corticosteroid (CS) therapy is frequent and chronic. However, current knowledge on the proteome-level effects of CS in liver and

Xenobiotics and the Human Gut Microbiome: Metatranscriptomics Reveal the Active Players

OpenAIRE

Ursell, Luke K.; Knight, Rob

2013-01-01

The human gut microbiome plays an important role in the metabolism of xenobiotics. In a recent issue of Cell, Maurice et al. identify the active members of the gut microbiome and show how gene expression profiles change within the gut microbial community in response to antibiotics and host-targeted xenobiotics.

In vitro approach to studying cutaneous metabolism and disposition of topically applied xenobiotics

International Nuclear Information System (INIS)

Kao, J.; Hall, J.; Shugart, L.R.; Holland, J.M.

1984-01-01

The extent to which cutaneous metabolism may be involved in the penetration and fate of topically applied xenobiotics was examined by metabolically viable and structurally intact mouse skin in organ culture. Evidence that skin penetration of certain chemicals is coupled to cutaneous metabolism was based upon observations utilizing [ 14 C]benzo[a]pyrene (BP). As judged by the recovery of radioactivity in the culture medium 24 hr after in vitro topical application of [ 14 C]BP to the skin from both control and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced C3H mice, skin penetration of BP was higher in the induced tissue. All classes of metabolites of BP were found in the culture medium; water-soluble metabolites predominated and negligible amounts of unmetabolized BP were found. As shown by enzymatic hydrolysis of the medium, TCDD induction resulted in shifting the cutaneous metabolism of BP toward the synthesis of more water-soluble conjugates. Differences in the degree of covalent binding of BP, via diol epoxide intermediates to epidermal DNA, from control and induced tissues were observed. These differences may reflect a change in the pathways of metabolism as a consequence of TCDD induction. These results indicated that topically applied BP is metabolized by the skin during its passage through the skin; and the degree of percutaneous penetration and disposition of BP was dependent upon the metabolic status of the tissue. This suggests that cutaneous metabolism may play an important role in the translocation and subsequent physiological disposition of topically applied BP. 33 references, 5 figures, 2 tables

Modulation of Xenobiotic Metabolizing Enzyme and Transporter Gene Expression in Primary Cultures of Human Hepatocytes by ToxCast Chemicals

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ToxCast chemicals were assessed for induction or suppression of xenobiotic metabolizing enzyme and transporter gene expression using primary human hepatocytes. The mRNA levels of 14 target and 2 control genes were measured: ABCB1, ABCB11, ABCG2, SLCO1B1, CYP1A1, CYP1A2, CYP2B6, C...

Bile Acid Signaling in Metabolic Disease and Drug Therapy

Science.gov (United States)

Li, Tiangang

2014-01-01

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid–activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein–coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. PMID:25073467

Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability.

Science.gov (United States)

Henderson, Colin J; McLaughlin, Lesley A; Osuna-Cabello, Maria; Taylor, Malcolm; Gilbert, Ian; McLaren, Aileen W; Wolf, C Roland

2015-02-01

The relative contribution of hepatic compared with intestinal oxidative metabolism is a crucial factor in drug oral bioavailability and therapeutic efficacy. Oxidative metabolism is mediated by the cytochrome P450 mono-oxygenase system to which cytochrome P450 reductase (POR) is the essential electron donor. In order to study the relative importance of these pathways in drug disposition, we have generated a novel mouse line where Cre recombinase is driven off the endogenous Cyp1a1 gene promoter; this line was then crossed on to a floxed POR mouse. A 40 mg/kg dose of the Cyp1a1 inducer 3-methylcholanthrene (3MC) eliminated POR expression in both liver and small intestine, whereas treatment at 4 mg/kg led to a more targeted deletion in the liver. Using this approach, we have studied the pharmacokinetics of three probe drugs--paroxetine, midazolam, nelfinavir--and show that intestinal metabolism is a determinant of oral bioavailability for the two latter compounds. The Endogenous Reductase Locus (ERL) mouse represents a significant advance on previous POR deletion models as it allows direct comparison of hepatic and intestinal effects on drug and xenobiotic clearance using lower doses of a single Cre inducing agent, and in addition minimizes any cytotoxic effects, which may compromise interpretation of the experimental data.

Energy Metabolism in the Liver

OpenAIRE

Rui, Liangyou

2014-01-01

The liver is an essential metabolic organ, and its metabolic activity is tightly controlled by insulin and other metabolic hormones. Glucose is metabolized into pyruvate through glycolysis in the cytoplasm, and pyruvate is completely oxidized to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, p...

Drug-induced liver toxicity and prevention by herbal antioxidants: an overview

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Divya eSingh

2016-01-01

Full Text Available The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for medication instigated liver danger. Endorsed medications (counting acetaminophen represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group (ALFSG of the patients admitted in 17 US healing facilities. Albeit different studies are accessible uncovering the mechanistic aspects of medication prompted hepatotoxicity, we are in the dilemma about the virtual story. The expanding prevalence and effectiveness of Ayurveda and herbal products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several plant products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less side reactions of the herbs provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed on the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication.

Approaching Resonant Absorption of Environmental Xenobiotics Harmonic Oscillation by Linear Structures

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Cornelia A. Bulucea

2012-03-01

Full Text Available Over the last several decades, it has become increasingly accepted that the term xenobiotic relates to environmental impact, since environmental xenobiotics are understood to be substances foreign to a biological system, which did not exist in nature before their synthesis by humans. In this context, xenobiotics are persistent pollutants such as dioxins and polychlorinated biphenyls, as well as plastics and pesticides. Dangerous and unstable situations can result from the presence of environmental xenobiotics since their harmful effects on humans and ecosystems are often unpredictable. For instance, the immune system is extremely vulnerable and sensitive to modulation by environmental xenobitics. Various experimental assays could be performed to ascertain the immunotoxic potential of environmental xenobiotics, taking into account genetic factors, the route of xenobiotic penetration, and the amount and duration of exposure, as well as the wave shape of the xenobiotic. In this paper, we propose an approach for the analysis of xenobiotic metabolism using mathematical models and corresponding methods. This study focuses on a pattern depicting mathematically modeled processes of resonant absorption of a xenobiotic harmonic oscillation by an organism modulated as an absorbing oscillator structure. We represent the xenobiotic concentration degree through a spatial concentration vector, and we model and simulate the oscillating regime of environmental xenobiotic absorption. It is anticipated that the results could be used to facilitate the assessment of the processes of environmental xenobiotic absorption, distribution, biotransformation and removal within the framework of compartmental analysis, by establishing appropriate mathematical models and simulations.

Transgenic plants for enhanced biodegradation and phytoremediation of organic xenobiotics.

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Abhilash, P C; Jamil, Sarah; Singh, Nandita

2009-01-01

Phytoremediation--the use of plants to clean up polluted soil and water resources--has received much attention in the last few years. Although plants have the inherent ability to detoxify xenobiotics, they generally lack the catabolic pathway for the complete degradation of these compounds compared to microorganisms. There are also concerns over the potential for the introduction of contaminants into the food chain. The question of how to dispose of plants that accumulate xenobiotics is also a serious concern. Hence the feasibility of phytoremediation as an approach to remediate environmental contamination is still somewhat in question. For these reasons, researchers have endeavored to engineer plants with genes that can bestow superior degradation abilities. A direct method for enhancing the efficacy of phytoremediation is to overexpress in plants the genes involved in metabolism, uptake, or transport of specific pollutants. Furthermore, the expression of suitable genes in root system enhances the rhizodegradation of highly recalcitrant compounds like PAHs, PCBs etc. Hence, the idea to amplify plant biodegradation of xenobiotics by genetic manipulation was developed, following a strategy similar to that used to develop transgenic crops. Genes from human, microbes, plants, and animals are being used successfully for this venture. The introduction of these genes can be readily achieved for many plant species using Agrobacterium tumefaciens-mediated plant transformation or direct DNA methods of gene transfer. One of the promising developments in transgenic technology is the insertion of multiple genes (for phase 1 metabolism (cytochrome P450s) and phase 2 metabolism (GSH, GT etc.) for the complete degradation of the xenobiotics within the plant system. In addition to the use of transgenic plants overexpressed with P450 and GST genes, various transgenic plants expressing bacterial genes can be used for the enhanced degradation and remediation of herbicides, explosives

Gender Differences in Adipocyte Metabolism and Liver Cancer Progression

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Otto Ka-Wing Cheung

2016-09-01

Full Text Available Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management.

Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination

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Benachour, Nora; Moslemi, Safa; Sipahutar, Herbert; Seralini, Gilles-Eric

2007-01-01

Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 μM (except for TBTO and DES, 10 μM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 μM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment

CHANGING METABOLIC FUNCTIONS IN EXPERIMENTAL ANIMALS AFTER INTRODUCTION OF THE XENOBIOTIC, IMMUNOTROPIC DRUG AND PROBIOTIC

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Zvyagintseva O.V.

2015-05-01

Saccharomyces cerevisiae. The peripheral blood leukocytes were cultured according to the method of Hereford in medium 199 with the addition of fetal calf serum in the absence and in the presence of T-cell mitogen – phytohemagglutinin. Results and discussion. In all studied groups (introduction of the xenobiotic, "Fungidol", probiotic experimental animals revealed a significant increase in the concentrations of ceruloplasmin and haptoglobin on the average in 1,5 times in comparison with the control, indicating the development of the inflammatory process after the toxic action of copper sulphate. During administration of sulphate of copper, the experimental animals showed a reduction in the index of completion of phagocytosis, indicating a failure of the process of endocytosis of bacterial antigens and reduced stimulation index due to the low activity of NADPoxidase system of phagocytes. The introduction of xenobiotic animals was increased 1,2 times compared with the control (23,33±1,38 % the number of transformed cells in the background of mitogenic inducer of cell proliferation. The proliferative activity of hemolytic after the joint action of the xenobiotic and immunotropic drug in cell culture with the mitogen was the highest and exceeded 1,5 times control (23,33±1,38%. After the introduction of copper sulfate and probiotic proliferative activity of hemolytic was also significantly higher spontaneous. Introduction biologic response modifier substance to a greater extent than probiotics stimulate a protective immune processes aimed at combating the negative effect of the xenobiotic. Conclusion. Thus, the introduction of copper sulfate launches in animals a cascade of reactions aimed at the disruption of homeostasis. It is a violation of various physiological processes of digestion, respiration, cell differentiation, water-salt metabolism, metabolism of carbohydrates, proteins, lipids, detoxification of exogenous substrates and metabolites, production of biologically active

Studies of liver-specific metabolic reactions with 15N. 1

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Hirschberg, K.; Jung, K.; Faust, H.; Matkowitz, R.

1987-01-01

The 15 N tracer technique was used to investigate liver-specific reactions (urea and hippurate synthesis) for studying the metabolism in the healthy and damaged pig liver. After [ 15 N]ammonium chloride administration the tracer distribution on non-protein compounds of serum and urine was followed. Blood samplings before and after liver passage rendered possible a direct analysis of the [ 15 N]ammonium metabolism. The thioacetamide-induced liver damage was used as model for an acute liver intoxication. The capacity for urea synthesis was not influenced by means of this noxious substance, but the metabolism of amino acids and hippuric acid. The considerably depressed excretion of [ 15 N]hippurate seems to be a suitable indicator of liver disfunction. (author)

Comparison of xenobiotic-metabolising human, porcine, rodent, and piscine cytochrome P450

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Burkina, Viktoriia; Rasmussen, Martin Krøyer; Pilipenko, Nadezhda; Zamaratskaia, Galia

2017-01-01

Highlights: • The percent identity of porcine, murine and piscine CYPs was compared with human CYPs. • Main similarities and differences were reviewed. • Understanding of molecular mechanisms of CYP system will provide further insights into the CYP regulatory processes, and responses to different factors. - Abstract: Cytochrome P450 proteins (CYP450s) are present in most domains of life and play a critical role in the metabolism of endogenous compounds and xenobiotics. The effects of exposure to xenobiotics depend heavily on the expression and activity of drug-metabolizing CYP450s, which is determined by species, genetic background, age, gender, diet, and exposure to environmental pollutants. Numerous reports have investigated the role of different vertebrate CYP450s in xenobiotic metabolism. Model organisms provide powerful experimental tools to investigate Phase I metabolism. The aim of the present review is to compare the existing data on human CYP450 proteins (1–3 families) with those found in pigs, mice, and fish. We will highlight differences and similarities and identify research gaps which need to be addressed in order to use these species as models that mimic human traits. Moreover, we will discuss the roles of nuclear receptors in the cellular regulation of CYP450 expression in select organisms.

Hepatic xenobiotic metabolizing enzyme and transporter gene expression through the life stages of the mouse.

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Janice S Lee

Full Text Available BACKGROUND: Differences in responses to environmental chemicals and drugs between life stages are likely due in part to differences in the expression of xenobiotic metabolizing enzymes and transporters (XMETs. No comprehensive analysis of the mRNA expression of XMETs has been carried out through life stages in any species. RESULTS: Using full-genome arrays, the mRNA expression of all XMETs and their regulatory proteins was examined during fetal (gestation day (GD 19, neonatal (postnatal day (PND 7, prepubescent (PND32, middle age (12 months, and old age (18 and 24 months in the C57BL/6J (C57 mouse liver and compared to adults. Fetal and neonatal life stages exhibited dramatic differences in XMET mRNA expression compared to the relatively minor effects of old age. The total number of XMET probe sets that differed from adults was 636, 500, 84, 5, 43, and 102 for GD19, PND7, PND32, 12 months, 18 months and 24 months, respectively. At all life stages except PND32, under-expressed genes outnumbered over-expressed genes. The altered XMETs included those in all of the major metabolic and transport phases including introduction of reactive or polar groups (Phase I, conjugation (Phase II and excretion (Phase III. In the fetus and neonate, parallel increases in expression were noted in the dioxin receptor, Nrf2 components and their regulated genes while nuclear receptors and regulated genes were generally down-regulated. Suppression of male-specific XMETs was observed at early (GD19, PND7 and to a lesser extent, later life stages (18 and 24 months. A number of female-specific XMETs exhibited a spike in expression centered at PND7. CONCLUSIONS: The analysis revealed dramatic differences in the expression of the XMETs, especially in the fetus and neonate that are partially dependent on gender-dependent factors. XMET expression can be used to predict life stage-specific responses to environmental chemicals and drugs.

Fatty Liver Index and Lipid Accumulation Product Can Predict Metabolic Syndrome in Subjects without Fatty Liver Disease

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Yuan-Lung Cheng

2017-01-01

Full Text Available Background. Fatty liver index (FLI and lipid accumulation product (LAP are indexes originally designed to assess the risk of fatty liver and cardiovascular disease, respectively. Both indexes have been proven to be reliable markers of subsequent metabolic syndrome; however, their ability to predict metabolic syndrome in subjects without fatty liver disease has not been clarified. Methods. We enrolled consecutive subjects who received health check-up services at Taipei Veterans General Hospital from 2002 to 2009. Fatty liver disease was diagnosed by abdominal ultrasonography. The ability of the FLI and LAP to predict metabolic syndrome was assessed by analyzing the area under the receiver operating characteristic (AUROC curve. Results. Male sex was strongly associated with metabolic syndrome, and the LAP and FLI were better than other variables to predict metabolic syndrome among the 29,797 subjects. Both indexes were also better than other variables to detect metabolic syndrome in subjects without fatty liver disease (AUROC: 0.871 and 0.879, resp., and the predictive power was greater among women. Conclusion. Metabolic syndrome increases the cardiovascular disease risk. The FLI and LAP could be used to recognize the syndrome in both subjects with and without fatty liver disease who require lifestyle modifications and counseling.

Studies on defense mechanism against xenobiotics in rats, using gold as a model

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Sugawa-Katayama, Yohko; Kojima, Akiko; Nakano, Yukihiro.

1994-01-01

For self-protection, a living organism has a special mechanism to prevent xenobiotics from being absorbed through the gastrointestinal tract. This led to the present study on the defense mechanism of the gastrointestinal tract where foods are digested and absorbed. The results obtained from this study showed that 1) starvation caused an insufficiency of the defense mechanism against xenobiotics in jejunal absorptive cells and Kupffer cells, 2) after refeeding diets, a reparative process occurred at the damaged cell sites, resulting in recovery of the defense mechanism against xenobiotics, and 3) a 5% fat diet seemed to be the best fat level for recovery of the defense mechanism against xenobiotics. In the nutritional point of view, the 5% fat diet is equivalent to 0.11 in fat energy ratio (fat energy/total energy of the diet). These data suggest that a diet with a much lower fat energy (equivalent to 0.11) can give a good effect on recovery of the defense mechanism against xenobiotics in the gastrointestinal tract and the liver. (author)

Transcriptional ontogeny of the developing liver

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Lee Janice S

2012-01-01

Full Text Available Abstract Background During embryogenesis the liver is derived from endodermal cells lining the digestive tract. These endodermal progenitor cells contribute to forming the parenchyma of a number of organs including the liver and pancreas. Early in organogenesis the fetal liver is populated by hematopoietic stem cells, the source for a number of blood cells including nucleated erythrocytes. A comprehensive analysis of the transcriptional changes that occur during the early stages of development to adulthood in the liver was carried out. Results We characterized gene expression changes in the developing mouse liver at gestational days (GD 11.5, 12.5, 13.5, 14.5, 16.5, and 19 and in the neonate (postnatal day (PND 7 and 32 compared to that in the adult liver (PND67 using full-genome microarrays. The fetal liver, and to a lesser extent the neonatal liver, exhibited dramatic differences in gene expression compared to adults. Canonical pathway analysis of the fetal liver signature demonstrated increases in functions important in cell replication and DNA fidelity whereas most metabolic pathways of intermediary metabolism were under expressed. Comparison of the dataset to a number of previously published microarray datasets revealed 1 a striking similarity between the fetal liver and that of the pancreas in both mice and humans, 2 a nucleated erythrocyte signature in the fetus and 3 under expression of most xenobiotic metabolism genes throughout development, with the exception of a number of transporters associated with either hematopoietic cells or cell proliferation in hepatocytes. Conclusions Overall, these findings reveal the complexity of gene expression changes during liver development and maturation, and provide a foundation to predict responses to chemical and drug exposure as a function of early life-stages.

Functional Analysis of the Unique Cytochrome P450 of the Liver Fluke Opisthorchis felineus.

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Mariya Y Pakharukova

2015-12-01

Full Text Available The basic metabolic cytochrome P450 (CYP system is essential for biotransformation of sterols and xenobiotics including drugs, for synthesis and degradation of signaling molecules in all living organisms. Most eukaryotes including free-living flatworms have numerous paralogues of the CYP gene encoding heme monooxygenases with specific substrate range. Notably, by contrast, the parasitic flatworms have only one CYP gene. The role of this enzyme in the physiology and biochemistry of helminths is not known. The flukes and tapeworms are the etiologic agents of major neglected tropical diseases of humanity. Three helminth infections (Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium are considered by the International Agency for Research on Cancer (IARC as definite causes of cancer. We focused our research on the human liver fluke Opisthorchis felineus, an emerging source of biliary tract disease including bile duct cancer in Russia and central Europe. The aims of this study were (i to determine the significance of the CYP activity for the morphology and survival of the liver fluke, (ii to assess CYP ability to metabolize xenobiotics, and (iii to localize the CYP activity in O. felineus tissues. We observed high constitutive expression of CYP mRNA (Real-time PCR in O. felineus. This enzyme metabolized xenobiotics selective for mammalian CYP2E1, CYP2B, CYP3A, but not CYP1A, as determined by liquid chromatography and imaging analyses. Tissue localization studies revealed the CYP activity in excretory channels, while suppression of CYP mRNA by RNA interference was accompanied by morphological changes of the excretory system and increased mortality rates of the worms. These results suggest that the CYP function is linked to worm metabolism and detoxification. The findings also suggest that the CYP enzyme is involved in vitally important processes in the organism of parasites and is a potential drug target.

Recellularization of rat liver: An in vitro model for assessing human drug metabolism and liver biology.

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Matthew J Robertson

Full Text Available Liver-like organoids that recapitulate the complex functions of the whole liver by combining cells, scaffolds, and mechanical or chemical cues are becoming important models for studying liver biology and drug metabolism. The advantages of growing cells in three-dimensional constructs include enhanced cell-cell and cell-extracellular matrix interactions and preserved cellular phenotype including, prevention of de-differentiation. In the current study, biomimetic liver constructs were made via perfusion decellularization of rat liver, with the goal of maintaining the native composition and structure of the extracellular matrix. We optimized our decellularization process to produce liver scaffolds in which immunogenic residual DNA was removed but glycosaminoglycans were maintained. When the constructs were recellularized with rat or human liver cells, the cells remained viable, capable of proliferation, and functional for 28 days. Specifically, the cells continued to express cytochrome P450 genes and maintained their ability to metabolize a model drug, midazolam. Microarray analysis showed an upregulation of genes involved in liver regeneration and fibrosis. In conclusion, these liver constructs have the potential to be used as test beds for studying liver biology and drug metabolism.

Effects of excess dietary tyrosine or certain xenobiotics on the cholesterogenesis in rats

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Nagaoka, S.; Masaki, H.; Aoyama, Y.; Yoshida, A.

1986-01-01

Comparison of the effects of excess dietary tyrosine, DDT, chlorobutanol (Chloretone) or butylated hydroxyanisole (BHA) on serum cholesterol, hepatic activities of the rate-limiting enzyme of cholesterol synthesis,3-hydroxy-3-methylglutaryl coenzyme A reductase and in vivo rates of the hepatic cholesterol synthesis measured by 3 H 2 O incorporation were investigated in rats. Serum cholesterol concentration was significantly higher in rats fed the DDT, chlorobutanol, BHA or excess tyrosine diets than in rats fed the control diet for 7 days. Serum cholesterol concentration remained higher compared to control rats when excess tyrosine was fed for 21 d. When rats were fed a basal diet after feeding a tyrosine excess diet for 2 wk, liver weight and serum cholesterol level returned to normal within 7 d. The incorporation of 3 H 2 O into liver cholesterol and the activity of liver 3-hydroxy-3-methylglutaryl coenzyme A reductase were greater in rats fed excess tyrosine or certain xenobiotics than in control rats. Present results suggested that the increase in serum cholesterol concentration due to excess dietary tyrosine or certain xenobiotics is mainly attributable to the stimulation of liver cholesterol synthesis

Time course of gene expression profiling in the liver of experimental mice infected with Echinococcus multilocularis.

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Renyong Lin

Full Text Available BACKGROUND: Alveolar echinococcosis (AE is a severe chronic parasitic disease which behaves like a slow-growing liver cancer. Clinical observations suggest that the parasite, Echinococcus multilocularis (E. multilocularis influences liver homeostasis and hepatic cell metabolism. However, this has never been analyzed during the time course of infection in the common model of secondary echinococcosis in experimental mice. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression profiles were assessed using DNA microarray analysis, 1, 2, 3 and 6 months after injection of E. multilocularis metacestode in the liver of susceptible mice. Data were collected at different time points to monitor the dynamic behavior of gene expression. 557 differentially expressed genes were identified at one or more time points, including 351 up-regulated and 228 down-regulated genes. Time-course analysis indicated, at the initial stage of E. multilocularis infection (month 1-2, that most of up-regulated pathways were related to immune processes and cell trafficking such as chemokine-, mitogen-activated protein kinase (MAPK signaling, and down-regulated pathways were related to xenobiotic metabolism; at the middle stage (month 3, MAPK signaling pathway was maintained and peroxisome proliferator-activated receptor (PPAR signaling pathway emerged; at the late stage (month 6, most of up-regulated pathways were related to PPAR signaling pathway, complement and coagulation cascades, while down-regulated pathways were related to metabolism of xenobiotics by cytochrome P450. Quantitative RT-PCR analysis of a random selection of 19 genes confirmed the reliability of the microarray data. Immunohistochemistry analysis showed that proliferating cell nuclear antigen (PCNA was increased in the liver of E. multilocularis infected mice from 2 months to 6 months. CONCLUSIONS: E. multilocularis metacestode definitely exerts a deep influence on liver homeostasis, by modifying a number of gene

Omics for Understanding the Gut-Liver-Microbiome Axis and Precision Medicine.

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Khalsa, Jag; Duffy, Linda C; Riscuta, Gabriela; Starke-Reed, Pamela; Hubbard, Van S

2017-03-01

Human metabolic disease opens a new view to understanding the contribution of the intestinal microbiome to drug metabolism and drug-induced toxicity in gut-liver function. The gut microbiome, a key determinant of intestinal inflammation, also plays a direct role in chronic inflammation and liver disease. Gut bacterial communities directly metabolize certain drugs, reducing their bioavailability and influencing individual variation in drug response. In addition, some microbiome-produced compounds may affect drug pharmacokinetics and pharmacodynamics via altered expression of metabolizing enzymes and drug transporters or genes coding for drug target proteins, drug response phenotypes, and disease states. Molecular-based high-throughput technologies are providing novel insight about host-gut microbiome interactions, homeostasis, and xenobiotic effects associated with wide variation in efficacy or toxicity in humans. It is envisioned that future approaches to treating and preventing liver disease will benefit from in-depth studies of the liver-microbiome axis. Thus, the microbiome shares a fundamental role in human physiology with various organ systems, and its importance must be considered in the rapid evolution of precision medicine. A new emerging perspective of understanding the effect of the gut microbiome on human response to drugs would be indispensable for developing efficacious, safe, and cost-effective precision therapies. © 2017, The American College of Clinical Pharmacology.

Effects of brussels sprouts, indole 3-carbinol and phenobarbital on xenobiotic metabolism and in vivo DNA binding of aflatoxin B1 in the rat

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Salbe, A.D.; Bjeldanes, L.F.

1986-01-01

Cruciferous vegetables have been shown to be potent inducers of xenobiotic-metabolizing enzymes in the rat and this may offer protection against chemical carcinogenesis. Adult, male, SD rats were fed on purified diets supplemented with 25% freeze-dried Brussels sprouts or 250 ppm idole 3-carbinol (I3C) for 2 weeks, or given phenobarbital (PB, 1 mg/ml) in the drinking water for 7 days prior to killing. Brussels sprouts caused a 50% decrease (p 3 H] aflatoxin B 1 (AFB 1 ) to liver DNA, and increased intestinal and hepatic glutathione S-transferase (GST) activity. Hepatic monooxygenase activity was not altered in this group but greater than 2-fold increases in intestinal aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin O-deethylase (ECD) activities were found. I3C did not decrease AFB 1 binding, nor did it increase hepatic or intestinal GST activity. I3C did increase both intestinal AHH and ECD activities. PB treatment significantly decreased AFB 1 binding by 60%, and significantly elevated hepatic but not intestinal GST activity. Hepatic AHH and ECD activities were also elevated in this group, while intestinal AHH and ECD activities were decreased. These results emphasize the importance of GST activity in the detoxification of AFB 1 and suggest a less important role for intestinal monooxygenase activity in the metabolism of this hepatocarcinogen

Transposable elements are enriched within or in close proximity to xenobiotic-metabolizing cytochrome P450 genes

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Li Xianchun

2007-03-01

Full Text Available Abstract Background Transposons, i.e. transposable elements (TEs, are the major internal spontaneous mutation agents for the variability of eukaryotic genomes. To address the general issue of whether transposons mediate genomic changes in environment-adaptation genes, we scanned two alleles per each of the six xenobiotic-metabolizing Helicoverpa zea cytochrome P450 loci, including CYP6B8, CYP6B27, CYP321A1, CYP321A2, CYP9A12v3 and CYP9A14, for the presence of transposon insertions by genome walking and sequence analysis. We also scanned thirteen Drosophila melanogaster P450s genes for TE insertions by in silico mapping and literature search. Results Twelve novel transposons, including LINEs (long interspersed nuclear elements, SINEs (short interspersed nuclear elements, MITEs (miniature inverted-repeat transposable elements, one full-length transib-like transposon, and one full-length Tcl-like DNA transpson, are identified from the alleles of the six H. zea P450 genes. The twelve transposons are inserted into the 5'flanking region, 3'flanking region, exon, or intron of the six environment-adaptation P450 genes. In D. melanogaster, seven out of the eight Drosophila P450s (CYP4E2, CYP6A2, CYP6A8, CYP6A9, CYP6G1, CYP6W1, CYP12A4, CYP12D1 implicated in insecticide resistance are associated with a variety of transposons. By contrast, all the five Drosophila P450s (CYP302A1, CYP306A1, CYP307A1, CYP314A1 and CYP315A1 involved in ecdysone biosynthesis and developmental regulation are free of TE insertions. Conclusion These results indicate that TEs are selectively retained within or in close proximity to xenobiotic-metabolizing P450 genes.

Associations between Zinc Deficiency and Metabolic Abnormalities in Patients with Chronic Liver Disease

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Takashi Himoto

2018-01-01

Full Text Available Zinc (Zn is an essential trace element which has favorable antioxidant, anti-inflammatory, and apoptotic effects. The liver mainly plays a crucial role in maintaining systemic Zn homeostasis. Therefore, the occurrence of chronic liver diseases, such as chronic hepatitis, liver cirrhosis, or fatty liver, results in the impairment of Zn metabolism, and subsequently Zn deficiency. Zn deficiency causes plenty of metabolic abnormalities, including insulin resistance, hepatic steatosis and hepatic encephalopathy. Inversely, metabolic abnormalities like hypoalbuminemia in patients with liver cirrhosis often result in Zn deficiency. Recent studies have revealed the putative mechanisms by which Zn deficiency evokes a variety of metabolic abnormalities in chronic liver disease. Zn supplementation has shown beneficial effects on such metabolic abnormalities in experimental models and actual patients with chronic liver disease. This review summarizes the pathogenesis of metabolic abnormalities deriving from Zn deficiency and the favorable effects of Zn administration in patients with chronic liver disease. In addition, we also highlight the interactions between Zn and other trace elements, vitamins, amino acids, or hormones in such patients.

Lactate metabolism in chronic liver disease

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Jeppesen, Johanne B; Mortensen, Christian; Bendtsen, Flemming

2013-01-01

Background. In the healthy liver there is a splanchnic net-uptake of lactate caused by gluconeogenesis. It has previously been shown that patients with acute liver failure in contrast have a splanchnic release of lactate caused by a combination of accelerated glycolysis in the splanchnic region...... and a reduction in hepatic gluconeogenesis. Aims. The aims of the present study were to investigate lactate metabolism and kinetics in patients with chronic liver disease compared with a control group with normal liver function. Methods. A total of 142 patients with chronic liver disease and 14 healthy controls...... underwent a liver vein catheterization. Blood samples from the femoral artery and the hepatic and renal veins were simultaneously collected before and after stimulation with galactose. Results. The fasting lactate levels, both in the hepatic vein and in the femoral artery, were higher in the patients than...

Genomics and the prediction of xenobiotic toxicity

International Nuclear Information System (INIS)

Meyer, Urs-A.; Gut, Josef

2002-01-01

The systematic identification and functional analysis of human genes is revolutionizing the study of disease processes and the development and rational use of drugs. It increasingly enables medicine to make reliable assessments of the individual risk to acquire a particular disease, raises the number and specificity of drug targets and explains interindividual variation of the effectiveness and toxicity of drugs. Mutant alleles at a single gene locus for more than 20 drug metabolizing enzymes are some of the best studied individual risk factors for adverse drug reactions and xenobiotic toxicity. Increasingly, genetic polymorphisms of transporter and receptor systems are also recognized as causing interindividual variation in drug response and drug toxicity. However, pharmacogenetic and toxicogenetic factors rarely act alone; they produce a phenotype in concert with other variant genes and with environmental factors. Environmental factors may affect gene expression in many ways. For instance, numerous drugs induce their own and the metabolism of other xenobiotics by interacting with nuclear receptors such as AhR, PPAR, PXR and CAR. Genomics is providing the information and technology to analyze these complex situations to obtain individual genotypic and gene expression information to assess the risk of toxicity

High hydrostatic pressure influences the in vitro response to xenobiotics in Dicentrarchus labrax liver.

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Lemaire, Benjamin; Mignolet, Eric; Debier, Cathy; Calderon, Pedro Buc; Thomé, Jean Pierre; Rees, Jean François

2016-04-01

Hydrostatic pressure (HP) increases by about 1 atmosphere (0.1MPa) for each ten-meter depth increase in the water column. This thermodynamical parameter could well influence the response to and effects of xenobiotics in the deep-sea biota, but this possibility remains largely overlooked. To grasp the extent of HP adaptation in deep-sea fish, comparative studies with living cells of surface species exposed to chemicals at high HP are required. We initially conducted experiments with precision-cut liver slices of a deep-sea fish (Coryphaenoides rupestris), co-exposed for 15h to the aryl hydrocarbon receptor (AhR) agonist 3-methylcholanthrene at HP levels representative of the surface (0.1MPa) and deep-sea (5-15MPa; i.e., 500-1500m depth) environments. The transcript levels of a suite of stress-responsive genes, such as the AhR battery CYP1A, were subsequently measured (Lemaire et al., 2012; Environ. Sci. Technol. 46, 10310-10316). Strikingly, the AhR agonist-mediated increase of CYP1A mRNA content was pressure-dependently reduced in C. rupestris. Here, the same co-exposure scenario was applied for 6 or 15h to liver slices of a surface fish, Dicentrarchus labrax, a coastal species presumably not adapted to high HP. Precision-cut liver slices of D. labrax were also used in 1h co-exposure studies with the pro-oxidant tert-butylhydroperoxide (tBHP) as to investigate the pressure-dependence of the oxidative stress response (i.e., reactive oxygen production, glutathione and lipid peroxidation status). Liver cells remained viable in all experiments (adenosine triphosphate content). High HP precluded the AhR agonist-mediated increase of CYP1A mRNA expression in D. labrax, as well as that of glutathione peroxidase, and significantly reduced that of heat shock protein 70. High HP (1h) also tended per se to increase the level of oxidative stress in liver cells of the surface fish. Trends to an increased resistance to tBHP were also noted. Whether the latter observation truly

Bile acid metabolism and signaling in cholestasis, inflammation and cancer

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Apte, Udayan

2015-01-01

Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid soluble vitamins. Bile acid synthesis, transport and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration and carcinogenesis. PMID:26233910

Concentrations, patterns and metabolites of organochlorine pesticides in relation to xenobiotic phase I and II enzyme activities in ringed seals (Phoca hispida) from Svalbard and the Baltic Sea

International Nuclear Information System (INIS)

Routti, Heli; Bavel, Bert van; Letcher, Robert J.; Arukwe, Augustine; Chu Shaogang; Gabrielsen, Geir W.

2009-01-01

The present study investigates the concentrations and patterns of organochlorine pesticides (OCPs) and their metabolites in liver and plasma of two ringed seal populations (Phoca hispida): lower contaminated Svalbard population and more contaminated Baltic Sea population. Among OCPs, p,p'-DDE and sum-chlordanes were the highest in concentration. With increasing hepatic contaminant concentrations and activities of xenobiotic-metabolizing enzymes, the concentrations of 3-methylsulfonyl-p,p'-DDE and the concentration ratios of pentachlorophenol/hexachlorobenzene increased, and the toxaphene pattern shifted more towards persistent Parlar-26 and -50 and less towards more biodegradable Parlar-44. Relative concentrations of the chlordane metabolites, oxychlordane and -heptachlorepoxide, to sum-chlordanes were higher in the seals from Svalbard compared to the seals from the Baltic, while the trend was opposite for cis- and trans-nonachlor. The observed differences in the OCP patterns in the seals from the two populations are probably related to the catalytic activity of xenobiotic-metabolizing enzymes, and also to differences in dietary exposure. - Contrasting patterns of organochlorine pesticides in two ringed seal populations.

Concentrations, patterns and metabolites of organochlorine pesticides in relation to xenobiotic phase I and II enzyme activities in ringed seals (Phoca hispida) from Svalbard and the Baltic Sea

Energy Technology Data Exchange (ETDEWEB)

Routti, Heli, E-mail: heli.routti@npolar.n [Norwegian Polar Institute, Polar Environmental Centre, 9296 Tromso (Norway); Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, 20014 Turku (Finland); Bavel, Bert van [MTM Research Centre, Orebro University, 70182 Orebro (Sweden); Letcher, Robert J. [Wildlife Toxicology and Disease Program, Wildlife and Landscape Science Directorate, Science and Technology Branch, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, Ontario K1A 0H3 (Canada); Arukwe, Augustine [Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim (Norway); Chu Shaogang [Wildlife Toxicology and Disease Program, Wildlife and Landscape Science Directorate, Science and Technology Branch, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, Ontario K1A 0H3 (Canada); Gabrielsen, Geir W. [Norwegian Polar Institute, Polar Environmental Centre, 9296 Tromso (Norway)

2009-08-15

The present study investigates the concentrations and patterns of organochlorine pesticides (OCPs) and their metabolites in liver and plasma of two ringed seal populations (Phoca hispida): lower contaminated Svalbard population and more contaminated Baltic Sea population. Among OCPs, p,p'-DDE and sum-chlordanes were the highest in concentration. With increasing hepatic contaminant concentrations and activities of xenobiotic-metabolizing enzymes, the concentrations of 3-methylsulfonyl-p,p'-DDE and the concentration ratios of pentachlorophenol/hexachlorobenzene increased, and the toxaphene pattern shifted more towards persistent Parlar-26 and -50 and less towards more biodegradable Parlar-44. Relative concentrations of the chlordane metabolites, oxychlordane and -heptachlorepoxide, to sum-chlordanes were higher in the seals from Svalbard compared to the seals from the Baltic, while the trend was opposite for cis- and trans-nonachlor. The observed differences in the OCP patterns in the seals from the two populations are probably related to the catalytic activity of xenobiotic-metabolizing enzymes, and also to differences in dietary exposure. - Contrasting patterns of organochlorine pesticides in two ringed seal populations.

Prioritizing Popular Proteins in Liver Cancer: Remodelling One-Carbon Metabolism.

Science.gov (United States)

Mora, María Isabel; Molina, Manuela; Odriozola, Leticia; Elortza, Félix; Mato, José María; Sitek, Barbara; Zhang, Pumin; He, Fuchu; Latasa, María Uxue; Ávila, Matías Antonio; Corrales, Fernando José

2017-12-01

Primary liver cancer (HCC) is recognized as the fifth most common neoplasm and the second leading cause of cancer death worldwide. Most risk factors are known, and the molecular pathogenesis has been widely studied in the past decade; however, the underlying molecular mechanisms remain to be unveiled, as they will facilitate the definition of novel biomarkers and clinical targets for more effective patient management. We utilize the B/D-HPP popular protein strategy. We report a list of popular proteins that have been highly cocited with the expression "liver cancer". Several enzymes highlight the known metabolic remodeling of liver cancer cells, four of which participate in one-carbon metabolism. This pathway is central to the maintenance of differentiated hepatocytes, as it is considered the connection between intermediate metabolism and epigenetic regulation. We designed a targeted selective reaction monitoring (SRM) method to follow up one-carbon metabolism adaptation in mouse HCC and in regenerating liver following exposure to CCl 4 . This method allows systematic monitoring of one-carbon metabolism and could prove useful in the follow-up of HCC and of chronically liver-diseased patients (cirrhosis) at risk of HCC. The SRM data are available via ProteomeXchange in PASSEL (PASS01060).

Osteopontin regulates the cross-talk between phosphatidylcholine and cholesterol metabolism in mouse liver.

Science.gov (United States)

Nuñez-Garcia, Maitane; Gomez-Santos, Beatriz; Buqué, Xabier; García-Rodriguez, Juan L; Romero, Marta R; Marin, Jose J G; Arteta, Beatriz; García-Monzón, Carmelo; Castaño, Luis; Syn, Wing-Kin; Fresnedo, Olatz; Aspichueta, Patricia

2017-09-01

Osteopontin (OPN) is involved in different liver pathologies in which metabolic dysregulation is a hallmark. Here, we investigated whether OPN could alter liver, and more specifically hepatocyte, lipid metabolism and the mechanism involved. In mice, lack of OPN enhanced cholesterol 7α-hydroxylase (CYP7A1) levels and promoted loss of phosphatidylcholine (PC) content in liver; in vivo treatment with recombinant (r)OPN caused opposite effects. rOPN directly decreased CYP7A1 levels through activation of focal adhesion kinase-AKT signaling in hepatocytes. PC content was also decreased in OPN-deficient (OPN-KO) hepatocytes in which de novo FA and PC synthesis was lower, whereas cholesterol (CHOL) synthesis was higher, than in WT hepatocytes. In vivo inhibition of cholesterogenesis normalized liver PC content in OPN-KO mice, demonstrating that OPN regulates the cross-talk between liver CHOL and PC metabolism. Matched liver and serum samples showed a positive correlation between serum OPN levels and liver PC and CHOL concentration in nonobese patients with nonalcoholic fatty liver. In conclusion, OPN regulates CYP7A1 levels and the metabolic fate of liver acetyl-CoA as a result of CHOL and PC metabolism interplay. The results suggest that CYP7A1 is a main axis and that serum OPN could disrupt liver PC and CHOL metabolism, contributing to nonalcoholic fatty liver disease progression in nonobese patients.

Phosphorylation of Isoflavones by Bacillus subtilis BCRC 80517 May Represent Xenobiotic Metabolism.

Science.gov (United States)

Hsu, Chen; Wu, Bo-Yuan; Chang, Yu-Chuan; Chang, Chi-Fon; Chiou, Tai-Ying; Su, Nan-Wei

2018-01-10

The soy isoflavones daidzein (DAI) and genistein (GEN) have beneficial effects on human health. However, their oral bioavailability is hampered by their low aqueous solubility. Our previous study revealed two water-soluble phosphorylated conjugates of isoflavones, daidzein 7-O-phosphate and genistein 7-O-phosphate, generated via biotransformation by Bacillus subtilis BCRC80517 cultivated with isoflavones. In this study, two novel derivatives of isoflavones, daidzein 4'-O-phosphate and genistein 4'-O-phosphate, were identified by HPLC-ESI-MS/MS and 1 H, 13 C, and 31 P NMR, and their biotransformation roadmaps were proposed. Primarily, isoflavone glucosides were deglycosylated and then phosphorylated predominantly into 7-O-phosphate conjugates with traces of 4'-O-phosphate conjugates. Inevitably, trace quantities of glucosides were converted into 6″-O-succinyl glucosides. GEN was more efficiently phosphorylated than DAI. Nevertheless, the presence of GEN prolonged the time until the exponential phase of cell growth, whereas the other isoflavones showed little effect on cell growth. Our findings provide new insights into the novel microbial phosphorylation of isoflavones involved in xenobiotic metabolism.

Phase I to II cross-induction of xenobiotic metabolizing enzymes: A feedforward control mechanism for potential hormetic responses

International Nuclear Information System (INIS)

Zhang Qiang; Pi Jingbo; Woods, Courtney G.; Andersen, Melvin E.

2009-01-01

Hormetic responses to xenobiotic exposure likely occur as a result of overcompensation by the homeostatic control systems operating in biological organisms. However, the mechanisms underlying overcompensation that leads to hormesis are still unclear. A well-known homeostatic circuit in the cell is the gene induction network comprising phase I, II and III metabolizing enzymes, which are responsible for xenobiotic detoxification, and in many cases, bioactivation. By formulating a differential equation-based computational model, we investigated in this study whether hormesis can arise from the operation of this gene/enzyme network. The model consists of two feedback and one feedforward controls. With the phase I negative feedback control, xenobiotic X activates nuclear receptors to induce cytochrome P450 enzyme, which bioactivates X into a reactive metabolite X'. With the phase II negative feedback control, X' activates transcription factor Nrf2 to induce phase II enzymes such as glutathione S-transferase and glutamate cysteine ligase, etc., which participate in a set of reactions that lead to the metabolism of X' into a less toxic conjugate X''. The feedforward control involves phase I to II cross-induction, in which the parent chemical X can also induce phase II enzymes directly through the nuclear receptor and indirectly through transcriptionally upregulating Nrf2. As a result of the active feedforward control, a steady-state hormetic relationship readily arises between the concentrations of the reactive metabolite X' and the extracellular parent chemical X to which the cell is exposed. The shape of dose-response evolves over time from initially monotonically increasing to J-shaped at the final steady state-a temporal sequence consistent with adaptation-mediated hormesis. The magnitude of the hormetic response is enhanced by increases in the feedforward gain, but attenuated by increases in the bioactivation or phase II feedback loop gains. Our study suggests a

Phase I to II cross-induction of xenobiotic metabolizing enzymes: a feedforward control mechanism for potential hormetic responses.

Science.gov (United States)

Zhang, Qiang; Pi, Jingbo; Woods, Courtney G; Andersen, Melvin E

2009-06-15

Hormetic responses to xenobiotic exposure likely occur as a result of overcompensation by the homeostatic control systems operating in biological organisms. However, the mechanisms underlying overcompensation that leads to hormesis are still unclear. A well-known homeostatic circuit in the cell is the gene induction network comprising phase I, II and III metabolizing enzymes, which are responsible for xenobiotic detoxification, and in many cases, bioactivation. By formulating a differential equation-based computational model, we investigated in this study whether hormesis can arise from the operation of this gene/enzyme network. The model consists of two feedback and one feedforward controls. With the phase I negative feedback control, xenobiotic X activates nuclear receptors to induce cytochrome P450 enzyme, which bioactivates X into a reactive metabolite X'. With the phase II negative feedback control, X' activates transcription factor Nrf2 to induce phase II enzymes such as glutathione S-transferase and glutamate cysteine ligase, etc., which participate in a set of reactions that lead to the metabolism of X' into a less toxic conjugate X''. The feedforward control involves phase I to II cross-induction, in which the parent chemical X can also induce phase II enzymes directly through the nuclear receptor and indirectly through transcriptionally upregulating Nrf2. As a result of the active feedforward control, a steady-state hormetic relationship readily arises between the concentrations of the reactive metabolite X' and the extracellular parent chemical X to which the cell is exposed. The shape of dose-response evolves over time from initially monotonically increasing to J-shaped at the final steady state-a temporal sequence consistent with adaptation-mediated hormesis. The magnitude of the hormetic response is enhanced by increases in the feedforward gain, but attenuated by increases in the bioactivation or phase II feedback loop gains. Our study suggests a

The fetal/neonatal mouse liver exhibits transcriptional features of the adult pancreas.

Science.gov (United States)

Metabolic homeostasis of the organism is maintained by the liver’s ability to detoxify and eliminate xenobiotics through the expression of xenobiotic metabolism enxymes (XME). The fetus and neonate have been hypothesized to exhibit increased sensitivity to xenobiotic toxicity. T...

Risk factors for metabolic syndrome after liver transplantation

DEFF Research Database (Denmark)

Thoefner, Line Buch; Rostved, Andreas Arendtsen; Pommergaard, Hans-Christian

2018-01-01

syndrome after liver transplantation. METHODS: The databases Medline and Scopus were searched for observational studies evaluating prevalence and risk factors for metabolic syndrome after liver transplantation. Meta-analyses were performed based on odds ratios (ORs) from multivariable analyses...

Bisphenol A sulfonation is impaired in metabolic and liver disease

International Nuclear Information System (INIS)

Yalcin, Emine B.; Kulkarni, Supriya R.; Slitt, Angela L.; King, Roberta

2016-01-01

Background: Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. The liver metabolizes and facilitates BPA excretion through glucuronidation and sulfonation. The sulfotransferase enzymes contributing to BPA sulfonation (detected in human and rodents) is poorly understood. Objectives: To determine the impact of metabolic and liver disease on BPA sulfonation in human and mouse livers. Methods: The capacity for BPA sulfonation was determined in human liver samples that were categorized into different stages of metabolic and liver disease (including obesity, diabetes, steatosis, and cirrhosis) and in livers from ob/ob mice. Results: In human liver tissues, BPA sulfonation was substantially lower in livers from subjects with steatosis (23%), diabetes cirrhosis (16%), and cirrhosis (18%), relative to healthy individuals with non-fatty livers (100%). In livers of obese mice (ob/ob), BPA sulfonation was lower (23%) than in livers from lean wild-type controls (100%). In addition to BPA sulfonation activity, Sult1a1 protein expression decreased by 97% in obese mouse livers. Conclusion: Taken together these findings establish a profoundly reduced capacity of BPA elimination via sulfonation in obese or diabetic individuals and in those with fatty or cirrhotic livers versus individuals with healthy livers. - Highlights: • Present study demonstrates that hepatic SULT 1A1/1A3 are primarily sulfonate BPA in mouse and human. • Hepatic BPA sulfonation is profoundly reduced steatosis, diabetes and cirrhosis. • With BPA-S detectable in urine under low or common exposures, these findings are novel and important.

Bisphenol A sulfonation is impaired in metabolic and liver disease

Energy Technology Data Exchange (ETDEWEB)

Yalcin, Emine B.; Kulkarni, Supriya R.; Slitt, Angela L., E-mail: angela_slitt@uri.edu; King, Roberta, E-mail: rking@uri.edu

2016-02-01

Background: Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. The liver metabolizes and facilitates BPA excretion through glucuronidation and sulfonation. The sulfotransferase enzymes contributing to BPA sulfonation (detected in human and rodents) is poorly understood. Objectives: To determine the impact of metabolic and liver disease on BPA sulfonation in human and mouse livers. Methods: The capacity for BPA sulfonation was determined in human liver samples that were categorized into different stages of metabolic and liver disease (including obesity, diabetes, steatosis, and cirrhosis) and in livers from ob/ob mice. Results: In human liver tissues, BPA sulfonation was substantially lower in livers from subjects with steatosis (23%), diabetes cirrhosis (16%), and cirrhosis (18%), relative to healthy individuals with non-fatty livers (100%). In livers of obese mice (ob/ob), BPA sulfonation was lower (23%) than in livers from lean wild-type controls (100%). In addition to BPA sulfonation activity, Sult1a1 protein expression decreased by 97% in obese mouse livers. Conclusion: Taken together these findings establish a profoundly reduced capacity of BPA elimination via sulfonation in obese or diabetic individuals and in those with fatty or cirrhotic livers versus individuals with healthy livers. - Highlights: • Present study demonstrates that hepatic SULT 1A1/1A3 are primarily sulfonate BPA in mouse and human. • Hepatic BPA sulfonation is profoundly reduced steatosis, diabetes and cirrhosis. • With BPA-S detectable in urine under low or common exposures, these findings are novel and important.

A proteomic-based characterization of liver metabolism in dairy cows and young pigs

DEFF Research Database (Denmark)

Sejersen, Henrik

This thesis deals with studies on liver metabolism in cows and pigs. Proteome analysis was used to quantify a large number of proteins involved in metabolic pathways. In cows, the objective was to characterize differences in the liver proteome between early lactation dairy cows with low or high...... liver fat content and suggest potential blood-based biomarkers for early detection of fatty liver to substantiate prevention strategies. Our results show that several proteins in liver metabolic pathways are affected by liver fat content and that blood aspartate aminotransferase, ß...

High hydrostatic pressure influences the in vitro response to xenobiotics in Dicentrarchus labrax liver

Energy Technology Data Exchange (ETDEWEB)

Lemaire, Benjamin; Mignolet, Eric; Debier, Cathy [Institut des Sciences de la Vie, Université Catholique de Louvain, Croix du Sud 2, B-1348 Louvain-la-Neuve (Belgium); Calderon, Pedro Buc [Louvain Drug Research Institute, Université Catholique de Louvain, Avenue Mounier 73, B-1200 Woluwé-Saint-Lambert (Belgium); Thomé, Jean Pierre [Laboratoire d’Ecologie Animale et Ecotoxicologie, Université de Liège, Allée du 6 août 15, B-4000 Liège (Belgium); Rees, Jean François, E-mail: jf.rees@uclouvain.be [Institut des Sciences de la Vie, Université Catholique de Louvain, Croix du Sud 2, B-1348 Louvain-la-Neuve (Belgium)

2016-04-15

Highlights: • The methodology of precision-cut liver slices was applied to the European seabass. • Liver slices remained viable and functional in short-term co-exposure studies. • CYP1A induction was blocked in slices exposed to an AhR agonist at high pressure. • HSP70 induction was lower in slices exposed to an AhR agonist at high pressure. • Oxidative stress responses to tBHP were less pronounced at high pressure. - Abstract: Hydrostatic pressure (HP) increases by about 1 atmosphere (0.1 MPa) for each ten-meter depth increase in the water column. This thermodynamical parameter could well influence the response to and effects of xenobiotics in the deep-sea biota, but this possibility remains largely overlooked. To grasp the extent of HP adaptation in deep-sea fish, comparative studies with living cells of surface species exposed to chemicals at high HP are required. We initially conducted experiments with precision-cut liver slices of a deep-sea fish (Coryphaenoides rupestris), co-exposed for 15 h to the aryl hydrocarbon receptor (AhR) agonist 3-methylcholanthrene at HP levels representative of the surface (0.1 MPa) and deep-sea (5–15 MPa; i.e., 500–1500 m depth) environments. The transcript levels of a suite of stress-responsive genes, such as the AhR battery CYP1A, were subsequently measured (Lemaire et al., 2012; Environ. Sci. Technol. 46, 10310–10316). Strikingly, the AhR agonist-mediated increase of CYP1A mRNA content was pressure-dependently reduced in C. rupestris. Here, the same co-exposure scenario was applied for 6 or 15 h to liver slices of a surface fish, Dicentrarchus labrax, a coastal species presumably not adapted to high HP. Precision-cut liver slices of D. labrax were also used in 1 h co-exposure studies with the pro-oxidant tert-butylhydroperoxide (tBHP) as to investigate the pressure-dependence of the oxidative stress response (i.e., reactive oxygen production, glutathione and lipid peroxidation status). Liver cells remained

High hydrostatic pressure influences the in vitro response to xenobiotics in Dicentrarchus labrax liver

International Nuclear Information System (INIS)

Lemaire, Benjamin; Mignolet, Eric; Debier, Cathy; Calderon, Pedro Buc; Thomé, Jean Pierre; Rees, Jean François

2016-01-01

Highlights: • The methodology of precision-cut liver slices was applied to the European seabass. • Liver slices remained viable and functional in short-term co-exposure studies. • CYP1A induction was blocked in slices exposed to an AhR agonist at high pressure. • HSP70 induction was lower in slices exposed to an AhR agonist at high pressure. • Oxidative stress responses to tBHP were less pronounced at high pressure. - Abstract: Hydrostatic pressure (HP) increases by about 1 atmosphere (0.1 MPa) for each ten-meter depth increase in the water column. This thermodynamical parameter could well influence the response to and effects of xenobiotics in the deep-sea biota, but this possibility remains largely overlooked. To grasp the extent of HP adaptation in deep-sea fish, comparative studies with living cells of surface species exposed to chemicals at high HP are required. We initially conducted experiments with precision-cut liver slices of a deep-sea fish (Coryphaenoides rupestris), co-exposed for 15 h to the aryl hydrocarbon receptor (AhR) agonist 3-methylcholanthrene at HP levels representative of the surface (0.1 MPa) and deep-sea (5–15 MPa; i.e., 500–1500 m depth) environments. The transcript levels of a suite of stress-responsive genes, such as the AhR battery CYP1A, were subsequently measured (Lemaire et al., 2012; Environ. Sci. Technol. 46, 10310–10316). Strikingly, the AhR agonist-mediated increase of CYP1A mRNA content was pressure-dependently reduced in C. rupestris. Here, the same co-exposure scenario was applied for 6 or 15 h to liver slices of a surface fish, Dicentrarchus labrax, a coastal species presumably not adapted to high HP. Precision-cut liver slices of D. labrax were also used in 1 h co-exposure studies with the pro-oxidant tert-butylhydroperoxide (tBHP) as to investigate the pressure-dependence of the oxidative stress response (i.e., reactive oxygen production, glutathione and lipid peroxidation status). Liver cells remained

Xenobiotic-Metabolizing Enzyme and Transporter Gene Expression in Primary Cultures of Human Hepatocytes Modulated by Toxcast Chemicals

Science.gov (United States)

Primary human hepatocyte cultures are useful in vitro model systems of human liver because when cultured under appropriate conditions the hepatocytes retain liver-like functionality such as metabolism, transport, and cell signaling. This model system was used to characterize the ...

Estimation of aerial deposition and foliar uptake of xenobiotics: Assessment of current models

Energy Technology Data Exchange (ETDEWEB)

Link, S.O.; Fellows, R.J.; Cataldo, D.A.; Droppo, J.G.; Van Voris, P.

1987-10-01

This report reviews existing mathematical and/or computer simulation models that estimate xenobiotic deposition to and transport through (both curricular and stomatal) vegetative surfaces. The report evaluates the potential for coupling the best of those models to the existing Uptake, Translocation, Accumulation, and Biodegradation model to be used for future xenobiotic exposure assessments. Here xenobiotic compounds are defined as airborne contaminants, both organic and gaseous pollutants, that are introduced into the environment by man. Specifically this document provides a detailed review of the state-of-the-art models that addressed aerial deposition of particles and gases to foliage; foliar and cuticular transport, metabolism, and uptake of organic xenobiotics; and stomatal transport of gaseous and volatile organic xenobiotic pollutants. Where detailed information was available, parameters for each model are provided on a chemical by chemical as well as species by species basis. Sufficient detail is provided on each model to assess the potential for adapting or coupling the model to the existing UTAB plant exposure model. 126 refs., 6 figs., 10 tabs.

Alanine metabolism in pyridoxine-depleted rat liver

International Nuclear Information System (INIS)

Okada, Mitsuko; Abe, Midori

1976-01-01

Alanine metabolism in normal and pyridoxine-deficient rats was studied in vivo and in vitro. Incorporation of 14 C-alanine into various liver components was determined and no difference was shown between normal and deficient animals in the incorporation into liver homogenates, lipid, protein and plasma glucose. Using the liver slice system, gluconeogenic activity from alanine or pyruvate was 40% lower in deficient rats compared with the activity of normal rats. However, inhibition was completely removed by the addition of 2-oxoglutarate to alanine. Penicillamine did not affect glucose formation from alanine in the liver slice. (auth.)

Fatty liver and drugs: the two sides of the same coin.

Science.gov (United States)

Miele, L; Liguori, A; Marrone, G; Biolato, M; Araneo, C; Vaccaro, F G; Gasbarrini, A; Grieco, A

2017-03-01

Drug-induced liver injury (DILI) is a common and underestimated cause of liver disease. Several drugs and other xenobiotics can be the cause of different clinicopathologic patterns of liver disease. Steatosis and steatohepatitis are rare but well-documented types of DILI. Over the past decades commonly used drugs like amiodarone, tamoxifen, irinotecan, methotrexate, valproic acid and glucocorticoids have been recognized to be associated with steatosis. Even though the pathophysiological pathways are still only partially understood, inhibition of mitochondrial beta-oxidation, reduced very low-density lipoprotein secretion, insulin resistance induction and increased de novo synthesis or increased liver uptake of fatty acids are considered the main pathogenic mechanisms through which drugs can lead to hepatic steatosis. On the other hand, fatty liver itself is a very common clinical condition, and there is a growing awareness of the potential risk factors for DILI due to the underlying metabolic condition itself.

Insulin resistance and postreceptor changes of liver metabolism in fat-fed mice

DEFF Research Database (Denmark)

Hedeskov, Carl Jørgen; Capito, Kirsten; Hansen, Svend Erik

1992-01-01

Medicinsk biokemi, animal diabetes, insulin resistance, postreceptor defects, liver metabolism, high-fat diet......Medicinsk biokemi, animal diabetes, insulin resistance, postreceptor defects, liver metabolism, high-fat diet...

Methods of measuring metabolism during surgery in humans: focus on the liver-brain relationship.

Science.gov (United States)

Battezzati, Alberto; Bertoli, Simona

2004-09-01

The purpose of this work is to review recent advances in setting methods and models for measuring metabolism during surgery in humans. Surgery, especially solid organ transplantation, may offer unique experimental models in which it is ethically acceptable to gain information on difficult problems of amino acid and protein metabolism. Two areas are reviewed: the metabolic study of the anhepatic phase during liver transplantation and brain microdialysis during cerebral surgery. The first model offers an innovative approach to understand the relative role of liver and extrahepatic organs in gluconeogenesis, and to evaluate whether other organs can perform functions believed to be exclusively or almost exclusively performed by the liver. The second model offers an insight to intracerebral metabolism that is closely bound to that of the liver. The recent advances in metabolic research during surgery provide knowledge immediately useful for perioperative patient management and for a better control of surgical stress. The studies during the anhepatic phase of liver transplantation have showed that gluconeogenesis and glutamine metabolism are very active processes outside the liver. One of the critical organs for extrahepatic glutamine metabolism is the brain. Microdialysis studies helped to prove that in humans there is an intense trafficking of glutamine, glutamate and alanine among neurons and astrocytes. This delicate network is influenced by systemic amino acid metabolism. The metabolic dialogue between the liver and the brain is beginning to be understood in this light in order to explain the metabolic events of brain damage during liver failure.

Influence of dietary macronutrients on liver fat accumulation and metabolism

OpenAIRE

Parry, Siôn A; Hodson, Leanne

2017-01-01

The liver is a principal metabolic organ within the human body and has a major role in regulating carbohydrate, fat, and protein metabolism. With increasing rates of obesity, the prevalence of non-alcoholic fatty liver disease (NAFLD) is growing. It remains unclear why NAFLD, which is now defined as the hepatic manifestation of the metabolic syndrome, develops but lifestyle factors such as diet (ie, total calorie and specific nutrient intakes), appear to play a key role. Here we review the av...

Hepatic toxicology following single and multiple exposure of engineered nanomaterials utilising a novel primary human 3D liver microtissue model

DEFF Research Database (Denmark)

Kermanizadeh, Ali; Løhr, Mille; Roursgaard, Martin

2014-01-01

BackgroundThe liver has a crucial role in metabolic homeostasis as well as being the principal detoxification centre of the body, removing xenobiotics and waste products which could potentially include some nanomaterials (NM). With the ever increasing public and occupational exposure associated...... with accumulative production of nanomaterials, there is an urgent need to consider the possibility of detrimental health consequences of engineered NM exposure. It has been shown that exposure via inhalation, intratracheal instillation or ingestion can result in NM translocation to the liver. Traditional in vitro...... or ex vivo hepatic nanotoxicology models are often limiting and/or troublesome (i.e. reduced metabolism enzymes, lacking important cell populations, unstable with very high variability, etc.).MethodsIn order to rectify these issues and for the very first time we have utilised a 3D human liver...

Xenobiotic/medium chain fatty acid: CoA ligase - a critical review on its role in fatty acid metabolism and the detoxification of benzoic acid and aspirin.

Science.gov (United States)

van der Sluis, Rencia; Erasmus, Elardus

2016-10-01

Activation of fatty acids by the acyl-CoA synthetases (ACSs) is the vital first step in fatty acid metabolism. The enzymatic and physiological characterization of the human xenobiotic/medium chain fatty acid: CoA ligases (ACSMs) has been severely neglected even though xenobiotics, such as benzoate and salicylate, are detoxified through this pathway. This review will focus on the nomenclature and substrate specificity of the human ACSM ligases; the biochemical and enzymatic characterization of ACSM1 and ACSM2B; the high sequence homology of the ACSM2 genes (ACSM2A and ACSM2B) as well as what is currently known regarding disease association studies. Several discrepancies exist in the current literature that should be taken note of. For example, the single nucleotide polymorphisms (SNPs) reported to be associated with aspirin metabolism and multiple risk factors of metabolic syndrome are incorrect. Kinetic data on the substrate specificity of the human ACSM ligases are non-existent and currently no data exist on the influence of SNPs on the enzyme activity of these ligases. One of the biggest obstacles currently in the field is that glycine conjugation is continuously studied as a one-step process, which means that key regulatory factors of the two individual steps remain unknown.

Skeletal Muscle Derived IL-6 in Liver and Adipose Tissue Metabolism

DEFF Research Database (Denmark)

Knudsen, Jakob Grunnet

Summary Physical activity can lead to metabolic disease and treatment of several metabolic diseases include exercise training. Skeletal muscle has, due to its central role in glucose and fat metabolism at rest and during exercise been studied in detail with regard to exercise training. The role...... of both liver and adipose tissue regulation in whole body metabolism has come in to focus and it has been shown that both tissues are subject to exercise training-induced adaptations. However, the contribution of endocrine factors to the regulation of exercise training-induced adaptations in liver...... and adipose tissue metabolism is unknown. It has been suggested that myokines, such as IL-6, released from skeletal muscle affects liver and adipose tissue and are involved in the regulation of exercise training adaptations. Thus, the aim of this thesis was to investigate the role of skeletal muscle derived...

Impact of environmental exposures on ovarian function and role of xenobiotic metabolism during ovotoxicity

Energy Technology Data Exchange (ETDEWEB)

Bhattacharya, Poulomi; Keating, Aileen F., E-mail: akeating@iastate.edu

2012-06-15

The mammalian ovary is a heterogeneous organ and contains oocyte-containing follicles at varying stages of development. The most immature follicular stage, the primordial follicle, comprises the ovarian reserve and is a finite number, defined at the time of birth. Depletion of all follicles within the ovary leads to reproductive senescence, known as menopause. A number of chemical classes can destroy follicles, thus hastening entry into the menopausal state. The ovarian response to chemical exposure can determine the extent of ovotoxicity that occurs. Enzymes capable of bioactivating as well as detoxifying xenobiotics are expressed in the ovary and their impact on ovotoxicity has been partially characterized for trichloroethylene, 7,12-dimethylbenz[a]anthracene, and 4-vinylcyclohexene. This review will discuss those studies, as well as illustrate where knowledge gaps remain for chemicals that have also been established as ovotoxicants. -- Highlights: ► Summary of ovotoxicant action during ovotoxicity. ► Discussion of impact of biotransformation on chemical toxicity. ► Identification of knowledge gaps in chemical metabolism.

Impact of environmental exposures on ovarian function and role of xenobiotic metabolism during ovotoxicity

International Nuclear Information System (INIS)

Bhattacharya, Poulomi; Keating, Aileen F.

2012-01-01

The mammalian ovary is a heterogeneous organ and contains oocyte-containing follicles at varying stages of development. The most immature follicular stage, the primordial follicle, comprises the ovarian reserve and is a finite number, defined at the time of birth. Depletion of all follicles within the ovary leads to reproductive senescence, known as menopause. A number of chemical classes can destroy follicles, thus hastening entry into the menopausal state. The ovarian response to chemical exposure can determine the extent of ovotoxicity that occurs. Enzymes capable of bioactivating as well as detoxifying xenobiotics are expressed in the ovary and their impact on ovotoxicity has been partially characterized for trichloroethylene, 7,12-dimethylbenz[a]anthracene, and 4-vinylcyclohexene. This review will discuss those studies, as well as illustrate where knowledge gaps remain for chemicals that have also been established as ovotoxicants. -- Highlights: ► Summary of ovotoxicant action during ovotoxicity. ► Discussion of impact of biotransformation on chemical toxicity. ► Identification of knowledge gaps in chemical metabolism.

Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging.

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Sato, Shogo; Solanas, Guiomar; Peixoto, Francisca Oliveira; Bee, Leonardo; Symeonidi, Aikaterini; Schmidt, Mark S; Brenner, Charles; Masri, Selma; Benitah, Salvador Aznar; Sassone-Corsi, Paolo

2017-08-10

The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD + -related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling.

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Christine T Ferrara

2008-03-01

Full Text Available Although numerous quantitative trait loci (QTL influencing disease-related phenotypes have been detected through gene mapping and positional cloning, identification of the individual gene(s and molecular pathways leading to those phenotypes is often elusive. One way to improve understanding of genetic architecture is to classify phenotypes in greater depth by including transcriptional and metabolic profiling. In the current study, we have generated and analyzed mRNA expression and metabolic profiles in liver samples obtained in an F2 intercross between the diabetes-resistant C57BL/6 leptin(ob/ob and the diabetes-susceptible BTBR leptin(ob/ob mouse strains. This cross, which segregates for genotype and physiological traits, was previously used to identify several diabetes-related QTL. Our current investigation includes microarray analysis of over 40,000 probe sets, plus quantitative mass spectrometry-based measurements of sixty-seven intermediary metabolites in three different classes (amino acids, organic acids, and acyl-carnitines. We show that liver metabolites map to distinct genetic regions, thereby indicating that tissue metabolites are heritable. We also demonstrate that genomic analysis can be integrated with liver mRNA expression and metabolite profiling data to construct causal networks for control of specific metabolic processes in liver. As a proof of principle of the practical significance of this integrative approach, we illustrate the construction of a specific causal network that links gene expression and metabolic changes in the context of glutamate metabolism, and demonstrate its validity by showing that genes in the network respond to changes in glutamine and glutamate availability. Thus, the methods described here have the potential to reveal regulatory networks that contribute to chronic, complex, and highly prevalent diseases and conditions such as obesity and diabetes.

Intrinsic Xenobiotic Metabolizing Enzyme Activities in Early Life Stages of Zebrafish (Danio rerio).

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Otte, Jens C; Schultz, Bernadette; Fruth, Daniela; Fabian, Eric; van Ravenzwaay, Bennard; Hidding, Björn; Salinas, Edward R

2017-09-01

Early life stages of zebrafish (Danio rerio, zf) are gaining attention as an alternative invivo test system for drug discovery, early developmental toxicity screenings and chemical testing in ecotoxicological and toxicological testing strategies. Previous studies have demonstrated transcriptional evidence for xenobiotic metabolizing enzymes (XME) during early zf development. However, elaborate experiments on XME activities during development are incomplete. In this work, the intrinsic activities of representative phase I and II XME were monitored by transformation of putative zf model substrates analyzed using photometry and high pressure liquid chromatography techniques. Six different defined stages of zf development (between 2.5 h postfertilization (hpf) to 120 hpf) were investigated by preparing a subcellular fraction from whole organism homogenates. We demonstrated that zf embryos as early as 2.5 hpf possess intrinsic metabolic activities for esterase, Aldh, Gst, and Cyp1a above the methodological detection limit. The activities of the enzymes Cyp3a and Nat were measurable during later stages in development. Activities represent dynamic patterns during development. The role of XME activities revealed in this work is relevant for the assessing toxicity in this test system and therefore contributes to a valuable characterization of zf embryos as an alternative testing organism in toxicology. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Studies of liver-specific metabolic reactions with /sup 15/N. 1. Metabolism of /sup 15/N-ammonium chloride in pigs

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Hirschberg, K; Jung, K; Faust, H; Matkowitz, R

1987-07-01

The /sup 15/N tracer technique was used to investigate liver-specific reactions (urea and hippurate synthesis) for studying the metabolism in the healthy and damaged pig liver. After (/sup 15/N)ammonium chloride administration the tracer distribution on non-protein compounds of serum and urine was followed. Blood samplings before and after liver passage rendered possible a direct analysis of the (/sup 15/N)ammonium metabolism. The thioacetamide-induced liver damage was used as model for an acute liver intoxication. The capacity for urea synthesis was not influenced by means of this noxious substance, but the metabolism of amino acids and hippuric acid. The considerably depressed excretion of (/sup 15/N)hippurate seems to be a suitable indicator of liver disfunction.

Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice.

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Palmisano, Brian T; Le, Thao D; Zhu, Lin; Lee, Yoon Kwang; Stafford, John M

2016-08-01

Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver β-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance β-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance β-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane x receptors.

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Luisier, Raphaëlle; Lempiäinen, Harri; Scherbichler, Nina; Braeuning, Albert; Geissler, Miriam; Dubost, Valerie; Müller, Arne; Scheer, Nico; Chibout, Salah-Dine; Hara, Hisanori; Picard, Frank; Theil, Diethilde; Couttet, Philippe; Vitobello, Antonio; Grenet, Olivier; Grasl-Kraupp, Bettina; Ellinger-Ziegelbauer, Heidrun; Thomson, John P; Meehan, Richard R; Elcombe, Clifford R; Henderson, Colin J; Wolf, C Roland; Schwarz, Michael; Moulin, Pierre; Terranova, Rémi; Moggs, Jonathan G

2014-06-01

The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CAR(KO)-PXR(KO)), double humanized CAR and PXR (CAR(h)-PXR(h)), and wild-type C57BL/6 mice. Wild-type and CAR(h)-PXR(h) mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CAR(KO)-PXR(KO) mouse livers and largely reversible in wild-type and CAR(h)-PXR(h) mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CAR(h)-PXR(h) mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.

Prevalence of non alcoholic fatty liver disease in patients with metabolic syndrome

International Nuclear Information System (INIS)

Iftikhar, R.; Kamran, S.M.

2015-01-01

To determine frequency of Non Alcoholic fatty liver disease in patients with Metabolic Syndrome (MetS). Study Design: Cross sectional study. Place and Duration of Study: Department of medicine, CMH Okara, Jan 2013 to July 2013. Patients and Methods: We included 491 adult males, diagnosed with metabolic syndrome (MetS), presenting in outpatient department for routine review. MetS was diagnosed as per the International Diabetes Federation (IDF) proposed criteria of 2004. Detailed history and examination of each individual was done and data entered in pre designed performa. Brightness and posterior attenuation on ultrasound abdomen were considered indices for fatty liver disease in presence of elevated ALT, negative hepatitis serology and absence of alcohol intake. All the data was analyzed using SPSS version 16. p value of less than 0.05 was considered statistically significant. Results: Out of 491 participants with MetS, 222 (45.2%) had fatty liver disease. Mean BMI in patients with metabolic syndrome was 26.1 (± .89) and mean BMI in fatty liver patients was 27.3 (± 0.67). Out of total 5 components of Mets, patients with fatty liver disease had 3.24 (± 0.25) components, as compared to 2.1 (± 0.34) in whole of study group. Conclusion: A large number of patients with metabolic syndrome have fatty liver disease. Fatty liver disease is more frequent in patients who are overweight and those having multiple risk factors of metabolic syndrome. (author)

Coactivator PGC-1α regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes

International Nuclear Information System (INIS)

Arpiainen, Satu; Jaervenpaeae, Sanna-Mari; Manninen, Aki; Viitala, Pirkko; Lang, Matti A.; Pelkonen, Olavi; Hakkola, Jukka

2008-01-01

The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor γ coactivator (PGC)-1α triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1α and CYP2A5 mRNAs in murine primary hepatocytes. Furthermore, the elevation of the PGC-1α expression level by adenovirus mediated gene transfer increased CYP2A5 transcription. Co-transfection of Cyp2a5 5' promoter constructs with the PGC-1α expression vector demonstrated that PGC-1α is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4α response element in the proximal promoter of the Cyp2a5 gene. Chromatin immunoprecipitation assays showed that PGC-1α binds, together with HNF-4α, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1α mediates the expression of CYP2A5 induced by cAMP in mouse hepatocytes through coactivation of transcription factor HNF-4α. This strongly suggests that PGC-1α is the major factor mediating the fasting response of CYP2A5

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD

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Ali Saeed

2017-12-01

Full Text Available Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs and retinoid X receptors (RXRs.The liver plays a central role in vitamin A metabolism: (1 it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2 it produces retinol binding protein 4 (RBP4 that distributes vitamin A, as retinol, to peripheral tissues; and (3 it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs. In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH; it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M is the most prominent

Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice[S

Science.gov (United States)

Palmisano, Brian T.; Le, Thao D.; Zhu, Lin; Lee, Yoon Kwang; Stafford, John M.

2016-01-01

Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver β-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance β-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance β-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism. PMID:27354419

Inherited metabolic liver diseases in infants and children: an overview

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Ivo Barić

2013-10-01

Full Text Available Inborn errors of metabolism, which affect the liver are a large, continuously increasing group of diseases. Their clinical onset can occur at any age, from intrauterine period presenting as liver failure already at birth to late adulthood. Inherited metabolic disorders must be considered in differential diagnosis of every unexplained liver disease. Specific diagnostic work-up for either their confirmation or exclusion should start immediately since any postponing can result in delayed diagnosis and death or irreversible disability. This can be particularly painful while many inherited metabolic liver diseases are relatively easily treatable if diagnosed on time, for instance galactosemia or hereditary fructose intolerance by simple dietary means. Any unexplained liver disease, even one looking initially benign, should be considered as a potential liver failure and therefore should deserve proper attention. Diagnosis in neonates is additionally complicated because of the factors which can mask liver disease, such as physiological neonatal jaundice, normally relatively enlarged liver and increased transaminases at that age. In everyday practice, in order to reveal the etiology, it is useful to classify and distinguish some clinical patterns which, together with a few routine, widely available laboratory tests (aminotransferases, prothrombine time, albumin, gammaGT, total and conjugated bilirubin, ammonia, alkaline phosphatase and glucose make the search for the cause much easier. These patterns are isolated hyperbilirubinemia, syndrome of cholestasis in early infancy, hepatocellular jaundice, Reye syndrome, portal cirrhosis and isolated hepatomegaly. Despite the fact that some diseases can present with more than one pattern (for instance, alpha-1-antitrypsin deficiency as infantile cholestasis, but also as hepatocellular jaundice, and that in some disesases one pattern can evolve into another (for instance, Wilson disease from hepatocellular

Carboxylesterases in lipid metabolism: from mouse to human

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Jihong Lian

2017-07-01

Full Text Available ABSTRACT Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (overexpression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders. In order to translate pre-clinical studies in cellular and mouse models to humans, differences and similarities of carboxylesterases between mice and human need to be elucidated. This review presents and discusses the research progress in structure and function of mouse and human carboxylesterases, and the role of these enzymes in lipid metabolism and metabolic disorders.

Influence of dietary macronutrients on liver fat accumulation and metabolism

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Parry, Siôn A; Hodson, Leanne

2017-01-01

The liver is a principal metabolic organ within the human body and has a major role in regulating carbohydrate, fat, and protein metabolism. With increasing rates of obesity, the prevalence of non-alcoholic fatty liver disease (NAFLD) is growing. It remains unclear why NAFLD, which is now defined as the hepatic manifestation of the metabolic syndrome, develops but lifestyle factors such as diet (ie, total calorie and specific nutrient intakes), appear to play a key role. Here we review the available observational and intervention studies that have investigated the influence of dietary macronutrients on liver fat content. Findings from observational studies are conflicting with some reporting that relative to healthy controls, patients with NAFLD consume diets higher in total fat/saturated fatty acids, whilst others find they consume diets higher in carbohydrates/sugars. From the limited number of intervention studies that have been undertaken, a consistent finding is a hypercaloric diet, regardless of whether the excess calories have been provided either as fat, sugar, or both, increases liver fat content. In contrast, a hypocaloric diet decreases liver fat content. Findings from both hyper- and hypo-caloric feeding studies provide some suggestion that macronutrient composition may also play a role in regulating liver fat content and this is supported by data from isocaloric feeding studies; fatty acid composition and/or carbohydrate content/type appear to influence whether there is accrual of liver fat or not. The mechanisms by which specific macronutrients, when consumed as part of an isocaloric diet, cause a change in liver fat remain to be fully elucidated. PMID:28947639

Coordinated and interactive expression of genes of lipid metabolism and inflammation in adipose tissue and liver during metabolic overload.

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Wen Liang

Full Text Available BACKGROUND: Chronic metabolic overload results in lipid accumulation and subsequent inflammation in white adipose tissue (WAT, often accompanied by non-alcoholic fatty liver disease (NAFLD. In response to metabolic overload, the expression of genes involved in lipid metabolism and inflammatory processes is adapted. However, it still remains unknown how these adaptations in gene expression in expanding WAT and liver are orchestrated and whether they are interrelated. METHODOLOGY/PRINCIPAL FINDINGS: ApoE*3Leiden mice were fed HFD or chow for different periods up to 12 weeks. Gene expression in WAT and liver over time was evaluated by micro-array analysis. WAT hypertrophy and inflammation were analyzed histologically. Bayesian hierarchical cluster analysis of dynamic WAT gene expression identified groups of genes ('clusters' with comparable expression patterns over time. HFD evoked an immediate response of five clusters of 'lipid metabolism' genes in WAT, which did not further change thereafter. At a later time point (>6 weeks, inflammatory clusters were induced. Promoter analysis of clustered genes resulted in specific key regulators which may orchestrate the metabolic and inflammatory responses in WAT. Some master regulators played a dual role in control of metabolism and inflammation. When WAT inflammation developed (>6 weeks, genes of lipid metabolism and inflammation were also affected in corresponding livers. These hepatic gene expression changes and the underlying transcriptional responses in particular, were remarkably similar to those detected in WAT. CONCLUSION: In WAT, metabolic overload induced an immediate, stable response on clusters of lipid metabolism genes and induced inflammatory genes later in time. Both processes may be controlled and interlinked by specific transcriptional regulators. When WAT inflammation began, the hepatic response to HFD resembled that in WAT. In all, WAT and liver respond to metabolic overload by

Metabolism, genomics, and DNA repair in the mouse aging liver

DEFF Research Database (Denmark)

Lebel, Michel; de Souza-Pinto, Nadja C; Bohr, Vilhelm A

2011-01-01

hepatic metabolic and detoxification activities, with implications for systemic aging and age-related disease. It has become clear, using rodent models as biological tools, that genetic instability in the form of gross DNA rearrangements or point mutations accumulate in the liver with age. DNA lesions......The liver plays a pivotal role in the metabolism of nutrients, drugs, hormones, and metabolic waste products, thereby maintaining body homeostasis. The liver undergoes substantial changes in structure and function within old age. Such changes are associated with significant impairment of many......, such as oxidized bases or persistent breaks, increase with age and correlate well with the presence of senescent hepatocytes. The level of DNA damage and/or mutation can be affected by changes in carcinogen activation, decreased ability to repair DNA, or a combination of these factors. This paper covers some...

Metabolic adaptations in models of fatty liver disease : Of mice and math

NARCIS (Netherlands)

Hijmans, Brenda

2017-01-01

The increasing incidence of overweight is accompanied by a plethora of medical symptoms together called the metabolic syndrome. Non-alcoholic fatty liver disease, characterized by persistent storage of lipids in the liver, is regarded as the hepatic component of the metabolic syndrome. An imbalance

Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease.

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Lee, Yun-Hee; Kim, Sou Hyun; Kim, Sang-Nam; Kwon, Hyun-Jung; Kim, Jeong-Dong; Oh, Ji Youn; Jung, Young-Suk

2016-07-26

Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.

A Liver-centric Multiscale Modeling Framework for Xenobiotics

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We describe a multi-scale framework for modeling acetaminophen-induced liver toxicity. Acetaminophen is a widely used analgesic. Overdose of acetaminophen can result in liver injury via its biotransformation into toxic product, which further induce massive necrosis. Our study foc...

Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice.

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Fu, Zidong Donna; Klaassen, Curtis D

2014-01-01

Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. Copyright © 2013 Elsevier Inc. All rights reserved.

Fatty liver as a risk factor for progression from metabolically healthy to metabolically abnormal in non-overweight individuals.

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Hashimoto, Yoshitaka; Hamaguchi, Masahide; Fukuda, Takuya; Ohbora, Akihiro; Kojima, Takao; Fukui, Michiaki

2017-07-01

Recent studies identified that metabolically abnormal non-obese phenotype is a risk factor for cardiovascular diseases. However, little is known about risk factor for progression from metabolically healthy non-overweight to metabolically abnormal phenotype. We hypothesized that fatty liver had a clinical impact on progression from metabolically healthy non-overweight to metabolically abnormal phenotype. In this retrospective cohort study, 14,093 Japanese (7557 men and 6736 women), who received the health-checkup program from 2004 to 2012, were enrolled. Overweight and obesity were defined as body mass index 23.0-25.0 and ≥25.0 kg/m 2 . Four metabolic factors (impaired fasting glucose, hypertension, hypertriglyceridemia and low high density lipoprotein-cholesterol concentration) were used for definition of metabolically healthy (less than two factors) or metabolically abnormal (two or more). We divided the participants into three groups: metabolically healthy non-overweight (9755 individuals, men/women = 4290/5465), metabolically healthy overweight (2547 individuals, 1800/747) and metabolically healthy obesity (1791 individuals, 1267/524). Fatty liver was diagnosed by ultrasonography. Over the median follow-up period of 5.3 years, 873 metabolically healthy non-overweight, 512 metabolically healthy overweight and 536 metabolically healthy obesity individuals progressed to metabolically abnormal. The adjusted hazard risks of fatty liver on progression were 1.49 (95% confidence interval 1.20-1.83, p = 0.005) in metabolically healthy non-overweight, 1.37 (1.12-1.66, p = 0.002) in metabolically healthy overweight and 1.38 (1.15-1.66, p overweight individuals.

The effectiveness of metformin in patients with metabolic syndrome and nonalcoholic fatty liver disease

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S A Butrova

2008-06-01

Full Text Available The mechanism of action of metformin is realized through activation of cAMP-dependent protein kinase, leading to a decrease hepatic glucose production as well as to decrease the synthesis of triglycerides and an increase in fat oxidation. Several studies have demonstrated the positive effect of the drug in non-alcoholic fatty liver disease, manifested in reducing the activity of enzymes, reducing the size of the liver and insulin resistance. The aim of our study was to evaluate the effectiveness of metformin in patients with metabolic syndrome and nonalcoholic fatty liver disease. The study found that the use Siofor 850 mg 2 times a day in conjunction with a reduced-calorie nutrition in patients with metabolic syndrome and nonalcoholic fatty liver disease leads to a significant reduction in insulin resistance associated with decreased activity of transaminases, improvement of metabolic parameters. The therapy Siofor majority of patients (60% with metabolic syndrome and nonalcoholic fatty liver disease achieved a clinically significant weight loss and improved body composition. Application Siofor improves lifestyle changes in obese patients with non-alcoholic liver disease dirovoy and metabolic disorders.

Influence of dietary macronutrients on liver fat accumulation and metabolism.

Science.gov (United States)

Parry, Siôn A; Hodson, Leanne

2017-12-01

The liver is a principal metabolic organ within the human body and has a major role in regulating carbohydrate, fat, and protein metabolism. With increasing rates of obesity, the prevalence of non-alcoholic fatty liver disease (NAFLD) is growing. It remains unclear why NAFLD, which is now defined as the hepatic manifestation of the metabolic syndrome, develops but lifestyle factors such as diet (ie, total calorie and specific nutrient intakes), appear to play a key role. Here we review the available observational and intervention studies that have investigated the influence of dietary macronutrients on liver fat content. Findings from observational studies are conflicting with some reporting that relative to healthy controls, patients with NAFLD consume diets higher in total fat/saturated fatty acids, whilst others find they consume diets higher in carbohydrates/sugars. From the limited number of intervention studies that have been undertaken, a consistent finding is a hypercaloric diet, regardless of whether the excess calories have been provided either as fat, sugar, or both, increases liver fat content. In contrast, a hypocaloric diet decreases liver fat content. Findings from both hyper- and hypo-caloric feeding studies provide some suggestion that macronutrient composition may also play a role in regulating liver fat content and this is supported by data from isocaloric feeding studies; fatty acid composition and/or carbohydrate content/type appear to influence whether there is accrual of liver fat or not. The mechanisms by which specific macronutrients, when consumed as part of an isocaloric diet, cause a change in liver fat remain to be fully elucidated. © American Federation for Medical Research (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Diet-induced metabolic hamster model of nonalcoholic fatty liver disease

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Bhathena J

2011-06-01

Full Text Available Jasmine Bhathena, Arun Kulamarva, Christopher Martoni, Aleksandra Malgorzata Urbanska, Meenakshi Malhotra, Arghya Paul, Satya PrakashBiomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Artificial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, Québec, CanadaBackground: Obesity, hypercholesterolemia, elevated triglycerides, and type 2 diabetes are major risk factors for metabolic syndrome. Hamsters, unlike rats or mice, respond well to diet-induced obesity, increase body mass and adiposity on group housing, and increase food intake due to social confrontation-induced stress. They have a cardiovascular and hepatic system similar to that of humans, and can thus be a useful model for human pathophysiology.Methods: Experiments were planned to develop a diet-induced Bio F1B Golden Syrian hamster model of dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hamsters were fed a normal control diet, a high-fat/high-cholesterol diet, a high-fat/high-cholesterol/methionine-deficient/choline-devoid diet, and a high-fat/high-cholesterol/choline-deficient diet. Serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, atherogenic index, and body weight were quantified biweekly. Fat deposition in the liver was observed and assessed following lipid staining with hematoxylin and eosin and with oil red O.Results: In this study, we established a diet-induced Bio F1B Golden Syrian hamster model for studying dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hyperlipidemia and elevated serum glucose concentrations were induced using this diet. Atherogenic index was elevated, increasing the risk for a cardiovascular event. Histological analysis of liver specimens at the end of four weeks showed increased fat deposition in the liver of animals fed

Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.

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Fuhrmeister, Jessica; Zota, Annika; Sijmonsma, Tjeerd P; Seibert, Oksana; Cıngır, Şahika; Schmidt, Kathrin; Vallon, Nicola; de Guia, Roldan M; Niopek, Katharina; Berriel Diaz, Mauricio; Maida, Adriano; Blüher, Matthias; Okun, Jürgen G; Herzig, Stephan; Rose, Adam J

2016-06-01

Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Detection of driver metabolites in the human liver metabolic network using structural controllability analysis

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2014-01-01

Background Abnormal states in human liver metabolism are major causes of human liver diseases ranging from hepatitis to hepatic tumor. The accumulation in relevant data makes it feasible to derive a large-scale human liver metabolic network (HLMN) and to discover important biological principles or drug-targets based on network analysis. Some studies have shown that interesting biological phenomenon and drug-targets could be discovered by applying structural controllability analysis (which is a newly prevailed concept in networks) to biological networks. The exploration on the connections between structural controllability theory and the HLMN could be used to uncover valuable information on the human liver metabolism from a fresh perspective. Results We applied structural controllability analysis to the HLMN and detected driver metabolites. The driver metabolites tend to have strong ability to influence the states of other metabolites and weak susceptibility to be influenced by the states of others. In addition, the metabolites were classified into three classes: critical, high-frequency and low-frequency driver metabolites. Among the identified 36 critical driver metabolites, 27 metabolites were found to be essential; the high-frequency driver metabolites tend to participate in different metabolic pathways, which are important in regulating the whole metabolic systems. Moreover, we explored some other possible connections between the structural controllability theory and the HLMN, and find that transport reactions and the environment play important roles in the human liver metabolism. Conclusion There are interesting connections between the structural controllability theory and the human liver metabolism: driver metabolites have essential biological functions; the crucial role of extracellular metabolites and transport reactions in controlling the HLMN highlights the importance of the environment in the health of human liver metabolism. PMID:24885538

Nonalcoholic Fatty Liver Disease: Prevalence, Influence on Age and Sex, and Relationship with Metabolic Syndrome and Insulin Resistance

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Hui-Yun Cheng

2013-12-01

Conclusion: Fatty liver can be considered as the hepatic consequence of metabolic syndrome, specifically IR. There is a high prevalence of metabolic syndrome and fatty liver among the elderly population. Metabolic disorders are closely related to fatty liver; moreover, fatty liver appears to be a good predictor for the clustering of risk factors for metabolic syndrome.

Involvement of hepatic xenobiotic related genes in bromadiolone resistance in wild Norway rats, Rattus norvegicus (Berk.)

DEFF Research Database (Denmark)

Markussen, Mette Drude; Heiberg, Ann-Charlotte; Alsbo, Carsten

2007-01-01

To examine the role of xenobiotic relevant genes in bromadiolone resistance in wild Norway rats (Rattus norvegicus) we compared the constitutive liver gene expression and expression upon bromadiolone administration in bromadiolone resistant and anticoagulant susceptible female rats using a LNA...... expressed in resistant than susceptible rats upon bromadiolone exposure. To establish how bromadiolone affected xenobiotic gene expression in the two strains we compared bromadiolone expression profiles to saline profiles of both strains. Bromadiolone mediated significant up-regulation of Cyp2e1 and Cyp3a3...... expression in the resistant rats whereas the rodenticide conferred down-regulation of Cyp2e1, Cyp3a3 and Gpox1 and induction of Cyp2c12 expression in susceptible rats. Cyp2c13 and Cyp3a2 expression were markedly suppressed in both strains upon treatment. This suggests that xenobiotic relevant enzymes play...

Intracerebroventricular ghrelin treatment affects lipid metabolism in liver of rainbow trout (Oncorhynchus mykiss).

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Velasco, Cristina; Librán-Pérez, Marta; Otero-Rodiño, Cristina; López-Patiño, Marcos A; Míguez, Jesús M; Soengas, José L

2016-03-01

We aimed to elucidate in rainbow trout (Oncorhynchus mykiss) the effects of central ghrelin (GHRL) treatment on the regulation of liver lipid metabolism, and the possible modulatory effect of central GHRL treatment on the simultaneous effects of raised levels of oleate. Thus, we injected intracerebroventricularly (ICV) rainbow trout GHRL in the presence or absence of oleate and evaluated in liver variables related to lipid metabolism. Oleate treatment elicited in liver of rainbow trout decreased lipogenesis and increased oxidative capacity in agreement with previous studies. Moreover, as demonstrated for the first time in fish in the present study, GHRL also acts centrally modulating lipid metabolism in liver, resulting in increased potential for lipogenesis and decreased potential for fatty acid oxidation, i.e. the converse effects to those elicited by central oleate treatment. The simultaneous treatment of GHRL and oleate confirmed these counteractive effects. Thus, the nutrient sensing mechanisms present in hypothalamus, particularly those involved in sensing of fatty acid, are involved in the control of liver energy metabolism in fish, and this control is modulated by the central action of GHRL. These results give support to the notion of hypothalamus as an integrative place for the regulation of peripheral energy metabolism in fish. Copyright © 2016 Elsevier Inc. All rights reserved.

HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology.

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Berndt, Nikolaus; Bulik, Sascha; Wallach, Iwona; Wünsch, Tilo; König, Matthias; Stockmann, Martin; Meierhofer, David; Holzhütter, Hermann-Georg

2018-06-19

The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).

Chemical carcinogenesis in feral fish: uptake, activation, and detoxication of organic xenobiotics

International Nuclear Information System (INIS)

Varanasi, U.; Stein, J.E.; Nishimoto, M.; Reichert, W.L.; Collier, T.K.

1987-01-01

The high prevalance of liver neoplasms in English sole (Parophrys vetulus) and substantially lower prevalence of neoplasms in a closely related species, starry flounder (Platichthys stellatus) captured from industrialized waterways, provide a unique opportunity to compare biochemical processes involved in chemical carcinogenesis in feral fish species. Because levels of aromatic hydrocarbons (AHs) in urban sediments are correlated with prevalences of liver neoplasms in English sole, the authors have initiated detailed studies to evaluate the effects of endogenous and exogenous factors on uptake, activation and detoxication of carcinogenic AHs, such as benzo[a]pyrene (BaP), using spectroscopic, chromatographic, and radiometric techniques. The results obtained thus far show that sole readily takes up AHs associated with sediment from urban areas and that the presence of other xenobiotics, such as PCBs, in sediment increases tissue concentrations of BaP metabolites. Extensive metabolism of BaP occurred whether sole was exposed to this AH via sediment, per os, or intraperitoneally. Substantial modification of hepatic DNA occurred and persisted for a period of 2-4 weeks after a single exposure to BaP. The level of covalent binding of BaP intermediates to hepatic DNA was 10-fold higher in juvenile than adult sole and 90-fold higher in juvenile sole than in Sprague-Dawley rat, a species which is resistant to BaP-induced hepatocarcinogenesis. These results, along with the authors findings that hepatic GST activity in flounder was two times higher than in sole, demonstrate that microsomal metabolism of BaP does not accurately reflect the differences in the ability of these fish to form BaP-DNA adducts in vivo and also suggest that detoxication of reactive intermediates is an important factor in determining the levels of DNA modification by AHs and resulting toxic effects in feral fish

Metabolism of 1-[14C]nitropyrene in isolated perfused rat livers

International Nuclear Information System (INIS)

Bond, J.A.; Medinsky, M.A.; Dutcher, J.S.

1984-01-01

1-Nitropyrene (1-NP), a constituent of diesel exhaust, is carcinogenic to rats and is a bacterial and mammalian mutagen. Biliary and fecal excretion of 1-NP metabolites are the major routes of excretion in rats, suggesting that hepatic metabolism plays a dominant role in determining the biological fate of 1-NP. The purpose of this investigation was to quantitate 1-[14C]NP metabolites formed in isolated perfused rat livers and excreted in bile from rats. Perfused rat livers displayed a capacity for oxidation, reduction, acetylation, and conjugation of 1-NP (or its metabolites). Reduction of 1-NP followed by N-acetylation was the major metabolic pathway observed in the perfused livers. Acetylaminopyrene (AAP) was the major metabolite detected, with total quantities (150 nmol) accounting for about 60% of the total 1-[14C]NP dose (258 nmol) added to the perfusate. Considerably smaller quantities of aminopyrene and hydroxynitropyrenes were also detected. Livers perfused with 1-[14C]NP excreted about 36 nmol equivalents of 1-[14C]NP (12% of the total 1-NP dose) in bile after 60 min. Some of the biliary metabolites were tentatively identified as metabolites of the mercapturic acid pathway. The spectrum of biliary metabolites was qualitatively identical to that seen in bile from intact rats. Quantities of 14C covalently bound to hepatic macromolecules from perfused livers were 0.4 nmol 1-NP eq/g liver. The data from this study indicate that the liver may be an important site for metabolism of 1-NP

Metabolism of six CYP probe substrates in fetal hepatocytes

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Abdul Naveed Shaik

2016-06-01

Full Text Available Cytochrome P-450 (CYP are the most common drug metabolizing enzymes and are abundantly expressed in liver apart from kidney, lungs, intestine, brain etc. Their expression levels change with physiological conditions and disease states. The expression of these CYPs is less in human foetus and neonates compared to adults, which results in lower clearance of xenobiotics in infants and neonates compared to adults. Hepatocytes are the cells which are largely used to study these CYPs. We have isolated hepatocytes from aborted foetus to study the metabolism of six probe substrates: phenacetin, diclofenac, S-mephenytoin, dextromethorphan, nifedipine and testosterone. The results obtained show the expression of various CYPs (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4 in human foetus and their involvement in metabolism of CYP probe substrates.

Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation.

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Cordes, Henrik; Thiel, Christoph; Baier, Vanessa; Blank, Lars M; Kuepfer, Lars

2018-01-01

Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis , which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future.

Apoptosis and Necrosis in the Liver

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Guicciardi, Maria Eugenia; Malhi, Harmeet; Mott, Justin L.; Gores, Gregory J.

2013-01-01

Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of “programmed” necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article. PMID:23720337

Current knowledge of detoxification mechanisms of xenobiotic in honey bees.

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Gong, Youhui; Diao, Qingyun

2017-01-01

The western honey bee Apis mellifera is the most important managed pollinator species in the world. Multiple factors have been implicated as potential causes or factors contributing to colony collapse disorder, including honey bee pathogens and nutritional deficiencies as well as exposure to pesticides. Honey bees' genome is characterized by a paucity of genes associated with detoxification, which makes them vulnerable to specific pesticides, especially to combinations of pesticides in real field environments. Many studies have investigated the mechanisms involved in detoxification of xenobiotics/pesticides in honey bees, from primal enzyme assays or toxicity bioassays to characterization of transcript gene expression and protein expression in response to xenobiotics/insecticides by using a global transcriptomic or proteomic approach, and even to functional characterizations. The global transcriptomic and proteomic approach allowed us to learn that detoxification mechanisms in honey bees involve multiple genes and pathways along with changes in energy metabolism and cellular stress response. P450 genes, is highly implicated in the direct detoxification of xenobiotics/insecticides in honey bees and their expression can be regulated by honey/pollen constitutes, resulting in the tolerance of honey bees to other xenobiotics or insecticides. P450s is also a key detoxification enzyme that mediate synergism interaction between acaricides/insecticides and fungicides through inhibition P450 activity by fungicides or competition for detoxification enzymes between acaricides. With the wide use of insecticides in agriculture, understanding the detoxification mechanism of insecticides in honey bees and how honeybees fight with the xenobiotis or insecticides to survive in the changing environment will finally benefit honeybees' management.

A20 modulates lipid metabolism and energy production to promote liver regeneration.

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Scott M Damrauer

2011-03-01

Full Text Available Liver regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-κB inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice.We performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20 and rAd.βgalactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-κB, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV.This Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid metabolism, and down-regulated inflammation. These findings

Assessment of metabolic stability using the rainbow trout (Oncorhynchus mykiss) liver S9 fraction

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Standard protocols are given for assessing metabolic stability in rainbow trout using the liver S9 fraction. These protocols describe the isolation of S9 fractions from trout livers, evaluation of metabolic stability using a substrate depletion approach, and expression of the res...

Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery.

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Kizawa, Hideki; Nagao, Eri; Shimamura, Mitsuru; Zhang, Guangyuan; Torii, Hitoshi

2017-07-01

The liver plays a central role in metabolism. Although many studies have described in vitro liver models for drug discovery, to date, no model has been described that can stably maintain liver function. Here, we used a unique, scaffold-free 3D bio-printing technology to construct a small portion of liver tissue that could stably maintain drug, glucose, and lipid metabolism, in addition to bile acid secretion. This bio-printed normal human liver tissue maintained expression of several kinds of hepatic drug transporters and metabolic enzymes that functioned for several weeks. The bio-printed liver tissue displayed glucose production via cAMP/protein kinase A signaling, which could be suppressed with insulin. Bile acid secretion was also observed from the printed liver tissue, and it accumulated in the culture medium over time. We observed both bile duct and sinusoid-like structures in the bio-printed liver tissue, which suggested that bile acid secretion occurred via a sinusoid-hepatocyte-bile duct route. These results demonstrated that our bio-printed liver tissue was unique, because it exerted diverse liver metabolic functions for several weeks. In future, we expect our bio-printed liver tissue to be applied to developing new models that can be used to improve preclinical predictions of long-term toxicity in humans, generate novel targets for metabolic liver disease, and evaluate biliary excretion in drug development.

Heart over mind: metabolic control of white adipose tissue and liver.

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Nakamura, Michinari; Sadoshima, Junichi

2014-12-01

Increasing evidence suggests that the heart controls the metabolism of peripheral organs. Olson and colleagues previously demonstrated that miR‐208a controls systemic energy homeostasis through the regulation of MED13 in cardiomyocytes (Grueter et al, 2012). In their follow‐up study in this issue of EMBO Molecular Medicine, white adipose tissue (WAT) and liver are identified as the physiological targets of cardiac MED13 signaling, most likely through cardiac‐derived circulating factors, which boost energy consumption by upregulating metabolic gene expression and increasing mitochondrial numbers (Baskin et al, 2014). In turn, increased energy expenditure in WAT and the liver confers leanness. These findings strengthen the evidence of metabolic crosstalk between the heart and peripheral tissues through cardiokines and also set the stage for the development of novel treatments for metabolic syndrome.

Depleted uranium: Metabolic disruptor?; Uranium appauvri: perturbateur metabolique?

Energy Technology Data Exchange (ETDEWEB)

Souidi, Maamar; Dublineau, Isabelle; Lestaevel, Philippe [Institut de Radioprotection et de Surete Nucleaire - IRSN, Direction de la radioprotection de l' homme, Laboratoire de radiotoxicologie experimentale, Service de radiobiologie et d' epidemiologie, BP 17, 92262 Fontenay-aux-Roses cedex (France)

2011-11-15

The presence of uranium in the environment can lead to long-term contamination of the food chain and of water intended for human consumption and thus raises many questions about the scientific and societal consequences of this exposure on population health. Although the biological effects of chronic low-level exposure are poorly understood, results of various recent studies show that contamination by depleted uranium (DU) induces subtle but significant biological effects at the molecular level in organs including the brain, liver, kidneys and testicles. For the first time, it has been demonstrated that DU induces effects on several metabolic pathways, including those metabolizing vitamin D, cholesterol, steroid hormones, acetylcholine and xenobiotics. This evidence strongly suggests that DU might well interfere with many metabolic pathways. It might thus contribute, together with other man-made substances in the environment, to increased health risks in some regions. (authors)

Estimation of liver glucose metabolism after refeeding

International Nuclear Information System (INIS)

Rognstad, R.

1987-01-01

Refeeding or infusing glucose to rats fasted for 24 hr or more causes rapid liver glycogen synthesis, the carbon source now considered to be largely from gluconeogenesis. While substrate cycling between plasma glucose and liver glucose-6P is known to occur, this cycling has apparently been ignored when calculations are made of % contribution of direct and indirect pathways to liver glycogen synthesis, or when hepatic glucose output is calculated from glucose turnover minus the glucose infusion rate. They show that, isotopically, an estimate of the fluxes of liver glucokinase and glucose-6-phosphatase is required to quantitate sources of carbon for liver glycogen synthesis, and to measure hepatic glucose output (or uptake). They propose a method to estimate these fluxes, involving a short infusion of a 14 C labelled gluconeogenic precursor plus (6T)glucose, with determination of isotopic yields in liver glycogen and total glucose. Given also the rate of liver glycogen synthesis, this procedure permits the estimation of net gluconeogenesis and hepatic glucose output or uptake. Also, in vitro evidence against the notion of a drastic zonation of liver carbohydrate metabolism is presented, e.g. raising the glucose concentration from 10 to 25 mM increases the 14 C yield from H 14 CO 3 - in lactate, with the increased pyruvate kinase flux and decreased gluconeogenesis occurring in the same cell type, not opposing pathways in different hepatocyte types (as has been postulated by some to occur in vivo after refeeding

Liver enzymes and markers of inflammation in Nigerian adults with metabolic syndrome

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Udenze Ifeoma Christiana

2015-01-01

Full Text Available Aims and objectives: The aim of this study is to determine the plasma levels of the liver enzymes alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, gamma-glutamyl transferase (GGT, and lactate dehydrogenase (LDH in people with metabolic syndrome and to determine the association between the liver enzymes and obesity, insulin resistance, interleukin 6 (IL-6, and C-reactive protein (CRP in adult Nigerians with metabolic syndrome. Materials and Methods: This was a case control study of 50 adult men and women with metabolic syndrome, and 50 age- and sex-matched males and females without metabolic syndrome. Metabolic syndrome was defined based on the National Cholesterol Education Program (NCEP-Adult Treatment Panel III (ATPIII criteria. Written informed consent was obtained from the participants. Sociodemographic and clinical data were collected using a structured questionnaire. Venous blood was collected after an overnight fast. The ethics committee of the Lagos University Teaching Hospital in Lagos, Nigeria, approved the study protocol. Comparison of continuous variables was done using the student′s t-test. Regression and correlation analysis were used to determine the associations between variables. Statistical significance was set at P < 0.05. Results: There was a statistically significant increase in the liver enzymes ALP (P = 0.031, ALT (P = 0.019, and GGT (P = 0.037, as well as in the inflammatory markers CRP (P = 0.019 and the cytokine IL-6 (P = 0.040 between the two study groups. ALP and ALT showed significant correlation with waist circumference, BMI, fasting insulin, and waist/hip ratio (P < 0.05. Multivariate regression also identified ALT, AST, and ALP to be associated with IL-6 and CRP (P < 0.05. Conclusion: Liver enzyme levels were increased in metabolic syndrome and associated with obesity, fasting insulin, and CRP. Elevated liver enzymes may indicate dysmetabolism and increased

Liver fat content in type 2 diabetes: relationship with hepatic perfusion and substrate metabolism

NARCIS (Netherlands)

Rijzewijk, Luuk J.; van der Meer, Rutger W.; Lubberink, Mark; Lamb, Hildo J.; Romijn, Johannes A.; de Roos, Albert; Twisk, Jos W.; Heine, Robert J.; Lammertsma, Adriaan A.; Smit, Johannes W. A.; Diamant, Michaela

2010-01-01

Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have indicated that increased liver fat may impair hepatic perfusion and metabolism. The aim of the current study was to

Risk assessment of silica nanoparticles on liver injury in metabolic syndrome mice induced by fructose.

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Li, Jianmei; He, Xiwei; Yang, Yang; Li, Mei; Xu, Chenke; Yu, Rong

2018-07-01

This study aims to assess the effects and the mechanisms of silica nanoparticles (SiNPs) on hepatotoxicity in both normal and metabolic syndrome mouse models induced by fructose. Here, we found that SiNPs exposure lead to improved insulin resistance in metabolic syndrome mice, but markedly worsened hepatic ballooning, inflammation infiltration, and fibrosis. Moreover, SiNPs exposure aggravated liver injury in metabolic syndrome mice by causing serious DNA damage. Following SiNPs exposure, liver superoxide dismutase and catalase activities in metabolic syndrome mice were stimulated, which is accompanied by significantly increased malondialdehyde and 8-hydroxy-2-deoxyguanosine levels as compared to normal mice. Scanning electron microscope (SEM) revealed that SiNPs were more readily deposited in the liver mitochondria of metabolic syndrome mice, resulting in more severe mitochondrial injury as compared to normal mice. We speculated that SiNPs-induced mitochondrial injury might be the cause of hepatic oxidative stress, which further lead to a series of liver lesions as observed in mice following SiNPs exposure. Based on these results, it is likely that SiNPs will increase the risk and severity of liver disease in individuals with metabolic syndrome. Therefore, SiNPs should be used cautiously in food additives and clinical settings. Copyright © 2018 Elsevier B.V. All rights reserved.

Sox17 regulates liver lipid metabolism and adaptation to fasting.

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Samuel Rommelaere

Full Text Available Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/- mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.

Immunosuppressive and postoperative effects of orthotopic liver transplantation on bone metabolism

NARCIS (Netherlands)

Guichelaar, MMJ; Malinchoc, M; Sibonga, J; Clarke, BL; Hay, JE

Bone loss occurs early after orthotopic liver transplantation (OLT) in all liver transplant recipients and leads to postoperative fractures, especially in cholestatic patients with the lowest bone mass. Little is known about the underlying changes in bone metabolism after OLT or about the etiology

Chlamydia pneumoniae acute liver infection affects hepatic cholesterol and triglyceride metabolism in mice.

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Marangoni, Antonella; Fiorino, Erika; Gilardi, Federica; Aldini, Rita; Scotti, Elena; Nardini, Paola; Foschi, Claudio; Donati, Manuela; Montagnani, Marco; Cevenini, Monica; Franco, Placido; Roda, Aldo; Crestani, Maurizio; Cevenini, Roberto

2015-08-01

Chlamydia pneumoniae has been linked to atherosclerosis, strictly associated with hyperlipidemia. The liver plays a central role in the regulation of lipid metabolism. Since in animal models C. pneumoniae can be found at hepatic level, this study aims to elucidate whether C. pneumoniae infection accelerates atherosclerosis by affecting lipid metabolism. Thirty Balb/c mice were challenged intra-peritoneally with C. pneumoniae elementary bodies and thirty with Chlamydia trachomatis, serovar D. Thirty mice were injected with sucrose-phosphate-glutamate buffer, as negative controls. Seven days after infection, liver samples were examined both for presence of chlamydia and expression of genes involved in inflammation and lipid metabolism. C. pneumoniae was isolated from 26 liver homogenates, whereas C. trachomatis was never re-cultivated (P triglycerides levels compared both with negative controls (P metabolism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Transferrin metabolism in alcoholic liver disease

International Nuclear Information System (INIS)

Potter, B.J.; Chapman, R.W.; Nunes, R.M.; Sorrentino, D.; Sherlock, S.

1985-01-01

The metabolism of transferrin was studied using purified 125 I-labeled transferrin in 11 alcoholic patients; six with fatty liver and five with cirrhosis. Six healthy subjects whose alcohol intake was les than 40 gm daily were studied as a control group. There were no significant differences in the mean fractional catabolic rate and plasma volume in the alcoholic groups when compared with control subjects. A significantly decreased mean serum transferrin concentration was found in the alcoholic cirrhotic patients (1.8 +/- 0.3 gm per liter vs. 2.9 +/- 0.2; p less than 0.01), resulting from diminished total body synthesis (0.9 +/- 0.2 mg per kg per hr vs. 1.8 +/- 0.2; p less than 0.01). In contrast, in the patients with alcoholic fatty liver, the mean total body transferrin synthesis (2.4 +/- 0.3 mg per kg per hr) was significantly increased when compared with controls (p less than 0.05). For all the alcoholic patients, the serum transferrin correlated with transferrin synthesis (r = +0.70; p less than 0.01) but the serum iron did not. These results suggest that, in alcoholic cirrhosis, transferrin synthesis is decreased, probably reflecting diminished synthetic capacity by the liver. In contrast, in patients with alcoholic fatty liver, transferrin turnover is accelerated

Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular CarcinomaSummary

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Zeribe Chike Nwosu

2017-09-01

Full Text Available Background & Aims: Cancer cells rely on metabolic alterations to enhance proliferation and survival. Metabolic gene alterations that repeatedly occur in liver cancer are largely unknown. We aimed to identify metabolic genes that are consistently deregulated, and are of potential clinical significance in human hepatocellular carcinoma (HCC. Methods: We studied the expression of 2,761 metabolic genes in 8 microarray datasets comprising 521 human HCC tissues. Genes exclusively up-regulated or down-regulated in 6 or more datasets were defined as consistently deregulated. The consistent genes that correlated with tumor progression markers (ECM2 and MMP9 (Pearson correlation P < .05 were used for Kaplan-Meier overall survival analysis in a patient cohort. We further compared proteomic expression of metabolic genes in 19 tumors vs adjacent normal liver tissues. Results: We identified 634 consistent metabolic genes, ∼60% of which are not yet described in HCC. The down-regulated genes (n = 350 are mostly involved in physiologic hepatocyte metabolic functions (eg, xenobiotic, fatty acid, and amino acid metabolism. In contrast, among consistently up-regulated metabolic genes (n = 284 are those involved in glycolysis, pentose phosphate pathway, nucleotide biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, proton transport, membrane lipid, and glycan metabolism. Several metabolic genes (n = 434 correlated with progression markers, and of these, 201 predicted overall survival outcome in the patient cohort analyzed. Over 90% of the metabolic targets significantly altered at the protein level were similarly up- or down-regulated as in genomic profile. Conclusions: We provide the first exposition of the consistently altered metabolic genes in HCC and show that these genes are potentially relevant targets for onward studies in preclinical and clinical contexts. Keywords: Liver Cancer, HCC, Tumor Metabolism

Diagnosis and management of non-alcoholic fatty liver disease and related metabolic disorders: Consensus statement from the Study Group of Liver and Metabolism, Chinese Society of Endocrinology

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Gao, Xin; Fan, Jian-Gao

2013-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries, affecting 20%–33% of the general population. Large population-based surveys in China indicate a prevalence of approximately 15%–30%. Worldwide, including in China, the prevalence of NAFLD has increased rapidly in parallel with regional trends of obesity, type2 diabetes and metabolic syndrome. In addition, NAFLD has contributed significantly to increased overall, as well as cardiovascular and liver-related, mortality in the general population. In view of rapid advances in research into NAFLD in recent years, this consensus statement provides a brief update on the progress in the field and suggests preferred approaches for the comprehensive management of NAFLD and its related metabolic diseases. PMID:23560695

Mechanistic and quantitative aspects of liver tumour promotion in mice

NARCIS (Netherlands)

Ravenzwaay, van B.

1988-01-01

A variety of xenobiotic compounds is known to induce characteristic changes in the livers of laboratory animals. These changes include enlargement of the liver, usually as a result of cell enlargement (hypertrophy) or Increased cell replication (hyperplasia), induction of drugmetabolizing enzymes

Dietary taurine alters ascorbic acid metabolism in rats fed diets containing polychlorinated biphenyls.

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Mochizuki, H; Oda, H; Yokogoshi, H

2000-04-01

The effect of dietary taurine on ascorbic acid metabolism and hepatic drug-metabolizing enzymes was investigated in rats fed diets containing polychlorinated biphenyls (PCB) to determine whether taurine has an adaptive and protective function in xenobiotic-treated animals. Young male Wistar rats (60 g) were fed diets containing 0 or 0.2 g/kg diet PCB with or without 30 g/kg diet of taurine for 14 d. The rats fed the PCB-containing diets had greater liver weight, higher ascorbic acid concentrations in the liver and spleen and greater hepatic cytochrome P-450 contents than control rats that were not treated with PCB (P ascorbic acid excretion was enhanced, and serum cholesterol concentration (especially HDL-cholesterol) was significantly elevated compared with those in control rats. Dietary taurine significantly potentiated the increases in the urinary excretion of ascorbic acid and the rise in the levels of cytochrome P-450 which were caused by PCB treatment. On the other hand, the supplementation of taurine to control diet did not alter these variables. Taurine may enhance the hepatic drug-metabolizing systems, leading to the stimulation of the ascorbic acid metabolism in rats fed diets containing PCB.

Relationship between hepatocellular carcinoma, metabolic syndrome and non-alcoholic fatty liver disease: which clinical arguments?

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Rosmorduc, Olivier

2013-05-01

Obesity and the metabolic syndrome are growing epidemics associated with an increased risk for many types of cancer. In the liver, inflammatory and angiogenic changes due to insulin resistance and fatty liver disease are associated with an increased incidence of liver cancer. Regardless of underlying liver disease, cirrhosis remains the most important risk factor for hepatocellular carcinoma (HCC) although are cases of HCC arising without cirrhosis raise the possibility of a direct carcinogenesis secondary to Non-alcoholic Fatty Liver Disease (NAFLD). Moreover, metabolic syndrome and its different features may also increase the risk of HCC in the setting of chronic liver diseases of other causes such as viral hepatitis or alcohol abuse. Taking into account all these data, it is necessary to better determine the risk of developing HCC in patients with metabolic syndrome to improve the screening guidelines and develop prophylactic treatments in this setting. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Humanizing π-class glutathione S-transferase regulation in a mouse model alters liver toxicity in response to acetaminophen overdose.

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Matthew P Vaughn

Full Text Available Glutathione S-transferases (GSTs metabolize drugs and xenobiotics. Yet despite high protein sequence homology, expression of π-class GSTs, the most abundant of the enzymes, varies significantly between species. In mouse liver, hepatocytes exhibit high mGstp expression, while in human liver, hepatocytes contain little or no hGSTP1 mRNA or hGSTP1 protein. π-class GSTs are known to be critical determinants of liver responses to drugs and toxins: when treated with high doses of acetaminophen, mGstp1/2+/+ mice suffer marked liver damage, while mGstp1/2-/- mice escape liver injury.To more faithfully model the contribution of π-class GSTs to human liver toxicology, we introduced hGSTP1, with its exons, introns, and flanking sequences, into the germline of mice carrying disrupted mGstp genes. In the resultant hGSTP1+mGstp1/2-/- strain, π-class GSTs were regulated differently than in wild-type mice. In the liver, enzyme expression was restricted to bile duct cells, Kupffer cells, macrophages, and endothelial cells, reminiscent of human liver, while in the prostate, enzyme production was limited to basal epithelial cells, reminiscent of human prostate. The human patterns of hGSTP1 transgene regulation were accompanied by human patterns of DNA methylation, with bisulfite genomic sequencing revealing establishment of an unmethylated CpG island sequence encompassing the gene promoter. Unlike wild-type or mGstp1/2-/- mice, when hGSTP1+mGstp1/2-/- mice were overdosed with acetaminophen, liver tissues showed limited centrilobular necrosis, suggesting that π-class GSTs may be critical determinants of toxin-induced hepatocyte injury even when not expressed by hepatocytes.By recapitulating human π-class GST expression, hGSTP1+mGstp1/2-/- mice may better model human drug and xenobiotic toxicology.

Dendrobium nobile Lindl. alkaloids regulate metabolism gene expression in livers of mice.

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Xu, Yun-Yan; Xu, Ya-Sha; Wang, Yuan; Wu, Qin; Lu, Yuan-Fu; Liu, Jie; Shi, Jing-Shan

2017-10-01

In our previous studies, Dendrobium nobile Lindl. alkaloids (DNLA) has been shown to have glucose-lowering and antihyperlipidaemia effects in diabetic rats, in rats fed with high-fat diets, and in mice challenged with adrenaline. This study aimed to examine the effects of DNLA on the expression of glucose and lipid metabolism genes in livers of mice. Mice were given DNLA at doses of 10-80 mg/kg, po for 8 days, and livers were removed for total RNA and protein isolation to perform real-time RT-PCR and Western blot analysis. Dendrobium nobile Lindl. alkaloids increased PGC1α at mRNA and protein levels and increased glucose metabolism gene Glut2 and FoxO1 expression. DNLA also increased the expression of fatty acid β-oxidation genes Acox1 and Cpt1a. The lipid synthesis regulator Srebp1 (sterol regulatory element-binding protein-1) was decreased, while the lipolysis gene ATGL was increased. Interestingly, DNLA increased the expression of antioxidant gene metallothionein-1 and NADPH quinone oxidoreductase-1 (Nqo1) in livers of mice. Western blot on selected proteins confirmed these changes including the increased expression of GLUT4 and PPARα. DNLA has beneficial effects on liver glucose and lipid metabolism gene expressions, and enhances the Nrf2-antioxidant pathway gene expressions, which could play integrated roles in regulating metabolic disorders. © 2017 Royal Pharmaceutical Society.

Alginate Immobilization of Metabolic Enzymes (AIME) for High ...

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Alginate Immobilization of Metabolic Enzymes (AIME) for High-Throughput Screening Assays DE DeGroot, RS Thomas, and SO SimmonsNational Center for Computational Toxicology, US EPA, Research Triangle Park, NC USAThe EPA’s ToxCast program utilizes a wide variety of high-throughput screening (HTS) assays to assess chemical perturbations of molecular and cellular endpoints. A key criticism of using HTS assays for toxicity assessment is the lack of xenobiotic metabolism (XM) which precludes both metabolic detoxification as well as bioactivation of chemicals tested in vitro thereby mischaracterizing the potential risk posed by these chemicals. To address this deficiency, we have developed an extracellular platform to retrofit existing HTS assays with XM activity. This platform utilizes the S9 fraction of liver homogenate encapsulated in an alginate gel network which reduces the cytotoxicity caused by direct addition of S9 to cells in culture. Alginate microspheres containing encapsulated human liver S9 were cross-linked to solid supports extending from a 96-well plate lid and were assayed using a pro-luciferin substrate specific for CYP3A4 (IPA). We demonstrate that S9 was successfully encapsulated and remained enzymatically active post-encapsulation with 5-10X the CYP3A4 activity as compared to 1 µg solubilized human liver S9. Ketoconazole, a known inhibitor of human CYP3A4, inhibited CYP3A4 activity in a concentration-dependent manner (IC50: 0.27 µM) and inhibiti

Interplay between FGF21 and insulin action in the liver regulates metabolism

DEFF Research Database (Denmark)

Emanuelli, Brice; Vienberg, Sara G; Smyth, Graham

2014-01-01

gluconeogenesis in these animals. Improvements in blood sugar were due in part to increased glucose uptake in brown fat, browning of white fat, and overall increased energy expenditure. These effects were preserved even after removal of the main interscapular brown fat pad. In contrast to its retained effects...... of insulin action in the liver by increasing energy metabolism via activation of brown fat and browning of white fat, but intact liver insulin action is required for FGF21 to control hepatic lipid metabolism....

Prediction of bacterial growth on xenobiotics

DEFF Research Database (Denmark)

Brock, Andreas Libonati; Kästner, Matthias; Trapp, Stefan

2016-01-01

to attain predictions closer to the experimentally observed yields [3]. However, this knowledge is seldom known for xenobiotics in the environment but is needed to assess the turnover leading to biomass production, i.e. for sludge production or biogenic residues. The objectives of the present study were...... method, we evaluated it with both simple substrates (e.g. acetate, methanol, and glyoxylate) and xenobiotics (e.g 2,4-D, linuron, carbofuran, carbon tetrachloride, and toluene). Experimental data for the simple substrates were taken from [4], for xenobiotics from [6] and own experimental data. For simple...... substrates, our approach predicts yields close to experimental values and also for xenobiotics the yield predictions for most of the compounds are close to the experimentally obtained values.Overall, with our method we were able to obtain yield predictions close to experimental values with a minimum of input...

Xenobiotic metabolism capacities of human skin in comparison with a 3D-epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: phase II enzymes.

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Götz, Christine; Pfeiffer, Roland; Tigges, Julia; Ruwiedel, Karsten; Hübenthal, Ulrike; Merk, Hans F; Krutmann, Jean; Edwards, Robert J; Abel, Josef; Pease, Camilla; Goebel, Carsten; Hewitt, Nicola; Fritsche, Ellen

2012-05-01

The 7th Amendment to the EU Cosmetics Directive prohibits the use of animals in cosmetic testing for certain endpoints, such as genotoxicity. Therefore, skin in vitro models have to replace chemical testing in vivo. However, the metabolic competence neither of human skin nor of alternative in vitro models has so far been fully characterized, although skin is the first-pass organ for accidentally or purposely (cosmetics and pharmaceuticals) applied chemicals. Thus, there is an urgent need to understand the xenobiotic-metabolizing capacities of human skin and to compare these activities to models developed to replace animal testing. We have measured the activity of the phase II enzymes glutathione S-transferase, UDP-glucuronosyltransferase and N-acetyltransferase in ex vivo human skin, the 3D epidermal model EpiDerm 200 (EPI-200), immortalized keratinocyte-based cell lines (HaCaT and NCTC 2544) and primary normal human epidermal keratinocytes. We show that all three phase II enzymes are present and highly active in skin as compared to phase I. Human skin, therefore, represents a more detoxifying than activating organ. This work systematically compares the activities of three important phase II enzymes in four different in vitro models directly to human skin. We conclude from our studies that 3D epidermal models, like the EPI-200 employed here, are superior over monolayer cultures in mimicking human skin xenobiotic metabolism and thus better suited for dermatotoxicity testing. © 2012 John Wiley & Sons A/S.

Metabolic syndrome and risk factors for non-alcoholic fatty liver disease

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Mônica Rodrigues de Araújo Souza

2012-03-01

Full Text Available CONTEXT: Non-alcoholic fatty liver disease (NAFLD, hepatic manifestation of metabolic syndrome, has been considered the most common liver disease nowadays, which is also the most frequent cause of elevated transaminases and cryptogenic cirrhosis. The greatest input of fatty acids into the liver and consequent increased beta-oxidation contribute to the formation of free radicals, release of inflammatory cytokines and varying degrees of hepatocytic aggression, whose histological expression may vary from steatosis (HS to non-alcoholic steatohepatitis (NASH. The differentiation of these forms is required by the potential risk of progression to cirrhosis and development of hepatocellular carcinoma. OBJECTIVE: To review the literature about the major risk factors for NAFLD in the context of metabolic syndrome, focusing on underlying mechanisms and prevention. METHOD: PubMed, MEDLINE and SciELO data basis analysis was performed to identify studies describing the link between risk factors for metabolic syndrome and NAFLD. A combination of descriptors was used, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, metabolic syndrome and risk factors. At the end, 96 clinical and experimental studies, cohorts, meta-analysis and systematic reviews of great impact and scientific relevance to the topic, were selected. RESULTS: The final analysis of all these data, pointed out the central obesity, type 2 diabetes, dyslipidemia and hypertension as the best risk factors related to NAFLD. However, other factors were highlighted, such as gender differences, ethnicity, genetic factors and the role of innate immunity system. How these additional factors may be involved in the installation, progression and disease prognosis is discussed. CONCLUSION: Risk factors for NAFLD in the context of metabolic syndrome expands the prospects to 1 recognize patients with metabolic syndrome at high risk for NAFLD, 2 elucidate pathways common to other co-morbidities, 3

Adrenergic Metabolic and Hemodynamic Effects of Octopamine in the Liver

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Adelar Bracht

2013-11-01

Full Text Available The fruit extracts of Citrus aurantium (bitter orange are traditionally used as weight-loss products and as appetite suppressants. A component of these extracts is octopamine, which is an adrenergic agent. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of octopamine on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways and hemodynamics. Octopamine increased glycogenolysis, glycolysis, oxygen uptake, gluconeogenesis and the portal perfusion pressure. Octopamine also accelerated the oxidation of exogenous fatty acids (octanoate and oleate, as revealed by the increase in 14CO2 production derived from 14C labeled precursors. The changes in glycogenolysis, oxygen uptake and perfusion pressure were almost completely abolished by α1-adrenergic antagonists. The same changes were partly sensitive to the β-adrenergic antagonist propranolol. It can be concluded that octopamine accelerates both catabolic and anabolic processes in the liver via adrenergic stimulation. Acceleration of oxygen uptake under substrate-free perfusion conditions also means acceleration of the oxidation of endogenous fatty acids, which are derived from lipolysis. All these effects are compatible with an overall stimulating effect of octopamine on metabolism, which is compatible with its reported weight-loss effects in experimental animals.

Mitochondrial-related proteomic changes during obesity and fasting in mice are greater in the liver than skeletal muscles.

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Nesteruk, Monika; Hennig, Ewa E; Mikula, Michal; Karczmarski, Jakub; Dzwonek, Artur; Goryca, Krzysztof; Rubel, Tymon; Paziewska, Agnieszka; Woszczynski, Marek; Ledwon, Joanna; Dabrowska, Michalina; Dadlez, Michal; Ostrowski, Jerzy

2014-03-01

Although mitochondrial dysfunction is implicated in the pathogenesis of obesity, the molecular mechanisms underlying obesity-related metabolic abnormalities are not well established. We performed mitochondrial quantitative proteomic and whole transcriptome analysis followed by functional annotations within liver and skeletal muscles, using fasted and non-fasted 16- and 48-week-old high-fat diet (HFD)-fed and normal diet-fed (control group) wild-type C56BL/6J mice, and hyperphagic ob/ob and db/db obese mice. Our study identified 1,675 and 704 mitochondria-associated proteins with at least two peptides in liver and muscle, respectively. Of these, 221 liver and 44 muscle proteins were differentially expressed (adjusted p values ≤ 0.05) between control and all obese mice, while overnight fasting altered expression of 107 liver and 35 muscle proteins. In the liver, we distinguished a network of 27 proteins exhibiting opposite direction of expression changes in HFD-fed and hyperphagic mice when compared to control. The network centered on cytochromes P450 3a11 (Cyp3a11) and 4a14 (Cyp4a14), and fructose-bisphosphate aldolase B (Aldob) proteins which bridged proteins cluster involved in Metabolism of xenobiotics with proteins engaged in Fatty acid metabolism and PPAR signaling pathways. Functional annotations revealed that most of the hepatic molecular alterations, which characterized both obesity and fasting, related to different aspects of energy metabolism (such as Fatty acid metabolism, Peroxisome, and PPAR signaling); however, only a limited number of functional annotations could be selected from skeletal muscle data sets. Thus, our comprehensive molecular overview revealed that both obesity and fasting states induce more pronounced mitochondrial proteome changes in the liver than in the muscles.

Metabolic Disturbances in Children with Chronic Liver Disease

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A Rezaeian

2014-04-01

Full Text Available Introduction: Liver disease results in complex pathophysiologic disturbances affecting nutrient digestion, absorption, distribution, storage, and use. This article aimed to present a classification of metabolic disturbances in chronic liver disease in children?   Materials and Methods: In this review study databases including proquest, pubmedcentral, scincedirect, ovid, medlineplus were been searched with keyword words such as” chronic liver disease"  ” metabolic disorder””children” between 1999 to 2014. Finally, 8 related articles have been found.   Results: Metabolic disorder in this population could be categorized in four set: 1carbohydrates, 2proteins,3 fats and 4vitamins. 1 Carbohydrates: Children with CLD are at increased risk for fasting hypoglycemia, because the capacity for glycogen storage and gluconeogenesis is reduced as a result of abnormal hepatocyte function and loss of hepatocyte mass. 2 Proteins: The liver’s capacity for plasma protein synthesis is impaired by reduced substrate availability, impaired hepatocyte function, and increased catabolism. This results in hypoalbuminemia, leading to peripheral edema and contributing to ascites. Reduced synthesis of insulin-like growth factor (IGF-1 and its binding protein IGF-BP3 by the chronically diseased liver results in growth hormone resistance and may contribute to the poor growth observed in these children. 3 Fats: There is increased fat oxidation in children with end-stage liver disease in the fed and fasting states compared with controls, which is probably related to reduced carbohydrate availability. The increased lipolysis results in a decrease in fat stores, which may not be easily replenished in the setting of the fat malabsorption that accompanies cholestasis. Reduced bile delivery to the gut results in impaired fat emulsification, and hence digestion. The products of fat digestion are also poorly absorbed, because bile is also required for micelle formation

Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level.

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Sookoian, Silvia; Castaño, Gustavo O; Scian, Romina; Fernández Gianotti, Tomas; Dopazo, Hernán; Rohr, Cristian; Gaj, Graciela; San Martino, Julio; Sevic, Ina; Flichman, Diego; Pirola, Carlos J

2016-02-01

Extensive epidemiologic studies have shown that cardiovascular disease and the metabolic syndrome (MetS) are associated with serum concentrations of liver enzymes; however, fundamental characteristics of this relation are currently unknown. We aimed to explore the role of liver aminotransferases in nonalcoholic fatty liver disease (NAFLD) and MetS. Liver gene- and protein-expression changes of aminotransferases, including their corresponding isoforms, were evaluated in a case-control study of patients with NAFLD (n = 42), which was proven through a biopsy (control subjects: n = 10). We also carried out a serum targeted metabolite profiling to the glycolysis, gluconeogenesis, and Krebs cycle (n = 48) and an exploration by the next-generation sequencing of aminotransferase genes (n = 96). An in vitro study to provide a biological explanation of changes in the transcriptional level and enzymatic activity of aminotransferases was included. Fatty liver was associated with a deregulated liver expression of aminotransferases, which was unrelated to the disease severity. Metabolite profiling showed that serum aminotransferase concentrations are a signature of liver metabolic perturbations, particularly at the amino acid metabolism and Krebs cycle level. A significant and positive association between systolic hypertension and liver expression levels of glutamic-oxaloacetic transaminase 2 (GOT2) messenger RNA (Spearman R = 0.42, P = 0.03) was observed. The rs6993 located in the 3' untranslated region of the GOT2 locus was significantly associated with features of the MetS, including arterial hypertension [P = 0.028; OR: 2.285 (95% CI: 1.024, 5.09); adjusted by NAFLD severity] and plasma lipid concentrations. In the context of an abnormal hepatic triglyceride accumulation, circulating aminotransferases rise as a consequence of the need for increased reactions of transamination to cope with the liver metabolic derangement that is associated with greater gluconeogenesis and

A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution

DEFF Research Database (Denmark)

Maida, Adriano; Zota, Annika; Sjøberg, Kim Anker

2016-01-01

of impaired glucose homeostasis independently of obesity and food intake. DPD-mediated metabolic inefficiency and improvement of glucose homeostasis were independent of uncoupling protein 1 (UCP1), but required expression of liver-derived fibroblast growth factor 21 (FGF21) in both lean and obese mice. FGF21...... expression and secretion as well as the associated metabolic remodeling induced by DPD also required induction of liver-integrated stress response-driven nuclear protein 1 (NUPR1). Insufficiency of select nonessential amino acids (NEAAs) was necessary and adequate for NUPR1 and subsequent FGF21 induction...... and secretion in hepatocytes in vitro and in vivo. Taken together, these data indicate that DPD promotes improved glucose homeostasis through an NEAA insufficiency-induced liver NUPR1/FGF21 axis....

Fasting augments PCB impact on liver metabolism in anadromous Arctic Char

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Vijayan, M.M.; Aluru, N.; Maule, A.G.; Jorgensen, E.H.

2006-01-01

Anadromous arctic char (Salvelinus alpinus) undertake short feeding migrations to seawater every summer and accumulate lipids, while the rest of the year is spent in fresh water where the accumulated lipid reserves are mobilized. We tested the hypothesis that winter fasting and the associated polychlorinated biphenyls' (PCBs) redistribution from lipid depots to critical tissues impair the liver metabolic capacity in these animals. Char were administered Aroclor 1254 (0, 1, 10, and 100 mg/ kg body mass) orally and maintained for 4 months without feeding to mimic seasonal winter fasting, while fed groups (0 and 100 mg Aroclor 1254/kg) were maintained for comparison. A clear dose-related increase in PCB accumulation and cytochrome P4501A (CYP1A) protein content was observed in the livers of fasted fish. This PCB concentration and CYP1A response with the high dose of Aroclor were 1.5-fold and 3-fold greater in the fasted than in the fed fish, respectively. In fed fish, PCB exposure lowered liver glycogen content, whereas none of the other metabolic indicators were significantly affected. In fasted fish, PCB exposure depressed liver glycogen content and activities of glucose-6-phosphate dehydrogenase, alanine aminotransferase, lactate dehydrogenase, and phosphoenolpyruvate carboxykinase and elevated 3-hydroxyacylcoA dehydrogenase activity and glucocorticoid receptor protein expression. There were no significant impacts of PCB on heat shock protein 70 (hsp70) and hsp90 contents in either fed or fasted fish. Collectively, our study demonstrates that winter emaciation associated with the anadromous lifestyle predisposes arctic char to PCB impact on hepatic metabolism including disruption of the adaptive metabolic responses to extended fasting. ?? 2006 Oxford University Press.

Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

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Oesch, F; Fabian, E; Guth, K; Landsiedel, R

2014-12-01

The exposure of the skin to medical drugs, skin care products, cosmetics, and other chemicals renders information on xenobiotic-metabolizing enzymes (XME) in the skin highly interesting. Since the use of freshly excised human skin for experimental investigations meets with ethical and practical limitations, information on XME in models comes in the focus including non-human mammalian species and in vitro skin models. This review attempts to summarize the information available in the open scientific literature on XME in the skin of human, rat, mouse, guinea pig, and pig as well as human primary skin cells, human cell lines, and reconstructed human skin models. The most salient outcome is that much more research on cutaneous XME is needed for solid metabolism-dependent efficacy and safety predictions, and the cutaneous metabolism comparisons have to be viewed with caution. Keeping this fully in mind at least with respect to some cutaneous XME, some models may tentatively be considered to approximate reasonable closeness to human skin. For dermal absorption and for skin irritation among many contributing XME, esterase activity is of special importance, which in pig skin, some human cell lines, and reconstructed skin models appears reasonably close to human skin. With respect to genotoxicity and sensitization, activating XME are not yet judgeable, but reactive metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the "Overview and Conclusions" section in the end of this review.

Isocaloric high-fat feeding directs hepatic metabolism to handling of nutrient imbalance promoting liver fat deposition

KAUST Repository

Diaz Rua, Ruben; Van Schothorst, E. M.; Keijer, J.; Palou, A.; Oliver, P.

2016-01-01

Background/Objectives: Consumption of fat-rich foods is associated with obesity and related alterations. However, there is a group of individuals, the metabolically obese normal-weight (MONW) subjects, who present normal body weight but have metabolic features characteristic of the obese status, including fat deposition in critical tissues such as liver, recognized as a major cause for the promotion of metabolic diseases. Our aim was to better understand metabolic alterations present in liver of MONW rats applying whole genome transcriptome analysis. Methods: Wistar rats were chronically fed a high-fat diet isocaloric relative to Control animals to avoid the hyperphagia and overweight and to mimic MONW features. Liver transcriptome analysis of both groups was performed. Results: Sustained intake of an isocaloric high-fat diet had a deep impact on the liver transcriptome, mainly affecting lipid metabolism. Although serum cholesterol levels were not affected, circulating triacylglycerols were lower, and metabolic adaptations at gene expression level indicated adaptation toward handling the increased fat content of the diet, an increased triacylglycerol and cholesterol deposition in liver of MONW rats was observed. Moreover, gene expression pointed to increased risk of liver injury. One of the top upregulated genes in this tissue was Krt23, a marker of hepatic disease in humans that was also increased at the protein level.Conclusion:Long-term intake of a high-fat diet, even in the absence of overweight/obesity or increase in classical blood risk biomarkers, promotes a molecular environment leading to hepatic lipid accumulation and increasing the risk of suffering from hepatic diseases.

Isocaloric high-fat feeding directs hepatic metabolism to handling of nutrient imbalance promoting liver fat deposition

KAUST Repository

Diaz Rua, Ruben

2016-03-22

Background/Objectives: Consumption of fat-rich foods is associated with obesity and related alterations. However, there is a group of individuals, the metabolically obese normal-weight (MONW) subjects, who present normal body weight but have metabolic features characteristic of the obese status, including fat deposition in critical tissues such as liver, recognized as a major cause for the promotion of metabolic diseases. Our aim was to better understand metabolic alterations present in liver of MONW rats applying whole genome transcriptome analysis. Methods: Wistar rats were chronically fed a high-fat diet isocaloric relative to Control animals to avoid the hyperphagia and overweight and to mimic MONW features. Liver transcriptome analysis of both groups was performed. Results: Sustained intake of an isocaloric high-fat diet had a deep impact on the liver transcriptome, mainly affecting lipid metabolism. Although serum cholesterol levels were not affected, circulating triacylglycerols were lower, and metabolic adaptations at gene expression level indicated adaptation toward handling the increased fat content of the diet, an increased triacylglycerol and cholesterol deposition in liver of MONW rats was observed. Moreover, gene expression pointed to increased risk of liver injury. One of the top upregulated genes in this tissue was Krt23, a marker of hepatic disease in humans that was also increased at the protein level.Conclusion:Long-term intake of a high-fat diet, even in the absence of overweight/obesity or increase in classical blood risk biomarkers, promotes a molecular environment leading to hepatic lipid accumulation and increasing the risk of suffering from hepatic diseases.

Plasma plasminogen activator inhibitor-1 levels and nonalcoholic fatty liver in individuals with features of metabolic syndrome.

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de Larrañaga, Gabriela; Wingeyer, Silvia Perés; Graffigna, Mabel; Belli, Susana; Bendezú, Karla; Alvarez, Silvia; Levalle, Oscar; Fainboim, Hugo

2008-07-01

Fatty liver represents the liver component of metabolic syndrome and may be involved in plasminogen activator inhibitor-1 (PAI-1) synthesis. We studied plasma PAI-1 levels and relationships with risk factors for metabolic syndrome, including fatty liver, in 170 patients. Liver ultrasound scan was performed on all patients, and a liver biopsy was performed on those patients with chronically elevated transaminase levels. Plasma PAI-1 levels correlated significantly (P < .05) with body mass index, degree of steatosis, insulin resistance, insulin level, waist circumference, triglycerides, and high-density lipoprotein (HDL) -cholesterol. However, only body mass index (beta = .455) and HDL-cholesterol (beta = .293) remained predictors of PAI-1 levels. Liver biopsy revealed a significant correlation (P < .05) between insulin resistance (r = 0.381) or insulin level (r = 0.519) and liver fibrosis. In patients presenting features of metabolic syndrome, plasma PAI-1 levels were mainly conditioned by the whole-body fat content.

A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro

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Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

2017-01-01

Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotransformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two-dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases. PMID:27959388

Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma.

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Nwosu, Zeribe Chike; Megger, Dominik Andre; Hammad, Seddik; Sitek, Barbara; Roessler, Stephanie; Ebert, Matthias Philip; Meyer, Christoph; Dooley, Steven

2017-09-01

Cancer cells rely on metabolic alterations to enhance proliferation and survival. Metabolic gene alterations that repeatedly occur in liver cancer are largely unknown. We aimed to identify metabolic genes that are consistently deregulated, and are of potential clinical significance in human hepatocellular carcinoma (HCC). We studied the expression of 2,761 metabolic genes in 8 microarray datasets comprising 521 human HCC tissues. Genes exclusively up-regulated or down-regulated in 6 or more datasets were defined as consistently deregulated. The consistent genes that correlated with tumor progression markers ( ECM2 and MMP9) (Pearson correlation P < .05) were used for Kaplan-Meier overall survival analysis in a patient cohort. We further compared proteomic expression of metabolic genes in 19 tumors vs adjacent normal liver tissues. We identified 634 consistent metabolic genes, ∼60% of which are not yet described in HCC. The down-regulated genes (n = 350) are mostly involved in physiologic hepatocyte metabolic functions (eg, xenobiotic, fatty acid, and amino acid metabolism). In contrast, among consistently up-regulated metabolic genes (n = 284) are those involved in glycolysis, pentose phosphate pathway, nucleotide biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, proton transport, membrane lipid, and glycan metabolism. Several metabolic genes (n = 434) correlated with progression markers, and of these, 201 predicted overall survival outcome in the patient cohort analyzed. Over 90% of the metabolic targets significantly altered at the protein level were similarly up- or down-regulated as in genomic profile. We provide the first exposition of the consistently altered metabolic genes in HCC and show that these genes are potentially relevant targets for onward studies in preclinical and clinical contexts.

Detection of xenobiotic-induced DNA damage by the comet assay applied to human and rat precision-cut liver slices

NARCIS (Netherlands)

Plazar, Janja; Hrejac, Irena; Pirih, Primoz; Filipic, Metka; Groothuis, Geny M. M.

The comet assay is a simple and sensitive method for measuring DNA damage at the level of individual cells and is extensively used in genotoxicity studies. It is commonly applied to cultured cells. The aim of this study was to apply the comet assay for use in fresh liver tissue, where metabolic

Radiorespirometric study of carbohydrate metabolism in childhood liver disease

International Nuclear Information System (INIS)

DaCosta, H.; Shreeve, W.W.; Merchant, S.

1976-01-01

The need for a suitable parameter to evaluate patients with chronic liver disease has been felt for some time, especially in order to judge the response to surgical shunts and the influence of certain drugs and diets on the liver. Since the liver is a major organ for carbohydrate metabolism, it was decided to analyze the in vivo oxidation of such substrates as glucose and galactose labeled with 14 C. Moderately advanced ''Indian childhood cirrhosis'' and idiopathic fatty hepatic infiltration were selected to represent diffuse chronic liver disease. Oral administration of 14 C-U-glucose or 14 C-1-galactose was followed by analyses of 14 CO 2 in breath by liquid scintillation counting. Conversion of 14 C-glucose to 14 CO 2 was accelerated by both diseases. On the other hand, oxidation of 14 C-galactose was slowed in fatty infiltration and was markedly subnormal in Indian childhood cirrhosis

[Study of enzymes of xenobiotic metabolism in the evaluation of quality of protein-containing wheat germ flakes and wallpaper flour].

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Martinchuk, A N; E En Gyn; Safronova, A M; Peskova, E V

1991-01-01

Intake of wheat upholstery meal by growing rats was attended by a sharp decrease in the content and activity of xenobiotic metabolism enzymes in the hepatic microsomes, that was caused by the low biological value of the meal proteins. Hepatic microsomes of the rats that were fed with wheat germ flakes showed increased specific content of cytochromes P-450 and b5, but the total blood protein content per 100 g of body mass was lower than during casein consumption. No significant changes were detected in hydroxylation rate of benz(a)pyrene, aniline and ethylmorphine. During consumption of wheat germ flakes induction of UDP-glucuronide-transferase was detected in hepatic microsomes. Wheat germ flakes induced a 5-fold increase of Se-dependent glutathione peroxidase activity. Wheat germ flakes produced no significant effect on glutathione-S-aryltransferase and glutathione reductase activity.

Metabolically based liver damage pathophysiology in patients with urea cycle disorders - A new hypothesis.

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Ivanovski, Ivan; Ješić, Miloš; Ivanovski, Ana; Garavelli, Livia; Ivanovski, Petar

2017-11-28

The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle (UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liver damage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.

Comparative Metabolism Study of Five Protoberberine Alkaloids in Liver Microsomes from Rat, Rhesus Monkey, and Human.

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Li, Yan; Zhou, Yanyan; Si, Nan; Han, Lingyu; Ren, Wei; Xin, Shaokun; Wang, Hongjie; Zuo, Ran; Wei, Xiaolu; Yang, Jian; Zhao, Haiyu; Bian, Baolin

2017-11-01

Protoberberine alkaloids including berberine, palmatine, jatrorrhizine, coptisine, and epiberberine are major components in many medicinal plants. They have been widely used for the treatment of cancer, inflammation, diabetes, depression, hypertension, and various infectious areas. However, the metabolism of five protoberberine alkaloids among different species has not been clarified previously. In order to elaborate on the in vitro metabolism of them, a comparative analysis of their metabolic profile in rat, rhesus monkey, and human liver microsomes was carried out using ultrahigh-performance liquid chromatography coupled with a high-resolution linear trap quadrupole-Orbitrap mass spectrometer (UHPLC-electrospray ionization-Orbitrap MS) for the first time. Each metabolite was identified and semiquantified by its accurate mass data and peak area. Fifteen metabolites were characterized based on accurate MS/MS spectra and the proposed MS/MS fragmentation pathways including demethylation, hydroxylation, and methyl reduction. Among them, the content of berberine metabolites in human liver microsomes was similar with those in rhesus monkey liver microsomes, whereas berberine in rat liver microsomes showed no demethylation metabolites and the content of metabolites showed significant differences with that in human liver microsomes. On the contrary, the metabolism of palmatine in rat liver microsomes resembled that in human liver microsomes. The content of jatrorrhizine metabolites presented obvious differences in all species. The HR-ESI-MS/MS fragmentation behavior of protoberberine alkaloids and their metabolic profile in rat, rhesus monkey, and human liver microsomes were investigated for the first time. The results demonstrated that the biotransformation characteristics of protoberberine alkaloids among different species had similarities as well differences that would be beneficial for us to better understand the pharmacological activities of protoberberine alkaloids

Multiple resistance to carcinogens and xenobiotics: P-glycoproteins as universal detoxifiers.

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Efferth, Thomas; Volm, Manfred

2017-07-01

The detoxification of toxic substances is of general relevance in all biological systems. The plethora of exogenous xenobiotic compounds and endogenous toxic metabolic products explains the evolutionary pressure of all organisms to develop molecular mechanisms to detoxify and excrete harmful substances from the body. P-glycoprotein and other members of the ATP-binding cassette (ABC) transporter family extrude innumerous chemical compounds out of cells. Their specific expression in diverse biological contexts cause different phenotypes: (1) multidrug resistance (MDR) and thus failure of cancer chemotherapy, (2) avoidance of accumulation of carcinogens and prevention of carcinogenesis in healthy tissues, (3) absorption, distribution, metabolization and excretion (ADME) of pharmacological drugs in human patients, (4) protection from environmental toxins in aquatic organisms (multi-xenobiotic resistance, MXR). Hence ABC-transporters may have opposing effects for organismic health reaching from harmful in MDR of tumors to beneficial for maintenance of health in MXR. While their inhibition by specific inhibitors may improve treatment success in oncology and avoid carcinogenesis, blocking of ABC-transporter-driven efflux by environmental pollutants leads to ecotoxicological consequences in marine biotopes. Poisoned seafood may enter the food-chain and cause intoxications in human beings. As exemplified with ABC-transporters, joining forces in interdisciplinary research may, therefore, be a wise strategy to fight problems in human medicine and environmental sciences.

Lipid profiling and transcriptomic analysis reveals a functional interplay between estradiol and growth hormone in liver.

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Leandro Fernández-Pérez

Full Text Available 17β-estradiol (E2 may interfere with endocrine, metabolic, and gender-differentiated functions in liver in both females and males. Indirect mechanisms play a crucial role because of the E2 influence on the pituitary GH secretion and the GHR-JAK2-STAT5 signaling pathway in the target tissues. E2, through its interaction with the estrogen receptor, exerts direct effects on liver. Hypothyroidism also affects endocrine and metabolic functions of the liver, rendering a metabolic phenotype with features that mimic deficiencies in E2 or GH. In this work, we combined the lipid and transcriptomic analysis to obtain comprehensive information on the molecular mechanisms of E2 effects, alone and in combination with GH, to regulate liver functions in males. We used the adult hypothyroid-orchidectomized rat model to minimize the influence of internal hormones on E2 treatment and to explore its role in male-differentiated functions. E2 influenced genes involved in metabolism of lipids and endo-xenobiotics, and the GH-regulated endocrine, metabolic, immune, and male-specific responses. E2 induced a female-pattern of gene expression and inhibited GH-regulated STAT5b targeted genes. E2 did not prevent the inhibitory effects of GH on urea and amino acid metabolism-related genes. The combination of E2 and GH decreased transcriptional immune responses. E2 decreased the hepatic content of saturated fatty acids and induced a transcriptional program that seems to be mediated by the activation of PPARα. In contrast, GH inhibited fatty acid oxidation. Both E2 and GH replacements reduced hepatic CHO levels and increased the formation of cholesterol esters and triacylglycerols. Notably, the hepatic lipid profiles were endowed with singular fingerprints that may be used to segregate the effects of different hormonal replacements. In summary, we provide in vivo evidence that E2 has a significant impact on lipid content and transcriptome in male liver and that E2 exerts a

Absolute Configuration of (-)-2-(4-Hydroxyphenyl)propionic acid: Stereochemistry of Soy Isoflavone Metabolism

Energy Technology Data Exchange (ETDEWEB)

Kim, Mihyang; Han, Jaehong [Chung-Ang Univ., Seoul (Korea, Republic of)

2014-06-15

We have elucidated stereochemistry of (-)-2-HPPA. Determination of (R)-2-HPPA stereochemistry also provided stereochemical information of genistein metabolism. Considering the stereochemistry of 2-HPPA, the precursor of (R)-2-HPPA should be (R)-6'-hydroxy-O-DMA. Besides, it is clear that only (S)-dihydrogenistein is the possible precursor of (R)-6'-hydroxy-O-DMA. Therefore, genistein metabolism is suggested to follow the same stereochemical pathway like daidzein. Biotransformation of natural products by human intestinal bacteria has recently drawn a significant interest, due to the emerging strong correlation between gut microbiota and human health. Microbial metabolism of natural products by intestinal bacteria in small intestine and colon proceeds the phase I and II xenobiotic metabolisms in the liver. The metabolites were found to exhibit different biological activities, and affect human etiology. For example, many beneficial effects of dietary polyphenols in human health are attributed to the microbial metabolites produced by intestinal bacteria and the modulation of gut microbiota composition.

Absolute Configuration of (-)-2-(4-Hydroxyphenyl)propionic acid: Stereochemistry of Soy Isoflavone Metabolism

International Nuclear Information System (INIS)

Kim, Mihyang; Han, Jaehong

2014-01-01

We have elucidated stereochemistry of (-)-2-HPPA. Determination of (R)-2-HPPA stereochemistry also provided stereochemical information of genistein metabolism. Considering the stereochemistry of 2-HPPA, the precursor of (R)-2-HPPA should be (R)-6'-hydroxy-O-DMA. Besides, it is clear that only (S)-dihydrogenistein is the possible precursor of (R)-6'-hydroxy-O-DMA. Therefore, genistein metabolism is suggested to follow the same stereochemical pathway like daidzein. Biotransformation of natural products by human intestinal bacteria has recently drawn a significant interest, due to the emerging strong correlation between gut microbiota and human health. Microbial metabolism of natural products by intestinal bacteria in small intestine and colon proceeds the phase I and II xenobiotic metabolisms in the liver. The metabolites were found to exhibit different biological activities, and affect human etiology. For example, many beneficial effects of dietary polyphenols in human health are attributed to the microbial metabolites produced by intestinal bacteria and the modulation of gut microbiota composition

A comparative integrated transcript analysis and functional characterization of differential mechanisms for induction of liver hypertrophy in the rat

International Nuclear Information System (INIS)

Boitier, Eric; Amberg, Alexander; Barbie, Valerie; Blichenberg, Arne; Brandenburg, Arnd; Gmuender, Hans; Gruhler, Albrecht; McCarthy, Diane; Meyer, Kirstin; Riefke, Bjoern; Raschke, Marian; Schoonen, Willem; Sieber, Maximilian; Suter, Laura; Thomas, Craig E.; Sajot, Nicolas

2011-01-01

The main goal of the present work was to better understand the molecular mechanisms underlying liver hypertrophy (LH), a recurrent finding observed following acute or repeated drug administration to animals, using transcriptomic technologies together with the results from conventional toxicology methods. Administration of 5 terminated proprietary drug candidates from participating companies involved in the EU Innomed PredTox Project or the reference hepatotoxicant troglitazone to rats for up to a 14-day duration induced LH as the main liver phenotypic toxicity outcome. The integrated analysis of transcriptomic liver expression data across studies turned out to be the most informative approach for the generation of mechanistic models of LH. In response to a xenobiotic stimulus, a marked increase in the expression of xenobiotic metabolizing enzymes (XME) was observed in a subset of 4 studies. Accumulation of these newly-synthesized proteins within the smooth endoplasmic reticulum (SER) would suggest proliferation of this organelle, which most likely is the main molecular process underlying the LH observed in XME studies. In another subset of 2 studies (including troglitazone), a marked up-regulation of genes involved in peroxisomal fatty acid β-oxidation was noted, associated with induction of genes involved in peroxisome proliferation. Therefore, an increase in peroxisome abundance would be the main mechanism underlying LH noted in this second study subset. Together, the use of transcript profiling provides a means to generate putative mechanistic models underlying the pathogenesis of liver hypertrophy, to distinguish between subtle variations in subcellular organelle proliferation and creates opportunities for improved mechanism-based risk assessment.

Evolving insights on metabolism, autophagy and epigenetics in liver myofibroblasts

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Zeribe Chike Nwosu

2016-06-01

Full Text Available Liver myofibroblasts (MFB are crucial mediators of extracellular matrix (ECM deposition in liver fibrosis. They arise mainly from hepatic stellate cells (HSCs upon a process termed activation. To a lesser extent, and depending on the cause of liver damage, portal fibroblasts, mesothelial cells and fibrocytes may also contribute to the MFB population. Targeting MFB to reduce liver fibrosis is currently an area of intense research. Unfortunately, a clog in the wheel of antifibrotic therapies is the fact that although MFB are known to mediate scar formation, and participate in liver inflammatory response, many of their molecular portraits are currently unknown. In this review, we discuss recent understanding of MFB in health and diseases, focusing specifically on three evolving research fields: metabolism, autophagy and epigenetics. We have emphasized on therapeutic prospects where applicable and mentioned techniques for use in MFB studies. Subsequently, we highlighted uncharted territories in MFB research to help direct future efforts aimed at bridging gaps in current knowledge.

Differences in the expression of xenobiotic-metabolizing enzymes between islets derived from the ventral and dorsal anlage of the pancreas.

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Standop, Jens; Ulrich, Alexis B; Schneider, Matthias B; Büchler, Markus W; Pour, Parviz M

2002-01-01

Chronic pancreatitis and pancreatic cancer have been linked to the exposure of environmental chemicals (xenobiotics), which generally require metabolic activation to highly reactive toxic or carcinogenic intermediates. The primary enzyme system involved is made up of numerous cytochrome P450 mono-oxygenases (CYP). Glutathione S-transferases (GST) belong to the enzyme systems that catalyze the conjugation of the reactive intermediates produced by CYPs to less toxic or readily excretable metabolites. Because the majority of chronic pancreatitis and pancreatic cancers develop in the organ's head, we compared the expression of selected CYP and GST enzymes between the tissues deriving from the ventral anlage (head) and dorsal anlage (corpus, tail). A total of 20 normal pancreatic tissue specimen from organ donors and early autopsy cases were processed immunohistochemically by using antibodies to CYP 1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, 3A1, 3A2 and 3A4, GST-alpha, GST-mu and GST-pi, and the NADPH cytochrome P450 oxido-reductase (NA-OR), the specificity of which has been verified in our previous study by Western blot and RT-PCR analyses. In all pancreatic regions, most of the enzymes were expressed in islet cells. However, more islets in the head region expressed CYP 2B6, 2C8/9/19, 2E1 and the NA-OR, than those in the body and tail. Moreover, the expression of CYP 2B6 and 2E1 was restricted to the pancreatic polypeptide (PP) cells, and the concentration of CYP 3A1 and 3A4 was stronger in PP cells than in other islet cells. On the other hand, GST-mu and GST-pi were expressed primarily in islet cells of the body and tail. The greater content of xenobiotic-metabolizing and carcinogen-activating CYP enzymes and a lower expression of detoxifying GST enzymes in the head of the pancreas could be one reason for the greater susceptibility of this region for inflammatory and malignant diseases. Copyright 2002 S. Karger AG, Basel and IAP

Role of Free Radicals, Oxidative Stress and Xenobiotics in Carcinogenesis by Environmental Pollutants

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Dibyajyoti Saha

2014-09-01

Full Text Available Carcinogenesis by many small molecular weight chemicals involves either a direct action of the chemical on cellular DNA or metabolism of the parent chemical to an active or ultimate form, which can than react with cellular DNA to produce a permanent chemical change in a DNA structure. A free radical is an atom or molecule that has one or more unpaired electron(s. These are highly reactive species capable of wide spread, indiscriminate oxidation and per oxidation of proteins, lipids and DNA which can lead to significant cellular damage and even tissue and/or organ failure. . Oxidative stress is a leading cause to damage cells by oxidation. The rate at which oxidative damage is induced (input and the rate at which it is efficiently repaired and removed (output. Xenobiotics are a compound that is foreign to the body. Xenobiotics can produce a variety of biological effects, including pharmacologic responses, toxicity, genes, immunologic reactions and cancer. Oxidative stress is a leading cause to damage cells by oxidation. The rate at which oxidative damage is induced (input and the rate at which it is efficiently repaired and removed (output. This communication highlights the role of carcinogens as environmental pollutants with the possible mechanism of free radicals, oxidative stress and xenobiotics.

Tocotrienols Reverse Cardiovascular, Metabolic and Liver Changes in High Carbohydrate, High Fat Diet-Fed Rats

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Weng-Yew Wong

2012-10-01

Full Text Available Tocotrienols have been reported to improve lipid profiles, reduce atherosclerotic lesions, decrease blood glucose and glycated haemoglobin concentrations, normalise blood pressure in vivo and inhibit adipogenesis in vitro, yet their role in the metabolic syndrome has not been investigated. In this study, we investigated the effects of palm tocotrienol-rich fraction (TRF on high carbohydrate, high fat diet-induced metabolic, cardiovascular and liver dysfunction in rats. Rats fed a high carbohydrate, high fat diet for 16 weeks developed abdominal obesity, hypertension, impaired glucose and insulin tolerance with increased ventricular stiffness, lower systolic function and reduced liver function. TRF treatment improved ventricular function, attenuated cardiac stiffness and hypertension, and improved glucose and insulin tolerance, with reduced left ventricular collagen deposition and inflammatory cell infiltration. TRF improved liver structure and function with reduced plasma liver enzymes, inflammatory cell infiltration, fat vacuoles and balloon hepatocytes. TRF reduced plasma free fatty acid and triglyceride concentrations but only omental fat deposition was decreased in the abdomen. These results suggest that tocotrienols protect the heart and liver, and improve plasma glucose and lipid profiles with minimal changes in abdominal obesity in this model of human metabolic syndrome.

Putrescine treatment reverses α-tocopherol-induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration

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Lourdes Sánchez-Sevilla

2016-10-01

Full Text Available Abstract Background The pre-treatment with α-tocopherol inhibits progression of rat liver proliferation induced by partial hepatectomy (PH, by decreasing and/or desynchronizing cyclin D1 expression and activation into the nucleus, activation and nuclear translocation of STAT-1 and -3 proteins and altering retinoid metabolism. Interactions between retinoic acid and polyamines have been reported in the PH-induced rat liver regeneration. Therefore, we evaluated the effect of low dosage of α-tocopherol on PH-induced changes in polyamine metabolism. Methods This study evaluated the participation of polyamine synthesis and metabolism during α-tocopherol-induced inhibition of rat liver regeneration. In PH-rats (Wistar treated with α-tocopherol and putrescine, parameters indicative of cell proliferation, lipid peroxidation, ornithine decarboxylase expression (ODC, and polyamine levels, were determined. Results Pre-treatment with α-tocopherol to PH-animals exerted an antioxidant effect, shifting earlier the increased ODC activity and expression, temporally affecting polyamine synthesis and ornithine metabolism. Whereas administration of putrescine induced minor changes in PH-rats, the concomitant treatment actually counteracted most of adverse actions exerted by α-tocopherol on the remnant liver, restituting its proliferative potential, without changing its antioxidant effect. Putrescine administration to these rats was also associated with lower ODC expression and activity in the proliferating liver, but the temporally shifting in the amount of liver polyamines induced by α-tocopherol, was also “synchronized” by the putrescine administration. The latter is supported by the fact that a close relationship was observed between fluctuations of polyamines and retinoids. Conclusions Putrescine counteracted most adverse actions exerted by α-tocopherol on rat liver regeneration, restoring liver proliferative potential and restituting the decreased

Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

Science.gov (United States)

Ushijima, Kentarou; Tsuruoka, Shu-ichi; Tsuda, Hidetoshi; Hasegawa, Gohki; Obi, Yuri; Kaneda, Tae; Takahashi, Masaki; Maekawa, Tomohiro; Sasaki, Tomohiro; Koshimizu, Taka-aki; Fujimura, Akio

2009-01-01

AIM To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9. METHODS The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics. RESULTS Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects. CONCLUSIONS Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations. PMID:19694738

Metabolic profiling of fatty liver in young and middle‐aged adults: Cross‐sectional and prospective analyses of the Young Finns Study

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Würtz, Peter; Suomela, Emmi; Lehtovirta, Miia; Kangas, Antti J.; Jula, Antti; Mikkilä, Vera; Viikari, Jorma S.A.; Juonala, Markus; Rönnemaa, Tapani; Hutri‐Kähönen, Nina; Kähönen, Mika; Lehtimäki, Terho; Soininen, Pasi; Ala‐Korpela, Mika; Raitakari, Olli T.

2016-01-01

Nonalcoholic fatty liver is associated with obesity‐related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis‐related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty‐eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population‐based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34‐49 years (19% prevalence). Cross‐sectional associations as well as 4‐year and 10‐year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P fatty acids including omega‐6 (OR = 0.37, 0.32‐0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P fatty liver diagnosis. Conclusion: Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk factors; these metabolic aberrations appear to precede the development of fatty liver in young adults. (Hepatology 2017;65:491‐500). PMID:27775848

Phase I and phase II reductive metabolism simulation of nitro aromatic xenobiotics with electrochemistry coupled with high resolution mass spectrometry.

Science.gov (United States)

Bussy, Ugo; Chung-Davidson, Yu-Wen; Li, Ke; Li, Weiming

2014-11-01

Electrochemistry combined with (liquid chromatography) high resolution mass spectrometry was used to simulate the general reductive metabolism of three biologically important nitro aromatic molecules: 3-trifluoromethyl-4-nitrophenol (TFM), niclosamide, and nilutamide. TFM is a pesticide used in the Laurential Great Lakes while niclosamide and nilutamide are used in cancer therapy. At first, a flow-through electrochemical cell was directly connected to a high resolution mass spectrometer to evaluate the ability of electrochemistry to produce the main reduction metabolites of nitro aromatic, nitroso, hydroxylamine, and amine functional groups. Electrochemical experiments were then carried out at a constant potential of -2.5 V before analysis of the reduction products by LC-HRMS, which confirmed the presence of the nitroso, hydroxylamine, and amine species as well as dimers. Dimer identification illustrates the reactivity of the nitroso species with amine and hydroxylamine species. To investigate xenobiotic metabolism, the reactivity of nitroso species to biomolecules was also examined. Binding of the nitroso metabolite to glutathione was demonstrated by the observation of adducts by LC-ESI(+)-HRMS and the characteristics of their MSMS fragmentation. In conclusion, electrochemistry produces the main reductive metabolites of nitro aromatics and supports the observation of nitroso reactivity through dimer or glutathione adduct formation.

Maternal obesity disrupts circadian rhythms of clock and metabolic genes in the offspring heart and liver.

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Wang, Danfeng; Chen, Siyu; Liu, Mei; Liu, Chang

2015-06-01

Early life nutritional adversity is tightly associated with the development of long-term metabolic disorders. Particularly, maternal obesity and high-fat diets cause high risk of obesity in the offspring. Those offspring are also prone to develop hyperinsulinemia, hepatic steatosis and cardiovascular diseases. However, the precise underlying mechanisms leading to these metabolic dysregulation in the offspring remain unclear. On the other hand, disruptions of diurnal circadian rhythms are known to impair metabolic homeostasis in various tissues including the heart and liver. Therefore, we investigated that whether maternal obesity perturbs the circadian expression rhythms of clock, metabolic and inflammatory genes in offspring heart and liver by using RT-qPCR and Western blotting analysis. Offspring from lean and obese dams were examined on postnatal day 17 and 35, when pups were nursed by their mothers or took food independently. On P17, genes examined in the heart either showed anti-phase oscillations (Cpt1b, Pparα, Per2) or had greater oscillation amplitudes (Bmal1, Tnf-α, Il-6). Such phase abnormalities of these genes were improved on P35, while defects in amplitudes still existed. In the liver of 17-day-old pups exposed to maternal obesity, the oscillation amplitudes of most rhythmic genes examined (except Bmal1) were strongly suppressed. On P35, the oscillations of circadian and inflammatory genes became more robust in the liver, while metabolic genes were still kept non-rhythmic. Maternal obesity also had a profound influence in the protein expression levels of examined genes in offspring heart and liver. Our observations indicate that the circadian clock undergoes nutritional programing, which may contribute to the alternations in energy metabolism associated with the development of metabolic disorders in early life and adulthood.

A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro.

Science.gov (United States)

Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

2017-01-01

Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two‑dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases.

Polymorphisms in xenobiotic metabolizing enzymes and diet influence colorectal adenoma risk.

Science.gov (United States)

Northwood, Emma L; Elliott, Faye; Forman, David; Barrett, Jennifer H; Wilkie, Murray J V; Carey, Francis A; Steele, Robert J C; Wolf, Roland; Bishop, Timothy; Smith, Gillian

2010-05-01

We have earlier shown that diet and xenobiotic metabolizing enzyme genotypes influence colorectal cancer risk, and now investigate whether similar associations are seen in patients with premalignant colorectal adenomas (CRA), recruited during the pilot phase of the Scottish Bowel Screening Programme. Nineteen polymorphisms in 13 genes [cytochrome P450 (P450), glutathione S-transferase (GST), N-acetyl transferase, quinone reductase (NQ01) and microsomal epoxide hydrolase (EPHX1) genes] were genotyped using multiplex PCR or Taqman-based allelic discrimination assays and analyzed in conjunction with diet, assessed by food frequency questionnaire, in a case-control study [317 CRA cases (308 cases genotyped), 296 controls]. Findings significant at a nominal 5% level are reported. CRA risk was inversely associated with fruit (P=0.02, test for trend) and vegetable (P=0.001, test for trend) consumption. P450 CYP2C9*3 heterozygotes had reduced CRA risk compared with homozygotes for the reference allele [odds ratio (OR): 0.60; 95% confidence interval (CI): 0.36-0.99], whereas CYP2D6*4 homozygotes (OR: 2.72; 95% CI: 1.18-6.27) and GSTM1 'null' individuals (OR: 1.43; 95% CI: 1.04-1.98) were at increased risk. The protective effect of fruit consumption was confined to GSTP1 (Ala114Val) reference allele homozygotes (OR: 0.49; 95% CI: 0.34-0.71, P=0.03 for interaction). CRA risk was not associated with meat consumption, although a significant interaction between red meat consumption and EPHX1 (His139Arg) genotype was noted (P=0.02 for interaction). We report the novel associations between P450 genotype and CRA risk, and highlight the risk association with GSTM1 genotype, common to our CRA and cancer case-control series. In addition, we report a novel modifying influence of GSTP1 genotype on dietary chemoprevention. These novel findings require independent confirmation.

Effects of acupuncture on the citrate and glucose metabolism in the liver under various types of stress

International Nuclear Information System (INIS)

Liao, Y.Y.; Seto, K.; Saito, H.; Kawakami, M.

1980-01-01

A study was made of the effect of acupuncture on citrate and glucose metabolism in the liver in terms of incorporation of 14 C-1, 5-citric acid and 14 C-u-glucose in some metabolites. The effect of acupuncture on citrate metabolism in the liver under control conditions was such as to increase production of G and reduce that of KB, FC and FFA. No effect of acupuncture on glucose metabolism in the liver under such conditions was observed. Both citrate and glucose metabolism were affected to a marked extent by immobilization stress or exposure to heat or cold. The deleterious effect of these types of stress was less prominent in animals receiving acupuncture at the Tsu-San-Li locus than in those treated otherwise or receiving no treatment

Effects of acupuncture on the citrate and glucose metabolism in the liver under various types of stress

Energy Technology Data Exchange (ETDEWEB)

Liao, Y.Y.; Seto, K.; Saito, H.; Kawakami, M.

A study was made of the effect of acupuncture on citrate and glucose metabolism in the liver in terms of incorporation of /sup 14/C-1, 5-citric acid and /sup 14/C-u-glucose in some metabolites. The effect of acupuncture on citrate metabolism in the liver under control conditions was such as to increase production of G and reduce that of KB, FC and FFA. No effect of acupuncture on glucose metabolism in the liver under such conditions was observed. Both citrate and glucose metabolism were affected to a marked extent by immobilization stress or exposure to heat or cold. The deleterious effect of these types of stress was less prominent in animals receiving acupuncture at the Tsu-San-Li locus than in those treated otherwise or receiving no treatment.

Metabolism and interactions of pesticides in human and animal in vitro hepatic models

OpenAIRE

Abass, K. M. (Khaled M.)

2010-01-01

Abstract Risk assessment of chemicals needs reliable scientific information and one source of information is the characterization of the metabolic fate and toxicokinetics of a chemical. Metabolism is often the most important factor contributing to toxicokinetics. Cytochrome P450 (CYP) enzymes are a superfamily of microsomal proteins playing a pivotal role in xenobiotic metabolism. In the present study, pesticides were used as representative xenobiotics since exposure to pesticides is ...

In vitro metabolism studies of 18F-labeled 1-phenylpiperazine using mouse liver S9 fraction

International Nuclear Information System (INIS)

Ryu, Eun Kyoung; Choe, Yearn Seong; Kim, Dong Hyun; Ko, Bong-Ho; Choi, Yong; Lee, Kyung-Han; Kim, Byung-Tae

2006-01-01

The in vitro metabolism of 1-(4-[ 18 F]fluoromethylbenzyl)-4-phenylpiperazine ([ 18 F]1) and 1-(4-[ 18 F]fluorobenzyl)-4-phenylpiperazine ([ 18 F]2) was investigated using mouse liver S9 fraction. Results were compared to those of in vivo metabolism using mouse blood and bone and to in vitro metabolism using mouse liver microsomes. Defluorination was the main metabolic pathway for [ 18 F]1 in vitro and in vivo. Based on TLC, HPLC and LC-MS data, [ 18 F]fluoride ion and less polar radioactive metabolites derived from aromatic ring oxidation were detected in vitro, and the latter metabolites were rapidly converted into the former with time, whereas only the [ 18 F]fluoride ion was detected in vivo. Similarly, the in vitro metabolism of [ 18 F]2 using either S9 fraction or microsomes showed the same pattern as the in vivo method using blood; however, the radioactive metabolites derived from aromatic ring oxidation were not detected in vivo. These results demonstrate that liver S9 fraction can be widely used to investigate the intermediate radioactive metabolites and to predict the in vivo metabolism of radiotracers

Liver carbohydrates metabolism: A new islet-neogenesis associated protein peptide (INGAP-PP) target.

Science.gov (United States)

Villagarcía, Hernán Gonzalo; Román, Carolina Lisi; Castro, María Cecilia; González, Luisa Arbeláez; Ronco, María Teresa; Francés, Daniel Eleazar; Massa, María Laura; Maiztegui, Bárbara; Flores, Luis Emilio; Gagliardino, Juan José; Francini, Flavio

2018-03-01

Islet-Neogenesis Associated Protein-Pentadecapeptide (INGAP-PP) increases β-cell mass and enhances glucose and amino acids-induced insulin secretion. Our aim was to demonstrate its effect on liver metabolism. For that purpose, adult male Wistar rats were injected twice-daily (10 days) with saline solution or INGAP-PP (250 μg). Thereafter, serum glucose, triglyceride and insulin levels were measured and homeostasis model assessment (HOMA-IR) and hepatic insulin sensitivity (HIS) were determined. Liver glucokinase and glucose-6-phosphatase (G-6-Pase) expression and activity, phosphoenolpyruvate carboxykinase (PEPCK) expression, phosphofructokinase-2 (PFK-2) protein content, P-Akt/Akt and glycogen synthase kinase-3β (P-GSK3/GSK3) protein ratios and glycogen deposit were also determined. Additionally, glucokinase activity and G-6-Pase and PEPCK gene expression were also determined in isolated hepatocytes from normal rats incubated with INGAP-PP (5 μg/ml). INGAP-PP administration did not modify any of the serum parameters tested but significantly increased activity of liver glucokinase and the protein level of its cytosolic activator, PFK-2. Conversely, INGAP-PP treated rats decreased gene expression and enzyme activity of gluconeogenic enzymes, G-6-Pase and PEPCK. They also showed a higher glycogen deposit and P-GSK3/GSK3 and P-Akt/Akt ratio. In isolated hepatocytes, INGAP-PP increased GK activity and decreased G-6-Pase and PEPCK expression. These results demonstrate a direct effect of INGAP-PP on the liver acting through P-Akt signaling pathway. INGAP-PP enhances liver glucose metabolism and deposit and reduces its production/output, thereby contributing to maintain normal glucose homeostasis. These results reinforce the concept that INGAP-PP might become a useful tool to treat people with impaired islet/liver glucose metabolism as it occurs in T2D. Copyright © 2018 Elsevier Inc. All rights reserved.

The metabolic effects of diuron in the rat liver.

Science.gov (United States)

da Silva Simões, Mellina; Bracht, Lívia; Parizotto, Angela Valderrama; Comar, Jurandir Fernando; Peralta, Rosane Marina; Bracht, Adelar

2017-09-01

A systematic study on the effects of diuron on the hepatic metabolism was conducted with emphasis on parameters linked to energy metabolism. The experimental system was the isolated perfused rat liver. The results demonstrate that diuron inhibited biosynthesis (gluconeogenesis) and ammonia detoxification, which are dependent of ATP generated within the mitochondria. Conversely, it stimulated glycolysis and fructolysis, which are compensatory phenomena for an inhibited mitochondrial ATP generation. Furthermore, diuron diminished the cellular ATP content under conditions where the mitochondrial respiratory chain was the only source of this compound. Besides the lack of circulating glucose due to gluconeogenesis inhibition, one can expect metabolic acidosis due to excess lactate production, impairment of ammonia detoxification and cell damage due to a deficient maintenance of its homeostasis. Some of the general signs of toxicity that were observed in diuron-treated rats can be attributed, partly at least, to the effects of the herbicide on energy metabolism. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of naphthenic acid exposure on development and liver metabolic processes in anuran tadpoles

International Nuclear Information System (INIS)

Melvin, Steven D.; Lanctôt, Chantal M.; Craig, Paul M.; Moon, Thomas W.; Peru, Kerry M.; Headley, John V.; Trudeau, Vance L.

2013-01-01

Naphthenic acids (NA) are used in a variety of commercial and industrial applications, and are primary toxic components of oil sands wastewater. We investigated developmental and metabolic responses of tadpoles exposed to sub-lethal concentrations of a commercial NA blend throughout development. We exposed Lithobates pipiens tadpoles to 1 and 2 mg/L NA for 75 days and monitored growth and development, condition factor, gonad and liver sizes, and levels of liver glucose, glycogen, lipids and cholesterol following exposure. NA decreased growth and development, significantly reduced glycogen stores and increased triglycerides, indicating disruption to processes associated with energy metabolism and hepatic glycolysis. Effects on liver function may explain reduced growth and delayed development observed in this and previous studies. Our data highlight the need for greater understanding of the mechanisms leading to hepatotoxicity in NA-exposed organisms, and indicate that strict guidelines may be needed for the release of NA into aquatic environments. -- Highlights: ► We exposed Lithobates pipiens tadpoles to 1–2 mg/L NA in the laboratory. ► We monitored survival, growth and development for 75 days. ► We measured liver glycogen, glucose, triglycerides, and cholesterol levels. ► NA significantly reduced growth and development compared to controls. ► NA significantly reduced glycogen levels and increased triglycerides. -- Leopard frog (Lithobates pipiens) tadpoles chronically exposed to sub-lethal NA concentrations (1–2 mg/L) suffered decreased growth and development and disruption to liver metabolic processes

Citrate Defines a Regulatory Link Between Energy Metabolism and the Liver Hormone Hepcidin

OpenAIRE

Ladeira Courelas da Silva, Ana Rita

2017-01-01

Iron plays a critical role as an oxygen carrier in hemoglobin as well as a constituent of iron-sulfur clusters. Increasing evidence suggests that mechanisms maintaining iron homeostasis cross-talk to intermediary metabolism. The liver hormone hepcidin is the key regulator of systemic iron metabolism. Hepcidin transcriptional control is linked to the nutrient-sensing mTOR pathway, proliferative signals, gluconeogenic responses during starvation and hormones that modulate energy metabolism. The...

Actions of juglone on energy metabolism in the rat liver

Energy Technology Data Exchange (ETDEWEB)

Saling, Simoni Cristina; Comar, Jurandir Fernando; Mito, Marcio Shigueaki; Peralta, Rosane Marina; Bracht, Adelar, E-mail: adebracht@uol.com.br

2011-12-15

Juglone is a phenolic compound used in popular medicine as a phytotherapic to treat inflammatory and infectious diseases. However, it also acts as an uncoupler of oxidative phosphorylation in isolated liver mitochondria and, thus, may interfere with the hepatic energy metabolism. The purpose of this work was to evaluate the effect of juglone on several metabolic parameters in the isolated perfused rat liver. Juglone, in the concentration range of 5 to 50 {mu}M, stimulated glycogenolysis, glycolysis and oxygen uptake. Gluconeogenesis from both lactate and alanine was inhibited with half-maximal effects at the concentrations of 14.9 and 15.7 {mu}M, respectively. The overall alanine transformation was increased by juglone, as indicated by the stimulated release of ammonia, urea, L-glutamate, lactate and pyruvate. A great increase (9-fold) in the tissue content of {alpha}-ketoglutarate was found, without a similar change in the L-glutamate content. The tissue contents of ATP were decreased, but those of ADP and AMP were increased. Experiments with isolated mitochondria fully confirmed previous notions about the uncoupling action of juglone. It can be concluded that juglone is active on metabolism at relatively low concentrations. In this particular it resembles more closely the classical uncoupler 2,4-dinitrophenol. Ingestion of high doses of juglone, thus, presents the same risks as the ingestion of 2,4-dinitrophenol which comprise excessive compromising of ATP production, hyperthermia and even death. Low doses, i.e., moderate consumption of natural products containing juglone, however, could be beneficial to health if one considers recent reports about the consequences of chronic mild uncoupling. -- Highlights: Black-Right-Pointing-Pointer We investigated how juglone acts on liver metabolism. Black-Right-Pointing-Pointer The actions on hepatic gluconeogenesis, glycolysis and ureogenesis. Black-Right-Pointing-Pointer Juglone stimulates glycolysis and ureagenesis and

Actions of juglone on energy metabolism in the rat liver

International Nuclear Information System (INIS)

Saling, Simoni Cristina; Comar, Jurandir Fernando; Mito, Márcio Shigueaki; Peralta, Rosane Marina; Bracht, Adelar

2011-01-01

Juglone is a phenolic compound used in popular medicine as a phytotherapic to treat inflammatory and infectious diseases. However, it also acts as an uncoupler of oxidative phosphorylation in isolated liver mitochondria and, thus, may interfere with the hepatic energy metabolism. The purpose of this work was to evaluate the effect of juglone on several metabolic parameters in the isolated perfused rat liver. Juglone, in the concentration range of 5 to 50 μM, stimulated glycogenolysis, glycolysis and oxygen uptake. Gluconeogenesis from both lactate and alanine was inhibited with half-maximal effects at the concentrations of 14.9 and 15.7 μM, respectively. The overall alanine transformation was increased by juglone, as indicated by the stimulated release of ammonia, urea, L-glutamate, lactate and pyruvate. A great increase (9-fold) in the tissue content of α-ketoglutarate was found, without a similar change in the L-glutamate content. The tissue contents of ATP were decreased, but those of ADP and AMP were increased. Experiments with isolated mitochondria fully confirmed previous notions about the uncoupling action of juglone. It can be concluded that juglone is active on metabolism at relatively low concentrations. In this particular it resembles more closely the classical uncoupler 2,4-dinitrophenol. Ingestion of high doses of juglone, thus, presents the same risks as the ingestion of 2,4-dinitrophenol which comprise excessive compromising of ATP production, hyperthermia and even death. Low doses, i.e., moderate consumption of natural products containing juglone, however, could be beneficial to health if one considers recent reports about the consequences of chronic mild uncoupling. -- Highlights: ► We investigated how juglone acts on liver metabolism. ► The actions on hepatic gluconeogenesis, glycolysis and ureogenesis. ► Juglone stimulates glycolysis and ureagenesis and inhibits gluconeogenesis. ► The cellular ATP content is diminished. ► Juglone can

Potential for anaerobic conversion of xenobiotics

DEFF Research Database (Denmark)

Mogensen, Anders Skibsted; Dolfing, J.; Haagensen, Frank

2003-01-01

This review covers the latest research on the anaerobic biodegradation of aromatic xenobiotic compounds, with emphasis on surfactants, polycyclic aromatic hydrocarbons, phthalate esters, polychlorinated biphenyls, halogenated phenols, and pesticides. The versatility of anaerobic reactor systems...... regarding the treatment of xenobiotics is shown with the focus on the UASB reactor, but the applicability of other reactor designs for treatment of hazardous waste is also included. Bioaugmentation has proved to be a viable technique to enhance a specific activity in anaerobic reactors and recent research...

[Comparative metabolism of three amide alkaloids from Piper longum in five different species of liver microsomes].

Science.gov (United States)

He, Huan; Guo, Wei-Wei; Chen, Xiao-Qing; Zhao, Hai-Yu; Wu, Xia

2016-08-01

Piperine, piperlonguminine and pellitorine are three major amide alkaloids from Piper longum, showing a variety of pharmacological activities. In order to investigate the different metabolism pathways of these compounds in five species of liver microsomes in vitro, the data of full mass spectrum, and MS2, MS3 spectra of these three alkaloids were collected and analyzed by using ultra-high-performance liquid chromatography coupled with a LTQ-orbitrap mass spectrometer (UHPLC-LTQ-Orbitrap MS); gragment ion information was collected and combined with fragmentation regularities of mass spectra and accurate mass spectrometry data of metabolites, to compare the metabolism difference of three amide alkaloids in liver microsomes of human, rhesus monkey, Beagle dogs, rats and mice. 3 metabolites of piperine, 2 metabolites of piperlonguminine and 1 metabolite of pellitorine were identified quickly. The results showed that the major metabolic pathways of these amide alkaloids in liver microsomes were methylenedioxy group demethylation and oxidation reaction, and metabolic rates were different between species. This study provides basis for further research on in vivo metabolism of piperine analogues from Piper longum. Copyright© by the Chinese Pharmaceutical Association.

Determination of aluminium induced metabolic changes in mice liver: a Fourier transform infrared spectroscopy study.

Science.gov (United States)

Sivakumar, S; Sivasubramanian, J; Khatiwada, Chandra Prasad; Manivannan, J; Raja, B

2013-06-01

In this study, we made a new approach to evaluate aluminium induced metabolic changes in liver tissue of mice using Fourier transform infrared spectroscopy analysis taking one step further in correlation with strong biochemical evidence. This finding reveals the alterations on the major biochemical constituents, such as lipids, proteins, nucleic acids and glycogen of the liver tissues of mice. The peak area value of amide A significantly decrease from 288.278±3.121 to 189.872±2.012 between control and aluminium treated liver tissue respectively. Amide I and amide II peak area value also decrease from 40.749±2.052 to 21.170±1.311 and 13.167±1.441 to 8.953±0.548 in aluminium treated liver tissue respectively. This result suggests an alteration in the protein profile. The absence of olefinicCH stretching band and CO stretching of triglycerides in aluminium treated liver suggests an altered lipid levels due to aluminium exposure. Significant shift in the peak position of glycogen may be the interruption of aluminium in the calcium metabolism and the reduced level of calcium. The overall findings exhibit that the liver metabolic program is altered through increasing the structural modification in proteins, triglycerides and quantitative alteration in proteins, lipids, and glycogen. All the above mentioned modifications were protected in desferrioxamine treated mice. Histopathological results also revealed impairment of aluminium induced alterations in liver tissue. The results of the FTIR study were found to be in agreement with biochemical studies and which demonstrate FTIR can be used successfully to indicate the molecular level changes. Copyright © 2013 Elsevier B.V. All rights reserved.

Mangosteen peel extract reduces formalin-induced liver cell death in rats

Directory of Open Access Journals (Sweden)

Afiana Rohmani

2014-08-01

Full Text Available Background Formalin is a xenobiotic that is now commonly used as a preservative in the food industry. The liver is an organ that has the highest metabolic capacity as compared to other organs. Mangosteen or Garcinia mangostana Linn (GML peel contains xanthones, which are a source of natural antioxidants. The purpose of this study was to evaluate the effect of mangosteen peel extract on formalin-induced liver cell mortality rate and p53 protein expression in Wistar rats. Methods Eighteen rats received formalin orally for 2 weeks, and were subsequently divided into 3 groups, consisting of the formalin-control group receiving a placebo and treatment groups 1 and 2, which were treated with mangosteen peel extract at doses of 200 and 400 mg/kgBW/day, respectively. The treatment was carried out for 1 week, and finally the rats were terminated. The differences in liver cell mortality rate and p53 protein expression were analyzed. Results One-way ANOVA analysis showed significant differences in liver cell mortality rate among the three groups (p=0.004. The liver cell mortality rate in the treatment group receiving 400 mg/kgBW/day extract was lower than that in the formalin-control group. There was no p53 expression in all groups. Conclusions Garcinia mangostana Linn peel extract reduced the mortality rate of liver cells in rats receiving oral formalin. Involvement of p53 expression in liver cell mortality in rats exposed to oral formalin is presumably negligible.

Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease.

Science.gov (United States)

Jegatheesan, Prasanthi; Beutheu, Stéphanie; Ventura, Gabrielle; Sarfati, Gilles; Nubret, Esther; Kapel, Nathalie; Waligora-Dupriet, Anne-Judith; Bergheim, Ina; Cynober, Luc; De-Bandt, Jean-Pascal

2016-02-01

Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non-alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose-induced non-alcoholic fatty liver disease. Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota. In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation. While nitrogen supply alone can attenuate fructose-induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition

Inhibition of the human liver microsomal and human cytochrome P450 1A2 and 3A4 metabolism of estradiol by deployment-related and other chemicals.

Science.gov (United States)

Usmani, Khawja A; Cho, Taehyeon M; Rose, Randy L; Hodgson, Ernest

2006-09-01

Cytochromes P450 (P450s) are major catalysts in the metabolism of xenobiotics and endogenous substrates such as estradiol (E2). It has previously been shown that E2 is predominantly metabolized in humans by CYP1A2 and CYP3A4 with 2-hydroxyestradiol (2-OHE2) the major metabolite. This study examines effects of deployment-related and other chemicals on E2 metabolism by human liver microsomes (HLM) and individual P450 isoforms. Kinetic studies using HLM, CYP3A4, and CYP1A2 showed similar affinities (Km) for E2 with respect to 2-OHE2 production. Vmax and CLint values for HLM are 0.32 nmol/min/mg protein and 7.5 microl/min/mg protein; those for CYP3A4 are 6.9 nmol/min/nmol P450 and 291 microl/min/nmol P450; and those for CYP1A2 are 17.4 nmol/min/nmol P450 and 633 microl/min/nmol P450. Phenotyped HLM use showed that individuals with high levels of CYP1A2 and CYP3A4 have the greatest potential to metabolize E2. Preincubation of HLM with a variety of chemicals, including those used in military deployments, resulted in varying levels of inhibition of E2 metabolism. The greatest inhibition was observed with organophosphorus compounds, including chlorpyrifos and fonofos, with up to 80% inhibition for 2-OHE2 production. Carbaryl, a carbamate pesticide, and naphthalene, a jet fuel component, inhibited ca. 40% of E2 metabolism. Preincubation of CYP1A2 with chlorpyrifos, fonofos, carbaryl, or naphthalene resulted in 96, 59, 84, and 87% inhibition of E2 metabolism, respectively. Preincubation of CYP3A4 with chlorpyrifos, fonofos, deltamethrin, or permethrin resulted in 94, 87, 58, and 37% inhibition of E2 metabolism. Chlorpyrifos inhibition of E2 metabolism is shown to be irreversible.

Nonalcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis in Childhood: Endocrine-Metabolic “Mal-Programming”

Science.gov (United States)

Manti, Sara; Romano, Claudio; Chirico, Valeria; Filippelli, Martina; Cuppari, Caterina; Loddo, Italia; Salpietro, Carmelo; Arrigo, Teresa

2014-01-01

Context: Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease in the pediatric population. NAFLD includes a broad spectrum of abnormalities (inflammation, fibrosis and cirrhosis), ranging from accumulation of fat (also known as steatosis) towards non-alcoholic steatohepatitis (NASH). The development of NAFLD in children is significantly increased. Evidence Acquisition: A literature search of electronic databases was undertaken for the major studies published from 1998 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the key words: "non-alcoholic fatty liver disease, children, non-alcoholic steatohepatitis and fatty liver". Results: NAFLD/NASH is probably promoted by “multiple parallel hits”: environmental and genetic factors, systemic immunological disorders (oxidative stress, persistent-low grade of inflammation) as well as obesity and metabolic alterations (insulin resistance and metabolic syndrome). However its exact cause still underdiagnosed and unknown. Conclusions: Pediatric NAFLD/NASH is emerging problem. Longitudinal follow-up studies, unfortunately still insufficient, are needed to better understand the natural history and outcome of NAFLD in children. This review focuses on the current knowledge regarding the epidemiology, pathogenesis, environmental, genetic and metabolic factors of disease. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for complete and personalized approach in the management of NAFLD/NASH. PMID:24829591

Investigation of the role of the enzymes of xenobiotic metabolism in the resistance of insects to insecticides

International Nuclear Information System (INIS)

Leonova, I.N.; Nedel'kina, S.V.; Naumova, N.B.; Salganik, R.I.

1986-01-01

The activity of three enzyme systems of xenobiotic metabolism: cytochrome P-450-dependent monooxygenases, nonspecific esterases, and glutathione S-transferases, was investigated on a sensitive strain (S) of the housefly M. domestica L. and strains resistant to tetrametrin (R/sub tetr/), permetrin (R/sub perm/), mecarbenyl (R/sub mec/), and chlorophos (R/sub chlor/). In the strains R/sub tetr/ and R/sub mec/, in comparison with strain S, an increase of 2.7 and 2.3-fold, respectively, in the activity of microsomal monooxygenases was observed. The position of the maxima of the CO-differential spectra of cytochrome P-450 in all the investigated resistant strains, with the exception of R/sub chlor/, is shifted by 1-2 nm in the shortwave direction. The activity of glutathione S-transferases in the strain R/sub tetr/ proved elevated in comparison with the strain S. The data of an investigation of the total esterase activity and the data of starch gel electrophoresis are evidence of quantitative and qualitative differences between the strains. For all the resistant strains except for R/sub mec/, supplementary zones of esterase activity appear. The data obtained are discussed in connection with the resistance of the insects to insecticides

Novel extrahepatic cytochrome P450s

International Nuclear Information System (INIS)

Karlgren, Maria; Miura, Shin-ichi; Ingelman-Sundberg, Magnus

2005-01-01

The cytochrome P450 enzymes are highly expressed in the liver and are involved in the metabolism of xenobiotics. Because of the initiatives associated with the Human Genome Project, a great progress has recently been seen in the identification and characterization of novel extrahepatic P450s, including CYP2S1, CYP2R1, CYP2U1 and CYP2W1. Like the hepatic enzymes, these P450s may play a role in the tissue-specific metabolism of foreign compounds, but they may also have important endogenous functions. CYP2S1 has been shown to metabolize all-trans retinoic acid and CYP2R1 is a major vitamin D 25-hydroxylase. Regarding their metabolism of xenobiotics, much remains to be established, but CYP2S1 metabolizes naphthalene and it is likely that these P450s are responsible for metabolic activation of several different kinds of xenobiotic chemicals and contribute to extrahepatic toxicity and carcinogenesis

Nor-Ursodeoxycholic Acid as a Novel Therapeutic Approach for Cholestatic and Metabolic Liver Diseases.

Science.gov (United States)

Halilbasic, Emina; Steinacher, Daniel; Trauner, Michael

2017-01-01

Norursodeoxycholic acid (norUDCA) is a side-chain-shortened derivative of ursodeoxycholic acid with relative resistance to amidation, which enables its cholehepatic shunting. Based on its specific pharmacologic properties, norUDCA is a promising drug for a range of cholestatic liver and bile duct disorders. Recently, norUDCA has been successfully tested clinically in patients with primary sclerosing cholangitis (PSC) as first application in patients. Moreover, hepatic enrichment of norUDCA facilitates direct therapeutic effects on both parenchymal and non-parenchymal liver cells, thereby counteracting cholestasis, steatosis, hepatic inflammation and fibrosis, inhibiting hepatocellular proliferation, and promoting autophagy. This may open its therapeutic use to other non-cholestatic and metabolic liver diseases. This review article is a summary of a lecture given at the XXIV International Bile Acid Meeting (Falk Symposium 203) on "Bile Acids in Health and Disease" held in Düsseldorf, on June 17-18, 2016 and summarizes the recent progress of norUDCA as novel therapeutic approach in cholestatic and metabolic liver disorders with a specific focus on PSC. © 2017 S. Karger AG, Basel.

Comparison of hepatotoxicity and metabolism of butyltin compounds in the liver of mice, rats and guinea pigs

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Ueno, Shunji; Kashimoto, Takashige; Susa, Nobuyuki; Ishii, Masamitsu; Chiba, Toshikazu [Laboratory of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Mutoh, Ken-ichiro [Laboratory of Veterinary Anatomy, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Hoshi, Fumio [Laboratory of Veterinary Anatomy, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Suzuki, Takashi [Laboratory of Environmental Health and Toxicology, Kyoto Prefectural University, Hangi-cho, Shimogamo, Sakyo-ku, 606-5822, Kyoto (Japan); Sugiyama, Masayasu [Sugiyama Pharmacy, 1335-1 Shimotama, Tamagawa-cho, 759-3112, Yamaguchi (Japan)

2003-03-01

The hepatotoxicity of tributyltin chloride (TBTC) and dibutyltin dichloride (DBTC) was compared among mice, rats and guinea pigs in vivo. Further, the metabolism of these butyltin compounds in the liver was also investigated in these species. The oral administration of TBTC and DBTC to mice induced obvious liver injury, as demonstrated by both serodiagnosis and histopathological diagnosis. The concentrations of TBTC and DBTC that induced hepatotoxicity in mice at 24 h after oral administration were 180 and 60 {mu}mol/kg, respectively. In the case of rats, the liver injury induced by TBTC and DBTC was detected at 24 h by the serodiagnosis, but not by histopathological diagnosis. On the other hand, in guinea pigs, TBTC and DBTC administration did not produce any clear liver injury at 24 h, as evaluated by these two diagnostic methods. Thus, the following ranking was obtained with regard to increasing order of sensitivity to liver injury caused by TBTC and DBTC: mice, rats and guinea pigs. The total butyltin contents in the liver of mice were equivalent at 3 h and 24 h after the administration of TBTC or DBTC; however, the contents in the liver of rats and guinea pigs were relatively lower at 3 h and higher at 24 h than those of mice, although there were no differences between rats and guinea pigs in the total liver butyltin content. Concerning the liver metabolism of these butyltin compounds, the main form of butyltin compounds in these animals treated with TBTC was DBTC within 3 h after oral administration, while the main metabolites at 24 h were different in each species, indicating that the liver metabolism of TBTC might vary by animal type. When the animals were treated with DBTC orally, DBTC was hardly metabolized in the livers of these animals even at 24 h, and the liver levels of DBTC were two times greater in mice and guinea pigs than in rats at 3 h and were lower in mice at 24 h than in rats and guinea pigs. The analysis of cellular distributions of DBTC in

Effects of Castration on Expression of Lipid Metabolism Genes in the Liver of Korean Cattle

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Baik, Myunggi; Nguyen, Trang Hoa; Jeong, Jin Young; Piao, Min Yu; Kang, Hyeok Joong

2015-01-01

Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p

Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues.

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Chai, Chofit; Rivkin, Mila; Berkovits, Liav; Simerzin, Alina; Zorde-Khvalevsky, Elina; Rosenberg, Nofar; Klein, Shiri; Yaish, Dayana; Durst, Ronen; Shpitzen, Shoshana; Udi, Shiran; Tam, Joseph; Heeren, Joerg; Worthmann, Anna; Schramm, Christoph; Kluwe, Johannes; Ravid, Revital; Hornstein, Eran; Giladi, Hilla; Galun, Eithan

2017-11-01

Effective treatments are needed for hepatic steatosis characterized by accumulation of triglycerides in hepatocytes, which leads to hepatocellular carcinoma. MicroRNA 122 (MIR122) is expressed only in the liver, where it regulates lipid metabolism. We investigated the mechanism by which free fatty acids (FFAs) regulate MIR122 expression and the effect of MIR122 on triglyceride synthesis. We analyzed MIR122 promoter activity and validated its target mRNAs by transfection of Luciferase reporter plasmids into Huh7, BNL-1ME, and HEK293 cultured cell lines. We measured levels of microRNAs and mRNAs by quantitative real-time PCR analysis of RNA extracted from plasma, liver, muscle, and adipose tissues of C57BL/6 mice given the FFA-inducer CL316243. MIR122 was inhibited using an inhibitor of MIR122. Metabolic profiles of mice were determined using metabolic chambers and by histologic analyses of liver tissues. We performed RNA sequence analyses to identify metabolic pathways involving MIR122. We validated human Agpat1 and Dgat1 mRNAs, involved in triglyceride synthesis, as targets of MIR122. FFAs increased MIR122 expression in livers of mice by activating the retinoic acid-related orphan receptor alpha, and induced secretion of MIR122 from liver to blood. Circulating MIR122 entered muscle and adipose tissues of mice, reducing mRNA levels of genes involved in triglyceride synthesis. Mice injected with an inhibitor of MIR122 and then given CL316243, accumulated triglycerides in liver and muscle tissues, and had reduced rates of β-oxidation. There was a positive correlation between level of FFAs and level of MIR122 in plasma samples from 6 healthy individuals, collected before and during fasting. In biochemical and histologic studies of plasma, liver, muscle, and adipose tissues from mice, we found that FFAs increase hepatic expression and secretion of MIR122, which regulates energy storage vs expenditure in liver and peripheral tissues. Strategies to reduce

Potential role of liver enzymes levels as predictor markers of glucose metabolism disorders in Tunisian population.

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Bouhajja, Houda; Abdelhedi, Rania; Amouri, Ali; Hadj Kacem, Faten; Marrakchi, Rim; Safi, Wajdi; Mrabet, Houcem; Chtourou, Lassaad; Charfi, Nadia; Fourati, Mouna; Bensassi, Salwa; Jamoussi, Kamel; Abid, Mohamed; Ayadi, Hammadi; Feki, Mouna Mnif; Elleuch, Noura Bougacha

2018-03-10

The relationship between liver enzymes and type 2 diabetes (T2D) risk is inconclusive. We aimed to evaluate the association between liver markers and risk of carbohydrate metabolism disorders and their discriminatory power for T2D prediction. This cross-sectional study enrolled 216 participants classified as normoglycemic, prediabetes, newly-diagnosed diabetes and diagnosed diabetes. All participants underwent anthropometric and biochemical measurements. The relationship between hepatic enzymes and glucose metabolism markers was evaluated by ANCOVA analyses. The associations between liver enzymes and incident carbohydrate metabolism disorders were analyzed through logistic regression and their discriminatory capacity for T2D by receiver operating characteristic (ROC) analysis. High alkaline phosphatase (AP), alanine aminotransferase (ALT), γ-glutamyltransferase (γGT) and aspartate aminotrasferase (AST) levels were independently related to decreased insulin sensitivity. Interestingly, higher AP level was significantly associated with increased risk of prediabetes (p=0.017), newly-diagnosed diabetes (p=0.004) and T2D (p=0.007). Elevated γGT level was an independent risk factor for T2D (p=0.032) and undiagnosed-T2D (p=0.010) in prediabetic and normoglycemic subjects, respectively. In ROC analysis, AP was a powerful predictor of incident diabetes and significantly improved T2D prediction. Liver enzymes within normal range, specifically AP levels, are associated with increased risk of carbohydrate metabolism disorders and significantly improved T2D prediction.

Liver Inflammation and Metabolic Signaling in ApcMin/+ Mice: The Role of Cachexia Progression

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Narsale, Aditi A.; Enos, Reilly T.; Puppa, Melissa J.; Chatterjee, Saurabh; Murphy, E. Angela; Fayad, Raja; Pena, Majorette O’; Durstine, J. Larry; Carson, James A.

2015-01-01

The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer

Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression.

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Aditi A Narsale

Full Text Available The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein, IRE-1α (endoplasmic reticulum to nucleus signaling 1, and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3. While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3. Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin, despite a suppression of Akt (thymoma viral proto-oncogene 1 and S6 (ribosomal protein S6 phosphorylation. Thus

A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

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Cherkaoui-Rbati, Mohammed H; Paine, Stuart W; Littlewood, Peter; Rauch, Cyril

2017-01-01

All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

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Mohammed H Cherkaoui-Rbati

Full Text Available All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs of new chemical entities (NCEs and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit, located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level. A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

Central melanin-concentrating hormone influences liver and adipose metabolism via specific hypothalamic nuclei and efferent autonomic/JNK1 pathways.

Science.gov (United States)

Imbernon, Monica; Beiroa, Daniel; Vázquez, María J; Morgan, Donald A; Veyrat-Durebex, Christelle; Porteiro, Begoña; Díaz-Arteaga, Adenis; Senra, Ana; Busquets, Silvia; Velásquez, Douglas A; Al-Massadi, Omar; Varela, Luis; Gándara, Marina; López-Soriano, Francisco-Javier; Gallego, Rosalía; Seoane, Luisa M; Argiles, Josep M; López, Miguel; Davis, Roger J; Sabio, Guadalupe; Rohner-Jeanrenaud, Françoise; Rahmouni, Kamal; Dieguez, Carlos; Nogueiras, Ruben

2013-03-01

Specific neuronal circuits modulate autonomic outflow to liver and white adipose tissue. Melanin-concentrating hormone (MCH)-deficient mice are hypophagic, lean, and do not develop hepatosteatosis when fed a high-fat diet. Herein, we sought to investigate the role of MCH, an orexigenic neuropeptide specifically expressed in the lateral hypothalamic area, on hepatic and adipocyte metabolism. Chronic central administration of MCH and adenoviral vectors increasing MCH signaling were performed in rats and mice. Vagal denervation was performed to assess its effect on liver metabolism. The peripheral effects on lipid metabolism were assessed by real-time polymerase chain reaction and Western blot. We showed that the activation of MCH receptors promotes nonalcoholic fatty liver disease through the parasympathetic nervous system, whereas it increases fat deposition in white adipose tissue via the suppression of sympathetic traffic. These metabolic actions are independent of parallel changes in food intake and energy expenditure. In the liver, MCH triggers lipid accumulation and lipid uptake, with c-Jun N-terminal kinase being an essential player, whereas in adipocytes MCH induces metabolic pathways that promote lipid storage and decreases lipid mobilization. Genetic activation of MCH receptors or infusion of MCH specifically in the lateral hypothalamic area modulated hepatic lipid metabolism, whereas the specific activation of this receptor in the arcuate nucleus affected adipocyte metabolism. Our findings show that central MCH directly controls hepatic and adipocyte metabolism through different pathways. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease.

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De Las Heras, Javier; Aldámiz-Echevarría, Luis; Martínez-Chantar, María-Luz; Delgado, Teresa C

2017-04-01

Ammonia-scavenging drugs, benzoate and phenylacetate (PA)/phenylbutyrate (PB), modulate hepatic nitrogen metabolism mainly by providing alternative pathways for nitrogen disposal. Areas covered: We review the major findings and potential novel applications of ammonia-scavenging drugs, focusing on urea cycle disorders and liver disease. Expert opinion: For over 40 years, ammonia-scavenging drugs have been used in the treatment of urea cycle disorders. Recently, the use of these compounds has been advocated in acute liver failure and cirrhosis for reducing hyperammonemic-induced hepatic encephalopathy. The efficacy and mechanisms underlying the antitumor effects of these ammonia-scavenging drugs in liver cancer are more controversial and are discussed in the review. Overall, as ammonia-scavenging drugs are usually safe and well tolerated among cancer patients, further studies should be instigated to explore the role of these drugs in liver cancer. Considering the relevance of glutamine metabolism to the progression and resolution of liver disease, we propose that ammonia-scavenging drugs might also be used to non-invasively probe liver glutamine metabolism in vivo. Finally, novel derivatives of classical ammonia-scavenging drugs with fewer and less severe adverse effects are currently being developed and used in clinical trials for the treatment of acute liver failure and cirrhosis.

Metabolism of 5-fluorouracil in human liver: an in vivo 19F NMR study

International Nuclear Information System (INIS)

Mohankrishnan, P.; Sprigg, J.; Cardwell, D.; Komoroski, R.A.; Hutchins, L.; Nauke, S.; Williamson, M.R.; Jagannathan, N.R.

1999-01-01

In vivo fluorine-19 nuclear magnetic resonance ( 19 F NMR) spectroscopy was used to study the metabolism and pharmacokinetics of 5-fluorouracil (5-FU) in human liver. Nine patients received 5-FU, and additional chemotherapeutic agents (methotrexate, leucovorin, or levamisole) either prophylactically after breast cancer surgery or for colorectal cancer. The time constant for the disappearance of 5-FU from the liver in vivo varied from 5 to 17 min, while the time constant for the appearance of α-fluoro-β-alanine (the major catabolite of 5 FU) varied from 7 to 86 min. The modulators of 5-FU metabolism did not appear to affect the time constant for the disappearance of 5-FU from the liver or for the appearance of α-fluoro-β-alanine. Results obtained indicate that the pharmacokinetics of 5-FU and α-fluoro-β-alanine may vary substantially at different times in a given individual. (author)

An enhanced in vivo stable isotope labeling by amino acids in cell culture (SILAC) model for quantification of drug metabolism enzymes.

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MacLeod, A Kenneth; Fallon, Padraic G; Sharp, Sheila; Henderson, Colin J; Wolf, C Roland; Huang, Jeffrey T-J

2015-03-01

Many of the enzymes involved in xenobiotic metabolism are maintained at a low basal level and are only synthesized in response to activation of upstream sensor/effector proteins. This induction can have implications in a variety of contexts, particularly during the study of the pharmacokinetics, pharmacodynamics, and drug-drug interaction profile of a candidate therapeutic compound. Previously, we combined in vivo SILAC material with a targeted high resolution single ion monitoring (tHR/SIM) LC-MS/MS approach for quantification of 197 peptide pairs, representing 51 drug metabolism enzymes (DME), in mouse liver. However, as important enzymes (for example, cytochromes P450 (Cyp) of the 1a and 2b subfamilies) are maintained at low or undetectable levels in the liver of unstimulated metabolically labeled mice, quantification of these proteins was unreliable. In the present study, we induced DME expression in labeled mice through synchronous ligand-mediated activation of multiple upstream nuclear receptors, thereby enhancing signals for proteins including Cyps 1a, 2a, 2b, 2c, and 3a. With this enhancement, 115 unique, lysine-containing, Cyp-derived peptides were detected in the liver of a single animal, as opposed to 56 in a pooled sample from three uninduced animals. A total of 386 peptide pairs were quantified by tHR/SIM, representing 68 Phase I, 30 Phase II, and eight control proteins. This method was employed to quantify changes in DME expression in the hepatic cytochrome P450 reductase null (HRN) mouse. We observed compensatory induction of several enzymes, including Cyps 2b10, 2c29, 2c37, 2c54, 2c55, 2e1, 3a11, and 3a13, carboxylesterase (Ces) 2a, and glutathione S-transferases (Gst) m2 and m3, along with down-regulation of hydroxysteroid dehydrogenases (Hsd) 11b1 and 17b6. Using DME-enhanced in vivo SILAC material with tHR/SIM, therefore, permits the robust analysis of multiple DME of importance to xenobiotic metabolism, with improved utility for the study of

Lowbush wild blueberries have the potential to modify gut microbiota and xenobiotic metabolism in the rat colon.

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Alison Lacombe

Full Text Available The gastrointestinal tract is populated by an array of microbial species that play an important role in metabolic and immune functions. The composition of microorganisms is influenced by the components of the host's diet and can impact health. In the present study, dietary enrichment of lowbush wild blueberries (LWB was examined to determine their effect on colon microbial composition and their potential in promoting gut health. The microbial composition and functional potential of the colon microbiota from Sprague Dawley rats fed control diets (AIN93 and LWB-enriched diets (AIN93+8% LWB powder substituting for dextrose for 6 weeks were assessed using Illumina shotgun sequencing and bioinformatics tools. Our analysis revealed an alteration in the relative abundance of 3 phyla and 22 genera as representing approximately 14 and 8% of all phyla and genera identified, respectively. The LWB-enriched diet resulted in a significant reduction in the relative abundance of the genera Lactobacillus and Enterococcus. In addition, hierarchal analysis revealed a significant increase in the relative abundance of the phylum Actinobacteria, the order Actinomycetales, and several novel genera under the family Bifidobacteriaceae and Coriobacteriaceae, in the LWB group. Functional annotation of the shotgun sequences suggested that approximately 9% of the 4709 Kyoto Encyclopaedia of Gene and Genome (KEGG hits identified were impacted by the LWB-diet. Open Reading Frames (ORFs assigned to KEGG category xenobiotics biodegradation and metabolism were significantly greater in the LWB-enriched diet compared to the control and included the pathway for benzoate degradation [PATH:ko00362] and glycosaminoglycan degradation [PATH:ko00531]. Moreover, the number of ORFs assigned to the bacterial invasion of epithelial cells [PATH:ko05100] pathway was approximately 8 fold lower in the LWB group compared to controls. This study demonstrated that LWBs have the potential to promote

Lack of the Lysosomal Membrane Protein, GLMP, in Mice Results in Metabolic Dysregulation in Liver.

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Xiang Yi Kong

Full Text Available Ablation of glycosylated lysosomal membrane protein (GLMP, formerly known as NCU-G1 has been shown to cause chronic liver injury which progresses into liver fibrosis in mice. Both lysosomal dysfunction and chronic liver injury can cause metabolic dysregulation. Glmp gt/gt mice (formerly known as Ncu-g1gt/gt mice were studied between 3 weeks and 9 months of age. Body weight gain and feed efficiency of Glmp gt/gt mice were comparable to wild type siblings, only at the age of 9 months the Glmp gt/gt siblings had significantly reduced body weight. Reduced size of epididymal fat pads was accompanied by hepatosplenomegaly in Glmp gt/gt mice. Blood analysis revealed reduced levels of blood glucose, circulating triacylglycerol and non-esterified fatty acids in Glmp gt/gt mice. Increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in Glmp gt/gt primary hepatocytes, as well as elevated triacylglycerol levels in Glmp gt/gt liver homogenates, compared to hepatocytes and liver from wild type mice. Gene expression analysis showed an increased expression of genes involved in fatty acid uptake and lipogenesis in Glmp gt/gt liver compared to wild type. Our findings are in agreement with the metabolic alterations observed in other mouse models lacking lysosomal proteins, and with alterations characteristic for advanced chronic liver injury.

Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease

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Raymond D. Hickey

2014-07-01

FAH-deficiency produced a lethal defect in utero that was corrected by administration of 2-(2-nitro-4-trifluoromethylbenzoyl-1,3 cyclohexanedione (NTBC throughout pregnancy. Animals on NTBC were phenotypically normal at birth; however, the animals were euthanized approximately four weeks after withdrawal of NTBC due to clinical decline and physical examination findings of severe liver injury and encephalopathy consistent with acute liver failure. Biochemical and histological analyses, characterized by diffuse and severe hepatocellular damage, confirmed the diagnosis of severe liver injury. FAH−/− pigs provide the first genetically engineered large animal model of a metabolic liver disorder. Future applications of FAH−/− pigs include discovery research as a large animal model of HT1 and spontaneous acute liver failure, and preclinical testing of the efficacy of liver cell therapies, including transplantation of hepatocytes, liver stem cells, and pluripotent stem cell-derived hepatocytes.

The significance of liver in metabolism of plutonium 239

International Nuclear Information System (INIS)

Netchev, Christo.

1977-01-01

Plutonium 239 has an important toxicological significance and is widely used in the nuclear industry which makes the study of its metabolism in the organism appear of substantial interest. The role of the liver in the distribution of radionuclide and its barrier capabilities, determining to a certain extent the back transport of the isotope from the blood plasma into the gut is studied. The storage of Plutonium 239 in the organ and its reexcretion by way of the gull is quantitatively demonstrated. This question is related to the exact determination of the coefficient of absorption of the radioisotope in the digestive tract. The radionuclide is inserted into organism as PuCl 3 directly into vein jugularis and vein portae. The peculiarities of its distribution in the liver by the two ways of introduction as well as the essential differences in the radioactivity of the products of excretion by portal application are described. The mechanism of the storage of the radioisotope in the organ is explained to a great extent with its physical and chemical condition in the liver tissue. Plutonium 239 is found in the liver completely as a complex compound with the tissue proteins, the combining with globulines predominating. The dynamics of exchange of the radionuclide in the organ is determined mainly by its complex combination with the globulins. The part of nuclide connected with the other protein fractions of liver is not significant and hence they do not much influence kinetics in the organ

The effect of selected metals on the central metabolic pathways in ...

African Journals Online (AJOL)

compounds, interfere with xenobiotic metabolic pathways, and may also affect glycolysis, the Krebs cycle, oxidative phosphorylation, protein amino acid metabolism as well as carbohydrate and lipid metabolism. Therefore, in this review, we discuss the two phases of the central metabolic pathways, as well as how metals ...

Inhibition of mirtazapine metabolism by Ecstasy (MDMA) in isolated perfused rat liver model.

Science.gov (United States)

Jamshidfar, Sanaz; Ardakani, Yalda H; Lavasani, Hoda; Rouini, Mohammadreza

2017-06-28

Nowadays MDMA (3,4-methylendioxymethamphetamine), known as ecstasy, is widely abused among the youth because of euphoria induction in acute exposure. However, abusers are predisposed to depression in chronic consumption of this illicit compound. Mirtazapine (MRZ), an antidepressant agent, may be prescribed in MDMA-induced depression. MRZ is extensively metabolized in liver by CYP450 isoenzymes. 8-hydroxymirtazapine (8-OH) is mainly produced by CYP2D6. N-desmethylmirtazapine (NDES) is generated by CYP3A4. MDMA is also metabolized by the mentioned isoenzymes and demonstrates mechanism-based inhibition (MBI) in association with CYP2D6. Several studies revealed that MDMA showed inhibitory effects on CYP3A4. In the present study, our aim was to evaluate the impact of MDMA on the metabolism of MRZ in liver. Therefore, isolated perfused rat liver model was applied as our model of choice in this assessment. The subjects of the study were categorized into two experimental groups. Rats in the control group received MRZ-containing Krebs-Henselit buffer (1 μg/ml). Rats in the treatment group received aqueous solution of 1 mg/ml MDMA (3 mg/kg) intraperitoneally 1 hour before receiving MRZ. Perfusate samples were analyzed by HPLC. Analyses of perfusate samples showed 80% increase in the parent drug concentrations and 50% decrease in the concentrations of both metabolites in our treatment group compared to the control group. In the treatment group compared to the control group, AUC (0-120) of the parent drug demonstrated 50% increase and AUC (0-120) of 8-OH and NDES showed 70% and 60% decrease, respectively. Observed decrease in metabolic ratios were 83% and 79% for 8-OH and NDES in treatment group compared to control group, respectively. Hepatic clearance (CL h ) and intrinsic clearance (Cl int ) showed 20% and 60% decrease in treatment group compared to control group. All findings prove the inhibitory effects of ecstasy on both CYP2D6 and CYP3A4 hepatic isoenzymes. In

Lipid biomarkers and metabolic effects of lycopene from tomato juice on liver of rats with induced hepatic steatosis.

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Bernal, Cristina; Martín-Pozuelo, Gala; Lozano, Ana B; Sevilla, Angel; García-Alonso, Javier; Canovas, Manuel; Periago, María J

2013-11-01

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver disorders, covering steatosis to nonalcoholic steatohepatitis (NASH). Dietary factors may modulate its evolution, and antioxidants have been proposed as therapeutic agents. Among them, lycopene has been demonstrated to prevent the development of steatohepatitis and even to inhibit NASH-promoted early hepatocarcinogenesis induced by a high-fat diet in rats. These conclusions have been related to its antioxidant activity; however, NAFLD is more complex than a simple redox imbalance state since it disturbs several metabolic systems in the liver. In consequence, there is a lack of information related to the action of lycopene beyond antioxidant biomarkers. In this work, NAFLD was induced in rats using a hypercholesterolemic and high-fat diet to evaluate the effect of lycopene consumption from tomato juice on liver metabolism. Several classical antioxidant biomarkers related to NAFLD were measured to check the state of this disease after 7 weeks of the controlled diet. Moreover, a metabolomics platform was applied to measure more than 70 metabolites. Results showed clear differences in the classical antioxidant biomarkers as well as in the metabolic pattern, attending not only to the diet but also to the intake of lycopene from tomato juice. Interestingly, tomato juice administration partially reverted the metabolic pattern from a high-fat diet to a normal diet even in metabolites not related to the redox state, which could lead to new targets for therapeutic agents against NAFLD and to achieving a better understanding of the role of lycopene in liver metabolism. Copyright © 2013 Elsevier Inc. All rights reserved.

(Systemic) phototoxicity of drugs and other xenobiotics.

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Beijersbergen van Henegouwen, G M

1991-08-01

Xenobiotics extensively used in drugs, cosmetics, food and agricultural chemicals can produce adverse biological effects. These toxic effects are separated into classes, e.g. hepatotoxicity, genotoxicity and neurotoxicity. Skin allergy, part of immunotoxicity, is also a subdivision of toxicology. When light is an essential condition for toxicity, the xenobiotic is called phototoxic. Thus it fits into the logic of toxicology that photoallergic compounds are a subdivision of phototoxic compounds. Phototoxicons as a group do not differ from the group of phototherapeutics with regard to their eventual biological effects. The primary photoreactions, secondary molecular processes, biomolecules involved and cellular and tissue damage are similar. The difference between the two groups is in the appreciation of the photobiological effects: adverse vs. desired. The aim of research is to determine the part of the molecular structure which makes a given compound phototoxic. With that knowledge the structure of the phototoxicon can be changed. This can result in a derivative which still has the desired properties of the parent compound, but is no longer phototoxic. This aim can be reached by combining data from both in vitro and in vivo research. The variety and number of phototoxic compounds is large. This, together with the limited research effort devoted to this subject so far, means that for most phototoxic xenobiotics a relationship between structure and in vivo photoreactivity is not available. In this review, emphasis is placed on xenobiotics whose in vitro and in vivo photochemistry have been studied. Furthermore, possible phototoxic effects which do not concern the skin but involve inner organs (systemic effects) are considered. References in this review mostly concern investigations over the last 10 years. For older literature or for additional information, references to other reviews are given. Important groups of phototoxic xenobiotics not dealt with in this article

Improved xenobiotic metabolism and reduced susceptibility to cancer in gluten-sensitive macaques upon introduction of a gluten-free diet.

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Karol Sestak

2011-04-01

Full Text Available A non-human primate (NHP model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta.Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD and gluten-containing (GD diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies,targeting expression of over 20,000 genes.When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories--cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function--this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function and actin-collagen-matrix metalloproteinases (MMP genes.A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research.

The fatty liver dystrophy (fld) mutation: Developmentally related alterations in hepatic triglyceride metabolism and protein expression

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Reue, K.; Rehnmark, S.; Cohen, R.D.; Leete, T.H.; Doolittle, M.H. [West Los Angeles VA Medical Center, CA (United States). Lipid Research Lab.]|[Univ. of California, Los Angeles, CA (United States). Dept. of Medicine; Giometti, C.S.; Mishler, K. [Argonne National Lab., IL (United States); Slavin, B.G. [Univ. of Southern California, Los Angeles, CA (United States)

1997-07-01

Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and development of a fatty liver in the early neonatal period. Also associated with the fld phenotype is a tissue-specific deficiency in the expression of lipoprotein lipase and hepatic lipase, as well as elevations in hepatic apolipoprotein A-IV and apolipoprotein C-II mRNA levels. Although these lipid abnormalities resolve at the age of weaning, adult mutant mice exhibit a peripheral neuropathy associated with abnormal myelin formation. The fatty liver in fld/fld neonates is characterized by the accumulation of large triglyceride droplets within the parenchymal cells, and these droplets persist within isolated hepatocytes maintained in culture for several days. To identify the metabolic defect that leads to lipid accumulation, the authors investigated several aspects of cellular triglyceride metabolism. The mutant mice exhibited normal activity of acid triacylglycerol lipase, an enzyme thought to be responsible for hydrolysis of dietary triglycerides in the liver. Metabolic labeling studies performed with oleic acid revealed that free fatty acids accumulate in the liver of 3 day old fld/fld mice, but not in adults. This accumulation in liver was mirrored by elevated free fatty acid levels in plasma of fld/fld neonates, with levels highest in very young mice and returning to normal by the age of one month. Quantitation of fatty acid oxidation in cells isolated from fld/fld neonates revealed that oxidation rate is reduced 60% in hepatocytes and 40% in fibroblasts; hepatocytes from adult fld/fld mice exhibited an oxidation rate similar to those from wild-type mice.

Host genes related to paneth cells and xenobiotic metabolism are associated with shifts in human ileum-associated microbial composition.

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Tianyi Zhang

Full Text Available The aim of this study was to integrate human clinical, genotype, mRNA microarray and 16 S rRNA sequence data collected on 84 subjects with ileal Crohn's disease, ulcerative colitis or control patients without inflammatory bowel diseases in order to interrogate how host-microbial interactions are perturbed in inflammatory bowel diseases (IBD. Ex-vivo ileal mucosal biopsies were collected from the disease unaffected proximal margin of the ileum resected from patients who were undergoing initial intestinal surgery. Both RNA and DNA were extracted from the mucosal biopsy samples. Patients were genotyped for the three major NOD2 variants (Leufs1007, R702W, and G908R and the ATG16L1T300A variant. Whole human genome mRNA expression profiles were generated using Agilent microarrays. Microbial composition profiles were determined by 454 pyrosequencing of the V3-V5 hypervariable region of the bacterial 16 S rRNA gene. The results of permutation based multivariate analysis of variance and covariance (MANCOVA support the hypothesis that host mucosal Paneth cell and xenobiotic metabolism genes play an important role in host microbial interactions.

Associations between liver 18F fluoro-2-deoxy-D-glucose accumulation and various clinical parameters in a Japanese population. Influence of the metabolic syndrome

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Kamimura, Kiyohisa; Nagamachi, Shigeki; Wakamatsu, Hideyuki

2010-01-01

Liver demonstrates a heterogeneous 18 F fluoro-2-deoxy-D-glucose ( 18 F-FDG) uptake pattern and sometimes shows an abnormally increased uptake even when there is no malignant tissue. The aim of this study was to evaluate the relationships of liver 18 F-FDG uptake as related to physical factors, fatty liver, blood glucose (BG), and other biochemical data. 18 F-FDG positron emission tomography (PET) imaging was performed in 101 consecutive subjects for cancer screening. Multiple stepwise regression analysis was used to define the best predictors of the liver standardized uptake value (SUV) among height, weight, waist circumference, body mass index (BMI), systolic and diastolic blood pressure, BG and other biochemical data, id est (i.e.), aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, total cholesterol, high-density lipoprotein cholesterol, triglycerides, total protein, total bilirubin, and alkaline phosphatase. Furthermore, we evaluated the association between liver 18 F-FDG uptake and the metabolic syndrome. The independent factors for increased liver 18 F-FDG uptake (mean SUV >=2) were BMI (P 18 F-FDG uptake. In addition, the liver 18 F-FDG uptake of metabolic syndrome subjects was significantly higher than that of a non-metabolic syndrome subjects. BMI was the strongest determinant of liver 18 F-FDG uptake, and the liver 18 F-FDG uptake of metabolic syndrome subjects was significantly higher than that of non-metabolic syndrome subjects. This result suggests that a subject with a high liver 18 F-FDG uptake should be screened for the metabolic syndrome. (author)

The association between donor genetic variations in one-carbon metabolism pathway genes and hepatitis B recurrence after liver transplantation.

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Lu, Di; Zhuo, Jianyong; Yang, Modan; Wang, Chao; Linhui, Pan; Xie, Haiyang; Xu, Xiao; Zheng, Shusen

2018-04-05

Hepatitis B recurrence adversely affects patients' survival after liver transplantation. This study aims to find association between donor gene variations of one carbon metabolism and post-transplant hepatitis B recurrence. This study enrolled 196 patients undergoing liver transplantation for HBV related end-stage liver diseases. We detected 11 single nucleotide polymorphisms (SNP) of 7 one-carbon metabolism pathway genes (including MTHFR, MTR, MTRR, ALDH1L1, GART, SHMT1 and CBS) in donor livers and analyzed their association with HBV reinfection after liver transplantation. Hepatitis B recurrence was observed in 19 of the 196 patients (9.7%) undergoing liver transplantation. Hepatitis B recurrence significantly affected post-transplant survival in the 196 patients (p = 0.018), and correlate with tumor recurrence in the subgroup of HCC patients (n = 99, p = 0.006). Among the 11 SNPs, donor liver mutation in rs1979277 (G > A) was adversely associated with post-transplant hepatitis B recurrence (p = 0.042). In the subgroup of HCC patients, survival analysis showed donor liver mutations in rs1801133 (G > A) and rs1979277 (G > A) were risk factors for hepatitis B recurrence (p B recurrence in non-HCC patients (n = 97, p > 0.05). Hepatitis B recurrence impaired post-transplant survival. Donor liver genetic variations in one-carbon metabolism pathway genes were significantly associated with post-transplant hepatitis B recurrence. Copyright © 2017. Published by Elsevier B.V.

Addressing the Impact of Environmental Xenobiotics in Coal-Fired Flue Gas

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Cornelia A. Bulucea

2015-03-01

Full Text Available Dangerous and unstable situations can result from the presence of environmental xenobiotics since their harmful effects on humans and ecosystems are often unpredictable, and building awareness of the environmental risk should be a main concern of humankind. The environmental xenobiotics in the flue gas from a fossil fuel-fired electrical generating station, such as particulate matter (PM, sulfur dioxide (SO2, nitrogen oxides (NOx, and carbon dioxide (CO2, are analyzed in this study, since these xenobiotics are persistent pollutants. Mathematical models of the environmental pollutant vector, estimating the emission factors specific to fossil fuel combustion, are applied to the operation of thermal units in the Turceni electrical generating station, each of which produces a net electrical power of 330 MW. For each stack gas component in the pollutant vector, emission factors and pollutant concentrations are determined. A pattern is also examined depicting the mathematically modelled processes of resonant absorption of an environmental xenobiotic harmonic oscillation by an organism modulated as an absorbing oscillator structure. The xenobiotic concentration degree is represented through a spatial concentration vector, which allows further modelling and simulation of the oscillating regime of environmental xenobiotic absorption.

Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver

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Lanaspa, Miguel A.; Sanchez-Lozada, Laura G.; Cicerchi, Christina; Li, Nanxing; Roncal-Jimenez, Carlos A.; Ishimoto, Takuji; Le, Myphuong; Garcia, Gabriela E.; Thomas, Jeffrey B.; Rivard, Christopher J.; Andres-Hernando, Ana; Hunter, Brandi; Schreiner, George; Rodriguez-Iturbe, Bernardo; Sautin, Yuri Y.; Johnson, Richard J.

2012-01-01

Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver. PMID:23112875

The Severity of Fatty Liver Disease Relating to Metabolic Abnormalities Independently Predicts Coronary Calcification

International Nuclear Information System (INIS)

Lee, Ying-Hsiang; Wu, Yih-Jer; Liu, Chuan-Chuan; Hou, Charles Jia-Yin; Yeh, Hung-I.; Tsai, Cheng-Ho; Shih, Shou-Chuan; Hung, Chung-Lieh

2011-01-01

Background. Nonalcoholic fatty liver disease (NAFLD) is one of the metabolic disorders presented in liver. The relationship between severity of NAFLD and coronary atherosclerotic burden remains largely unknown. Methods and Materials. We analyzed subjects undergoing coronary calcium score evaluation by computed tomography (MDCT) and fatty liver assessment using abdominal ultrasonography. Framingham risk score (FRS) and metabolic risk score (MRS) were obtained in all subjects. A graded, semiquantitative score was established to quantify the severity of NAFLD. Multivariate logistic regression analysis was used to depict the association between NAFLD and calcium score. Results. Of all, 342 participants (female: 22.5%, mean age: 48.7 ± 7.0 years) met the sufficient information rendering detailed analysis. The severity of NAFLD was positively associated with MRS (X 2 = 6.12, trend P < 0.001) and FRS (X 2 = 5.88, trend P < 0.001). After multivariable adjustment for clinical variables and life styles, the existence of moderate to severe NAFLD was independently associated with abnormal calcium score (P < 0.05). Conclusion. The severity of NAFLD correlated well with metabolic abnormality and was independently predict coronary calcification beyond clinical factors. Our data suggests that NAFLD based on ultrasonogram could positively reflect the burden of coronary calcification

Polycyclic aromatic hydrocarbon metabolism in mullets, Chelon labrosus, treated by polychlorinated biphenyls

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Narbonne, J.F.; Suteau, P.; Daubeze, M.; Audy, C.

1987-01-01

Contamination of the ocean by hydrocarbons has become a major environmental problem. Consequently, it is not surprising that residues of potentially toxic xenobiotics, such as benzo(a)pyrene (B(a)P), are present in marine species used as human food. The oxidative metabolism of aromatic hydrocarbons proceeds via intermediate arene oxides. Some of these metabolites are very reactive electrophiles and may interact with cellular macromolecules such as proteins, DNA and RNA. Thus, the ability of an organism to further metabolize arene oxides can be an important protective mechanism against the possible toxic effect of these molecules. The existence of hepatic cytochrome P-450 dependent monooxygenase activities in fish is now well established. The exposure of fish to polychlorinated biphenyls (PCB) increases both the monooxygenase activities and the total amount of cytochrome P-450 in the microsomal fractions of fish liver. The purpose of this study was to compare the toxication-detoxication balance in both control and PCB induced estuarine fish (Grey mullets)

Glycogen metabolism in the liver of Indian desert gerbils (Meriones hurrianae, Jerdon) exposed to internal beta irradiation

International Nuclear Information System (INIS)

Gupta, N.K.

1996-01-01

Glycogen content and the activities of phosphorylase, glycogen synthetase, phosphohexose isomerase, glucose-6-phosphatase, succinate dehydrogenase, alanine and aspartate aminotransferases have been biochemically determined in the liver of Indian desert gerbils following radiocalcium internal irradiation. Decline in glycogen, phosphohexose isomerase, with a concomitant increase in phosphorylase, succinate dehydrogenase reveals a switch over from glycolytic to oxidative metabolism in liver. Activities of aminotransferases indicate the utilization of transamination products of alanine and aspartate in oxidative pathway during early periods. Transiently increased glucose-6-phosphatase seems to restrict glycogenolytic and glycolytic metabolism and thereby pave way for the acceleration of oxidative metabolism. (author). 52 refs., 2 tabs

Regional metabolic liver function measured in patients with cirrhosis by 2-[¹⁸F]fluoro-2-deoxy-D-galactose PET/CT.

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Sørensen, Michael; Mikkelsen, Kasper S; Frisch, Kim; Villadsen, Gerda E; Keiding, Susanne

2013-06-01

There is a clinical need for methods that can quantify regional hepatic function non-invasively in patients with cirrhosis. Here we validate the use of 2-[(18)F]fluoro-2-deoxy-d-galactose (FDGal) PET/CT for measuring regional metabolic function to this purpose, and apply the method to test the hypothesis of increased intrahepatic metabolic heterogeneity in cirrhosis. Nine cirrhotic patients underwent dynamic liver FDGal PET/CT with blood samples from a radial artery and a liver vein. Hepatic blood flow was measured by indocyanine green infusion/Fick's principle. From blood measurements, hepatic systemic clearance (Ksyst, Lblood/min) and hepatic intrinsic clearance (Vmax/Km, Lblood/min) of FDGal were calculated. From PET data, hepatic systemic clearance of FDGal in liver parenchyma (Kmet, mL blood/mL liver tissue/min) was calculated. Intrahepatic metabolic heterogeneity was evaluated in terms of coefficient-of-variation (CoV, %) using parametric images of Kmet. Mean approximation of Ksyst to Vmax/Km was 86% which validates the use of FDGal as PET tracer of hepatic metabolic function. Mean Kmet was 0.157 mL blood/mL liver tissue/min, which was lower than 0.274 mL blood/mL liver tissue/min, previously found in healthy subjects (pdynamic FDGal PET/CT with arterial sampling provides an accurate measure of regional hepatic metabolic function in patients with cirrhosis. This is likely to have clinical implications for the assessment of patients with liver disease as well as treatment planning and monitoring. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Adipose Tissue Dysfunction and Altered Systemic Amino Acid Metabolism Are Associated with Non-Alcoholic Fatty Liver Disease.

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Sulin Cheng

Full Text Available Fatty liver is a major cause of obesity-related morbidity and mortality. The aim of this study was to identify early metabolic alterations associated with liver fat accumulation in 50- to 55-year-old men (n = 49 and women (n = 52 with and without NAFLD.Hepatic fat content was measured using proton magnetic resonance spectroscopy (1H MRS. Serum samples were analyzed using a nuclear magnetic resonance (NMR metabolomics platform. Global gene expression profiles of adipose tissues and skeletal muscle were analyzed using Affymetrix microarrays and quantitative PCR. Muscle protein expression was analyzed by Western blot.Increased branched-chain amino acid (BCAA, aromatic amino acid (AAA and orosomucoid were associated with liver fat accumulation already in its early stage, independent of sex, obesity or insulin resistance (p<0.05 for all. Significant down-regulation of BCAA catabolism and fatty acid and energy metabolism was observed in the adipose tissue of the NAFLD group (p<0.001for all, whereas no aberrant gene expression in the skeletal muscle was found. Reduced BCAA catabolic activity was inversely associated with serum BCAA and liver fat content (p<0.05 for all.Liver fat accumulation, already in its early stage, is associated with increased serum branched-chain and aromatic amino acids. The observed associations of decreased BCAA catabolism activity, mitochondrial energy metabolism and serum BCAA concentration with liver fat content suggest that adipose tissue dysfunction may have a key role in the systemic nature of NAFLD pathogenesis.

Conservation and divergence of chemical defense system in the tunicate Oikopleura dioica revealed by genome wide response to two xenobiotics

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Yadetie Fekadu

2012-02-01

Full Text Available Abstract Background Animals have developed extensive mechanisms of response to xenobiotic chemical attacks. Although recent genome surveys have suggested a broad conservation of the chemical defensome across metazoans, global gene expression responses to xenobiotics have not been well investigated in most invertebrates. Here, we performed genome survey for key defensome genes in Oikopleura dioica genome, and explored genome-wide gene expression using high density tiling arrays with over 2 million probes, in response to two model xenobiotic chemicals - the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP the pharmaceutical compound Clofibrate (Clo. Results Oikopleura genome surveys for key genes of the chemical defensome suggested a reduced repertoire. Not more than 23 cytochrome P450 (CYP genes could be identified, and neither CYP1 family genes nor their transcriptional activator AhR was detected. These two genes were present in deuterostome ancestors. As in vertebrates, the genotoxic compound BaP induced xenobiotic biotransformation and oxidative stress responsive genes. Notable exceptions were genes of the aryl hydrocarbon receptor (AhR signaling pathway. Clo also affected the expression of many biotransformation genes and markedly repressed genes involved in energy metabolism and muscle contraction pathways. Conclusions Oikopleura has the smallest number of CYP genes among sequenced animal genomes and lacks the AhR signaling pathway. However it appears to have basic xenobiotic inducible biotransformation genes such as a conserved genotoxic stress response gene set. Our genome survey and expression study does not support a role of AhR signaling pathway in the chemical defense of metazoans prior to the emergence of vertebrates.

The use of cultured hepatocytes to investigate the metabolism of drugs and mechanisms of drug hepatotoxicity.

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Gómez-Lechón, M J; Ponsoda, X; Bort, R; Castell, J V

2001-01-01

Hepatotoxins can be classified as intrinsic when they exert their effects on all individuals in a dose-dependent manner, and as idiosyncratic when their effects are the consequence of an abnormal metabolism of the drug by susceptible individuals (metabolic idiosyncrasy) or of an immune-mediated injury to hepatocytes (allergic hepatitis). Some xenobiotics are electrophilic, and others are biotransformed by the liver into highly reactive metabolites that are usually more toxic than the parent compound. This activation process is the key to many hepatotoxic phenomena. Mitochondria are a frequent target of hepatotoxic drugs, and the alteration of their function has immediate effects on the energy balance of cells (depletion of ATP). Lipid peroxidation, oxidative stress, alteration of Ca(2+) homeostasis, and covalent binding to cell macromolecules are the molecular mechanisms that are frequently involved in the toxicity of xenobiotics. Against these potential hazards, cells have their own defence mechanisms (for example, glutathione, DNA repair, suicide inactivation). Ultimately, toxicity is the balance between bioactivation and detoxification, which determines whether a reactive metabolite elicits a toxic effect. The ultimate goal of in vitro experiments is to generate the type of scientific information needed to identify compounds that are potentially toxic to man. For this purpose, both the design of the experiments and the interpretation of the results are critical.

Use of biomarkers to evaluate the ecological risk of xenobiotics associated with agriculture.

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Lima, Liana Bezerra Dias de; Morais, Paula Benevides de; Andrade, Ricardo Lopes Tortorela de; Mattos, Luciana Vieira; Moron, Sandro Estevan

2018-06-01

This research aimed to evaluate the ecological risk of xenobiotics associated with agricultural activities by determining metal contents and biomarker responses using tucunaré (Cichla sp.) as a bioindicator. The work was conducted in the southwest region of the state of Tocantins, in the cities of Lagoa da Confusão and Pium. Water samples and specimens of Cichla sp. were collected in the Javaés and Formoso Rivers at three collection points (A, B and C). The concentrations of Cd, Pb, Cu, Cr, Mn, Ni and Zn in water and fish were analyzed. In fish, genotoxic, biochemical (glucose serum levels, AST (aspartate aminotransferase) and ALT (alanine aminotransferase) and histological (gills and liver) biomarkers were assessed. In the water, the Cr and Mn concentrations at the three collection points exceeded the values for Class 1 rivers. In the muscle, Cr was above the maximum limit allowed for human consumption at the three collection points, although the values at Points B and C were not significantly different from that at Point A (p > 0.05). At the three collection points, the micronucleus test revealed a low frequency of micronuclei. Significant hyperglycemia and a decrease in the AST activity of the fish collected at Point C was observed. In the gills, the most frequent alterations were at Stages I and II, which indicated mild to moderate damage, and epithelial detachment was the most frequent variation. In the liver tissue, the most frequently observed histological changes were at Stages I and II and included cytoplasmic vacuolization, nuclear hypertrophy, dilated sinusoids and bile stagnation. The integrated evaluation of these biomarkers indicated that fish collected from areas with intense agricultural activities presented adaptive responses that were likely caused by the availability and bioaccumulation of certain xenobiotics in the environment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Two Horizontally Transferred Xenobiotic Resistance Gene Clusters Associated with Detoxification of Benzoxazolinones by Fusarium Species

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Glenn, Anthony E.; Davis, C. Britton; Gao, Minglu; Gold, Scott E.; Mitchell, Trevor R.; Proctor, Robert H.; Stewart, Jane E.; Snook, Maurice E.

2016-01-01

Microbes encounter a broad spectrum of antimicrobial compounds in their environments and often possess metabolic strategies to detoxify such xenobiotics. We have previously shown that Fusarium verticillioides, a fungal pathogen of maize known for its production of fumonisin mycotoxins, possesses two unlinked loci, FDB1 and FDB2, necessary for detoxification of antimicrobial compounds produced by maize, including the γ-lactam 2-benzoxazolinone (BOA). In support of these earlier studies, microarray analysis of F. verticillioides exposed to BOA identified the induction of multiple genes at FDB1 and FDB2, indicating the loci consist of gene clusters. One of the FDB1 cluster genes encoded a protein having domain homology to the metallo-β-lactamase (MBL) superfamily. Deletion of this gene (MBL1) rendered F. verticillioides incapable of metabolizing BOA and thus unable to grow on BOA-amended media. Deletion of other FDB1 cluster genes, in particular AMD1 and DLH1, did not affect BOA degradation. Phylogenetic analyses and topology testing of the FDB1 and FDB2 cluster genes suggested two horizontal transfer events among fungi, one being transfer of FDB1 from Fusarium to Colletotrichum, and the second being transfer of the FDB2 cluster from Fusarium to Aspergillus. Together, the results suggest that plant-derived xenobiotics have exerted evolutionary pressure on these fungi, leading to horizontal transfer of genes that enhance fitness or virulence. PMID:26808652

High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice.

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Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas D E; Rozen, Rima

2015-03-01

Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Folic acid-supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr(+/+) and Mthfr(+/-) mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr(+/-) mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr(+/-) livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr(+/-) mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot

The Role of Lipid and Lipoprotein Metabolism in Non‐Alcoholic Fatty Liver Disease

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Francesco Massimo Perla

2017-06-01

Full Text Available Due to the epidemic of obesity across the world, nonalcoholic fatty liver disease (NAFLD has become one of the most prevalent chronic liver disorders in children and adolescents. NAFLD comprises a spectrum of fat-associated liver conditions that can result in end-stage liver disease and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in NAFLD and may progress to nonalcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. The mechanism of the liver injury in NAFLD is currently thought to be a “multiple-hit process” where the first “hit” is an increase in liver fat, followed by multiple additional factors that trigger the inflammatory activity. At the onset of disease, NAFLD is characterized by hepatic triglyceride accumulation and insulin resistance. Liver fat accumulation is associated with increased lipotoxicity from high levels of free fatty acids, free cholesterol and other lipid metabolites. As a consequence, mitochondrial dysfunction with oxidative stress and production of reactive oxygen species and endoplasmic reticulum stress-associated mechanisms, are activated. The present review focuses on the relationship between intra-cellular lipid accumulation and insulin resistance, as well as on lipid and lipoprotein metabolism in NAFLD.

Oxidation and adduct formation of xenobiotics in a microfluidic electrochemical cell with boron doped diamond electrodes and an integrated passive gradient rotation mixer

NARCIS (Netherlands)

van den Brink, Floris Teunis Gerardus; Wigger, Tina; Ma, Liwei; Odijk, Mathieu; Olthuis, Wouter; Karst, U.; van den Berg, Albert

2016-01-01

Reactive xenobiotic metabolites and their adduct formation with biomolecules such as proteins are important to study as they can be detrimental to human health. Here, we present a microfluidic electrochemical cell with integrated micromixer to study phase I and phase II metabolism as well as protein

Gene expression of drug metabolizing enzymes in adult and aged mouse liver: A modulation by immobilization stress

International Nuclear Information System (INIS)

Mikhailova, O.N.; Gulyaeva, L.F.; Filipenko, M.L.

2005-01-01

The role of stress in the regulation of enzymatic systems involved in the biotransformation of xenobiotics, as well as endogenous substrates in the liver was investigated using single immobilization stress as a model. Adult (3 months of age) and aged (26 months) C3H/a male mice were used. Cytochrome P450 1A1 and 1A2 (CYP1A1 and CYP1A2), glutathione S-transferase M1 (GSTM1), aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor nuclear translocator (ARNT) and catechol-O-methyltransferase (COMT) mRNA levels in the mouse liver were measured by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. Excluding CYP1A1, experiments revealed significant differences in the expression of these genes between adult- and aged-control animals. The influence of stress on the expression of genes studied was shown to be higher in adult mice than in aged ones. Our results clearly demonstrate the lack of response or even the attenuation of gene expression in aged animals that may play an important role in age-related pathologies and diseases

Aetiology and pathogenesis of alcoholic liver disease.

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Lieber, C S

1993-09-01

Until the 1960s, liver disease of the alcoholic patient was attributed exclusively to dietary deficiencies. Since then, however, our understanding of the impact of alcoholism on nutritional status has undergone a progressive evolution. Alcohol, because of its high energy content, was at first perceived to act exclusively as 'empty calories' displacing other nutrients in the diet, and causing primary malnutrition through decreased intake of essential nutrients. With improvement in the overall nutrition of the population, the role of primary malnutrition waned and secondary malnutrition was emphasized as a result of a better understanding of maldigestion and malabsorption caused by chronic alcohol consumption and various diseases associated with chronic alcoholism. At the same time, the concept of the direct toxicity of alcohol came to the forefront as an explanation for the widespread cellular injury. Some of the hepatotoxicity was found to result from the metabolic disturbances associated with the oxidation of ethanol via the liver alcohol dehydrogenase (ADH) pathway and the redox changes produced by the generated NADH, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone contributes to the exacerbation of the ethanol-induced lesions in zone 3. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450IIE1 (CYP2E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by CYP2E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, 'over the counter' analgesics, chemical

Xenobiotics-induced hepatotoxicity and an influence of HLA typisation

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Žunić Miodrag

2014-01-01

, Antibiotics (4 pts, Vitamins (3 pts, Antihypertensive drugs (3 pts, Antiplatelet drugs (2 pts, Anticonvulsants (2 pts, Drugs for osteoporosis (2 pts, Antihipertireoidni drugs (1 pt, Oral antidiabetic agents (1 pt, Oral contraceptives (1 pt, Glucocorticoids (1 pt and Antidepressants (1 pt. We got the results of HLA typing for 29 patients of the 52 patients with hepatotoxic liver injury and for 22 patients of 52 patients with chronic viral hepatitis. Conclusion: The paper points to hepatotoxicity, which is not rare in our population. Structure of xenobiotics causing liver toxicity in our environment is mainly industrial toxins, as well as food and beverages, more than drugs. It would be necessary to examine what are the ingredients of food causing hepatotoxicity. It would be very important to cover the wider population with HLA typing, in order to create a database with the frequency of certain HLA haplotypes in our population for the identification of patients at risk for developing hepatotoxicity.

Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet

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Sestak, Karol; Conroy, Lauren; Aye, Pyone P.; Mehra, Smriti; Doxiadis, Gaby G.; Kaushal, Deepak

2011-01-01

Background A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta). Methodology Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes. Principal Findings When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories - cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function - this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes. Conclusions/Significance A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research. PMID:21533263

Diet and liver apoptosis in rats: a particular metabolic pathway.

Science.gov (United States)

Monteiro, Maria Emilia Lopes; Xavier, Analucia Rampazzo; Azeredo, Vilma Blondet

2017-03-30

Various studies have indicated an association between modifi cation in dietary macronutrient composition and liver apoptosis. To explain how changes in metabolic pathways associated with a high-protein, high-fat, and low-carbohydrate diet causes liver apoptosis. Two groups of rats were compared. An experimental diet group (n = 8) using a high-protein (59.46%), high-fat (31.77%), and low-carbohydrate (8.77%) diet versus a control one (n = 9) with American Institute of Nutrition (AIN)-93-M diet. Animals were sacrificed after eight weeks, the adipose tissue weighed, the liver removed for flow cytometry analysis, and blood collected to measure glucose, insulin, glucagon, IL-6, TNF, triglycerides, malondialdehyde, and β-hydroxybutyrate. Statistical analysis was carried out using the unpaired and parametric Student's t-test and Pearson's correlation coeffi ents. Significance was set at p triglycerides lower levels compared with the control group. The results show a positive and significant correlation between the percentage of nonviable hepatocytes and malondialdehyde levels (p = 0.0217) and a statistically significant negative correlation with triglycerides levels (p = 0.006). Results suggest that plasmatic malondialdehyde and triglyceride levels are probably good predictors of liver damage associated with an experimental low-carbohydrate diet in rats.

Pigs in Toxicology: Breed Differences in Metabolism and Background Findings.

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Helke, Kristi L; Nelson, Keith N; Sargeant, Aaron M; Jacob, Binod; McKeag, Sean; Haruna, Julius; Vemireddi, Vimala; Greeley, Melanie; Brocksmith, Derek; Navratil, Nicole; Stricker-Krongrad, Alain; Hollinger, Charlotte

2016-06-01

Both a rodent and a nonrodent species are required for evaluation in nonclinical safety studies conducted to support human clinical trials. Historically, dogs and nonhuman primates have been the nonrodent species of choice. Swine, especially the miniature swine or minipigs, are increasingly being used in preclinical safety as an alternate nonrodent species. The pig is an appropriate option for these toxicology studies based on metabolic pathways utilized in xenobiotic biotransformation. Both similarities and differences exist in phase I and phase II biotransformation pathways between humans and pigs. There are numerous breeds of pigs, yet only a few of these breeds are characterized with regard to both xenobiotic-metabolizing enzymes and background pathology findings. Some specific differences in these enzymes based on breed and sex are known. Although swine have been used extensively in biomedical research, there is also a paucity of information in the current literature detailing the incidence of background lesions and differences between commonly used breeds. Here, the xenobiotic-metabolizing enzymes are compared between humans and pigs, and minipig background pathology changes are reviewed with emphasis on breed differences. © The Author(s) 2016.

Effects of disturbed liver growth and oxidative stress of high-fat diet-fed dams on cholesterol metabolism in offspring mice.

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Kim, Juyoung; Kim, Juhae; Kwon, Young Hye

2016-08-01

Changes in nutritional status during gestation and lactation have detrimental effects on offspring metabolism. Several animal studies have shown that maternal high-fat diet (HFD) can predispose the offspring to development of obesity and metabolic diseases, however the mechanisms underlying these transgenerational effects are poorly understood. Therefore, we examined the effect of maternal HFD consumption on metabolic phenotype and hepatic expression of involved genes in dams to determine whether any of these parameters were associated with the metabolic outcomes in the offspring. Female C57BL/6 mice were fed a low-fat diet (LFD: 10% calories from fat) or a high-fat diet (HFD: 45% calories from fat) for three weeks before mating, and during pregnancy and lactation. Dams and their male offspring were studied at weaning. Dams fed an HFD had significantly higher body and adipose tissue weights and higher serum triglyceride and cholesterol levels than dams fed an LFD. Hepatic lipid levels and mRNA levels of genes involved in lipid metabolism, including LXRα, SREBP-2, FXR, LDLR, and ABCG8 were significantly changed by maternal HFD intake. Significantly lower total liver DNA and protein contents were observed in dams fed an HFD, implicating the disturbed liver adaptation in the pregnancy-related metabolic demand. HFD feeding also induced significant oxidative stress in serum and liver of dams. Offspring of dams fed an HFD had significantly higher serum cholesterol levels, which were negatively correlated with liver weights of dams and positively correlated with hepatic lipid peroxide levels in dams. Maternal HFD consumption induced metabolic dysfunction, including altered liver growth and oxidative stress in dams, which may contribute to the disturbed cholesterol homeostasis in the early life of male mice offspring.

Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation.

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Fu, Peter P

2017-01-17

Pyrrolizidine alkaloids (PAs) and PA N-oxides are a class of phytochemical carcinogens contained in over 6000 plant species spread around the world. It has been estimated that approximately half of the 660 PAs and PA N-oxides that have been characterized are cytotoxic, genotoxic, and tumorigenic. It was recently determined that a genotoxic mechanism of liver tumor initiation mediated by PA-derived DNA adducts is a common metabolic activation pathway of a number of PAs. We proposed this set of PA-derived DNA adducts could be a common biological biomarker of PA exposure and a potential biomarker of PA-induced liver tumor formation. We have also found that several reactive secondary pyrrolic metabolites can dissociate and interconvert to other secondary pyrrolic metabolites, resulting in the formation of the same exogenous DNA adducts. This present perspective reports the current progress on these new findings and proposes future research needed for obtaining a greater understanding of the role of this activation pathway and validating the use of this set of PA-derived DNA adducts as a biological biomarker of PA-induced liver tumor initiation.

Liver X receptor alpha mediated genistein induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1) in Hep G2 cells

Energy Technology Data Exchange (ETDEWEB)

Chen, Yue; Zhang, Shunfen [Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078 (United States); Zhou, Tianyan [Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100083 (China); Huang, Chaoqun; McLaughlin, Alicia [Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078 (United States); Chen, Guangping, E-mail: guangping.chen@okstate.edu [Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078 (United States)

2013-04-15

Cytosolic sulfotransferases are one of the major families of phase II drug metabolizing enzymes. Sulfotransferase-catalyzed sulfonation regulates hormone activities, metabolizes drugs, detoxifies xenobiotics, and bioactivates carcinogens. Human dehydroepiandrosterone sulfotransferase (hSULT2A1) plays important biological roles by sulfating endogenous hydroxysteroids and exogenous xenobiotics. Genistein, mainly existing in soy food products, is a naturally occurring phytoestrogen with both chemopreventive and chemotherapeutic potential. Our previous studies have shown that genistein significantly induces hSULT2A1 in Hep G2 and Caco-2 cells. In this study, we investigated the roles of liver X receptor (LXRα) in the genistein induction of hSULT2A1. LXRs have been shown to induce expression of mouse Sult2a9 and hSULT2A1 gene. Our results demonstrate that LXRα mediates the genistein induction of hSULT2A1, supported by Western blot analysis results, hSULT2A1 promoter driven luciferase reporter gene assay results, and mRNA interference results. Chromatin immunoprecipitation (ChIP) assay results demonstrate that genistein increase the recruitment of hLXRα binding to the hSULT2A1 promoter. These results suggest that hLXRα plays an important role in the hSULT2A1 gene regulation. The biological functions of phytoestrogens may partially relate to their induction activity toward hydroxysteroid SULT. - Highlights: ► Liver X receptor α mediated genistein induction of hSULT2A1 in Hep G2 cells. ► LXRα and RXRα dimerization further activated this induction. ► Western blot results agreed well with luciferase reporter gene assay results. ► LXRs gene silencing significantly decreased hSULT2A1 expression. ► ChIP analysis suggested that genistein enhances hLXRα binding to the hSULT2A1 promoter.

Effects of Ginkgo biloba extract on free radical metabolism of liver in ...

African Journals Online (AJOL)

This study investigated the effect of Ginkgo biloba extract on Free Radical Metabolism of Liver in mice during endurance exercise. Forty-eight mice were divided into the quiet group and the exercised group. And the two groups were both grouped again, including the control group and the drug-treated group.

Influence of nutrition on liver oxidative metabolism.

Science.gov (United States)

Jorquera, F; Culebras, J M; González-Gallego, J

1996-06-01

The liver plays a major role in the disposition of the majority of drugs. This is due to the presence of several drug-metabolizing enzyme systems, including a group of membrane-bound mixed-function oxidative enzymes, mainly the cytochrome P450 system. Hepatic oxidative capacity can be assessed by changes in antipyrine metabolism. Different drugs and other factors may induce or inhibit the cytochrome P450-dependent system. This effect is important in terms of the efficacy or toxicity of drugs that are substrates for the system. Microsomal oxidation in animals fed with protein-deficient diets is depressed. The mixed-function oxidase activity recovers after a hyperproteic diet or the addition of lipids. Similar findings have been reported in patients with protein-calorie malnutrition, although results in the elderly are conflicting. Different studies have revealed that microsomal oxidation is impaired by total parenteral nutrition and that this effect is absent when changing the caloric source from carbohydrates to a conventional amino acid solution or after lipid addition, especially when administered as medium-chain/long-chain triglyceride mixtures. Peripheral parenteral nutrition appears to increase antipyrine clearance.

Geraniol Pharmacokinetics, Bioavailability and Its Multiple Effects on the Liver Antioxidant and Xenobiotic-Metabolizing Enzymes

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Barbara Pavan

2018-01-01

Full Text Available Geraniol is a natural monoterpene showing anti-inflammatory, antioxidant, neuroprotective and anticancer effects. No pharmacokinetic and bioavailability data on geraniol are currently available. We therefore performed a systematic study to identify the permeation properties of geraniol across intestinal cells, and its pharmacokinetics and bioavailability after intravenous and oral administration to rats. In addition, we systematically investigated the potential hepatotoxic effects of high doses of geraniol on hepatic phase I, phase II and antioxidant enzymatic activities and undertook a hematochemical analysis on mice. Permeation studies performed via HPLC evidenced geraniol permeability coefficients across an in vitro model of the human intestinal wall for apical to basolateral and basolateral to apical transport of 13.10 ± 2.3 × 10-3 and 2.1 ± 0.1⋅× 10-3 cm/min, respectively. After intravenous administration of geraniol to rats (50 mg/kg, its concentration in whole blood (detected via HPLC decreased following an apparent pseudo-first order kinetics with a half-life of 12.5 ± 1.5 min. The absolute bioavailability values of oral formulations (50 mg/kg of emulsified geraniol or fiber-adsorbed geraniol were 92 and 16%, respectively. Following emulsified oral administration, geraniol amounts in the cerebrospinal fluid of rats ranged between 0.72 ± 0.08 μg/mL and 2.6 ± 0.2 μg/mL within 60 min. Mice treated with 120 mg/kg of geraniol for 4 weeks showed increased anti-oxidative defenses with no signs of liver toxicity. CYP450 enzyme activities appeared only slightly affected by the high dosage of geraniol.

Differential effect of waterborne cadmium exposure on lipid metabolism in liver and muscle of yellow catfish Pelteobagrus fulvidraco

International Nuclear Information System (INIS)

Chen, Qi-Liang; Gong, Yuan; Luo, Zhi; Zheng, Jia-Lang; Zhu, Qing-Ling

2013-01-01

Highlights: •Cd triggered hepatic lipid accumulation through the improvement of lipogenesis. •Lipid homeostasis in muscle after Cd exposure derived from the down-regulation of both lipogenesis and lipolysis. •Our study determines the mechanism of waterborne Cd exposure on lipid metabolism in fish on a molecular level. •Our study indicates the tissue-specific regulatory effect of lipid metabolism under waterborne Cd exposure. -- Abstract: The present study was conducted to investigate the effect of waterborne cadmium (Cd) exposure on lipid metabolism in liver and muscle of juvenile yellow catfish Pelteobagrus fulvidraco. Yellow catfish were exposed to 0 (control), 0.49 and 0.95 mg Cd/l, respectively, for 6 weeks, the lipid deposition, Cd accumulation, the activities and expression level of several enzymes as well as the mRNA expression of transcription factors involved in lipid metabolism in liver and muscle were determined. Waterborne Cd exposure reduced growth performance, but increased Cd accumulation in liver and muscle. In liver, lipid content, the activities and the mRNA expression of lipogenic enzymes (6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), fatty acid synthetase (FAS)) and lipoprotein lipase (LPL) activity increased with increasing waterborne Cd concentrations. However, the mRNA expressions of LPL and peroxisome proliferators-activated receptor (PPAR) α were down-regulated by Cd exposure. Carnitine palmitoyltransferase 1 (CPT1) activity as well as the mRNA expressions of CPT1 and PPARγ showed no significant differences among the treatments. In muscle, lipid contents showed no significant differences among the treatments. The mRNA expression of 6PGD, FAS, CPT1, LPL, PPARα and PPARγ were down-regulated by Cd exposure. Thus, our study indicated that Cd triggered hepatic lipid accumulation through the improvement of lipogenesis, and that lipid homeostasis in muscle was probably conducted by the down

Differential effect of waterborne cadmium exposure on lipid metabolism in liver and muscle of yellow catfish Pelteobagrus fulvidraco

Energy Technology Data Exchange (ETDEWEB)

Chen, Qi-Liang; Gong, Yuan [Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan 430070 (China); Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Wuhan 430070 (China); Luo, Zhi, E-mail: luozhi99@mail.hzau.edu.cn [Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan 430070 (China); Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Wuhan 430070 (China); Zheng, Jia-Lang; Zhu, Qing-Ling [Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan 430070 (China); Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Wuhan 430070 (China)

2013-10-15

Highlights: •Cd triggered hepatic lipid accumulation through the improvement of lipogenesis. •Lipid homeostasis in muscle after Cd exposure derived from the down-regulation of both lipogenesis and lipolysis. •Our study determines the mechanism of waterborne Cd exposure on lipid metabolism in fish on a molecular level. •Our study indicates the tissue-specific regulatory effect of lipid metabolism under waterborne Cd exposure. -- Abstract: The present study was conducted to investigate the effect of waterborne cadmium (Cd) exposure on lipid metabolism in liver and muscle of juvenile yellow catfish Pelteobagrus fulvidraco. Yellow catfish were exposed to 0 (control), 0.49 and 0.95 mg Cd/l, respectively, for 6 weeks, the lipid deposition, Cd accumulation, the activities and expression level of several enzymes as well as the mRNA expression of transcription factors involved in lipid metabolism in liver and muscle were determined. Waterborne Cd exposure reduced growth performance, but increased Cd accumulation in liver and muscle. In liver, lipid content, the activities and the mRNA expression of lipogenic enzymes (6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), fatty acid synthetase (FAS)) and lipoprotein lipase (LPL) activity increased with increasing waterborne Cd concentrations. However, the mRNA expressions of LPL and peroxisome proliferators-activated receptor (PPAR) α were down-regulated by Cd exposure. Carnitine palmitoyltransferase 1 (CPT1) activity as well as the mRNA expressions of CPT1 and PPARγ showed no significant differences among the treatments. In muscle, lipid contents showed no significant differences among the treatments. The mRNA expression of 6PGD, FAS, CPT1, LPL, PPARα and PPARγ were down-regulated by Cd exposure. Thus, our study indicated that Cd triggered hepatic lipid accumulation through the improvement of lipogenesis, and that lipid homeostasis in muscle was probably conducted by the down

Bone metabolism dynamics in the early post-transplant period following kidney and liver transplantation.

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Schreiber, Peter W; Bischoff-Ferrari, Heike A; Boggian, Katia; Bonani, Marco; van Delden, Christian; Enriquez, Natalia; Fehr, Thomas; Garzoni, Christian; Hirsch, Hans H; Hirzel, Cédric; Manuel, Oriol; Meylan, Pascal; Saleh, Lanja; Weisser, Maja; Mueller, Nicolas J

2018-01-01

Bone disease contributes to relevant morbidity after solid organ transplantation. Vitamin D has a crucial role for bone metabolism. Activation of vitamin D depends on the endocrine function of both, liver and kidney. Our study assessed key markers of bone metabolism at time of transplantation and 6 months after transplantation among 70 kidney and 70 liver recipients. In 70 kidney recipients 25-OH vitamin D levels did not differ significantly between peri-transplant (median 32.5nmol/l) and 6 months post-transplant (median 41.9nmol/l; P = 0.272). Six months post-transplant median 1, 25-(OH)2 vitamin D levels increased by >300% (from 9.1 to 36.5ng/l; Ptransplantation and of intact parathyroid hormone 6 months post-transplant. Among 70 liver recipients, 25-OH vitamin D, 1, 25-(OH)2 vitamin D and intact parathyroid hormone levels were not significantly altered between peri-transplant and 6 months post-transplant. Contrary to kidney recipients, median CTx increased by 60.0% (from 0.45 to 0.72 ng/ml; P = 0.002) and P1NP by 49.3% (from 84.0 to 125.4ng/ml; P = 0.001) in the longitudinal course. Assessed biomarkers didn't differ between liver recipients with and without fractures. To conclude, the assessed panel of biomarkers proved highly dynamic after liver as well as kidney transplantation in the early post-transplant period. After kidney transplantation a significant gain in 1, 25-(OH)2 vitamin D combined with a decline in iPTH, CTx and P1NP, whereas after liver transplantation an increase in CTx and P1NP were characteristic.

Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome.

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Keiyu Oshida

Full Text Available The growth hormone (GH-activated transcription factor signal transducer and activator of transcription 5b (STAT5b is a key regulator of sexually dimorphic gene expression in the liver. Suppression of hepatic STAT5b signaling is associated with lipid metabolic dysfunction leading to steatosis and liver cancer. In the companion publication, a STAT5b biomarker gene set was identified and used in a rank-based test to predict both increases and decreases in liver STAT5b activation status/function with high (≥ 97% accuracy. Here, this computational approach was used to identify chemicals and hormones that activate (masculinize or suppress (feminize STAT5b function in a large, annotated mouse liver and primary hepatocyte gene expression compendium. Exposure to dihydrotestosterone and thyroid hormone caused liver masculinization, whereas glucocorticoids, fibroblast growth factor 15, and angiotensin II caused liver feminization. In mouse models of diabetes and obesity, liver feminization was consistently observed and was at least partially reversed by leptin or resveratrol exposure. Chemical-induced feminization of male mouse liver gene expression profiles was a relatively frequent phenomenon: of 156 gene expression biosets from chemically-treated male mice, 29% showed feminization of liver STAT5b function, while <1% showed masculinization. Most (93% of the biosets that exhibited feminization of male liver were also associated with activation of one or more xenobiotic-responsive receptors, most commonly constitutive activated receptor (CAR or peroxisome proliferator-activated receptor alpha (PPARα. Feminization was consistently associated with increased expression of peroxisome proliferator-activated receptor gamma (Pparg but not other lipogenic transcription factors linked to steatosis. GH-activated STAT5b signaling in mouse liver is thus commonly altered by diverse chemicals, and provides a linkage between chemical exposure and dysregulated gene

High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice12345

Science.gov (United States)

Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas DE

2015-01-01

Background: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Design: Folic acid–supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr+/+ and Mthfr+/− mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Results: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr+/− mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr+/− livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr+/− mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2

Celastrol ameliorates liver metabolic damage caused by a high-fat diet through Sirt1

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Yinliang Zhang

2017-01-01

. Conclusions: Celastrol ameliorates NAFLD by decreasing lipid synthesis and improving the anti-oxidative and anti-inflammatory status. And Sirt1 has an important role in Celastrol-ameliorating liver metabolic damage caused by HFD. Keywords: Nonalcoholic fatty liver disease, Celastrol, Sirt1, Lipid metabolism, Chronic inflammation, Oxidative stress

Energy metabolism and biotransformation as endpoints to pre-screen hepatotoxicity using a liver spheroid model

International Nuclear Information System (INIS)

Xu Jinsheng; Purcell, Wendy M.

2006-01-01

The current study investigated liver spheroid culture as an in vitro model to evaluate the endpoints relevant to the status of energy metabolism and biotransformation after exposure to test toxicants. Mature rat liver spheroids were exposed to diclofenac, galactosamine, isoniazid, paracetamol, m-dinitrobenzene (m-DNB) and 3-nitroaniline (3-NA) for 24 h. Pyruvate uptake, galactose biotransformation, lactate release and glucose secretion were evaluated after exposure. The results showed that pyruvate uptake and lactate release by mature liver spheroids in culture were maintained at a relatively stable level. These endpoints, together with glucose secretion and galactose biotransformation, were related to and could reflect the status of energy metabolism and biotransformation in hepatocytes. After exposure, all of the test agents significantly reduced glucose secretion, which was shown to be the most sensitive endpoint of those evaluated. Diclofenac, isoniazid, paracetamol and galactosamine reduced lactate release (P < 0.01), but m-DNB increased lactate release (P < 0.01). Diclofenac, isoniazid and paracetamol also reduced pyruvate uptake (P < 0.01), while galactosamine had little discernible effect. Diclofenac, galactosamine, paracetamol and m-DNB also reduced galactose biotransformation (P < 0.01), by contrast, isoniazid did not. The metabolite of m-DNB, 3-NA, which served as a negative control, did not cause significant changes in lactate release, pyruvate uptake or galactose biotransformation. It is concluded that pyruvate uptake, galactose biotransformation, lactate release and glucose secretion can be used as endpoints for evaluating the status of energy metabolism and biotransformation after exposure to test agents using the liver spheroid model to pre-screen hepatotoxicity

Intestinal first pass metabolism of midazolam in liver cirrhosis --effect of grapefruit juice

DEFF Research Database (Denmark)

Andersen, Vibeke; Pedersen, Natalie; Larsen, Niels-Erik

2002-01-01

Grapefruit juice inhibits CYP3A4 in the intestinal wall leading to a reduced intestinal first pass metabolism and thereby an increased oral bioavailability of certain drugs. For example, it has been shown that the oral bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy...... subjects after ingestion of grapefruit juice. However, this interaction has not been studied in patients with impaired liver function. Accordingly, the effect of grapefruit juice on the AUC of midazolam and the metabolite alpha-hydroxymidazolam was studied in patients with cirrhosis of the liver....

Alteration of liver parameters in non-alcoholic fatty liver disease in patients with metabolic síndrome

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Alicia Sahuquillo Martínez

2016-06-01

Full Text Available The interest of non-alcoholic fatty liver disease (NAFLD is growing due to several reasons: high prevalence of the disease in the Western World, its capability to progress towards more aggressive histological forms and its association with diseases that increase cardiovascular risk. Objective: To analyze the alteration of liver parameters in NAFLD in patients with metabolic syndrome. Methods: A transverse, descriptive study of 100 patients with two or more cardiovascular risk factors was conducted. All patients signed informed consent. Patients selected were among those attending our Medical Office of Primary Attention and who had very little or no alcoholic consumption. A complete battery of analysis was performed including total abdominal ultrasound. Steatosis was evaluated and, if determined positive, patients were stratified in three degrees. The following determinations were collected: sex, personal and familial history of diabetes, arterial hypertension, dyslipidemia, age, weight, BMI, present pharmacological treatment, analytical parameters, blood pressure and abdominal perimeter. Results: 100 patients were included in the study, 56 (56% women and 44 (44% men, with an average age of 61,84 + 9,5 years 23% of all patients did not have NAFLD; 29% had mild NAFLD, 29% had moderate NAFLD and 19% had severe NAFLD. 82% of men presented NAFLD. 29% of women did not nave NAFLD. 22% were overweight and 38% were obese. Blood pressure was altered in 22% of men and 18% of women. 60% had altered fasting blood glucose. 36% had hypertriglyceridemia, 41% hypercholesterolemia with 65% high LDL cholesterol and 16% of low HDL cholesterol. 83% of patients had two or more criteria of metabolic syndrome. Average transaminases were: ALT 24.98 u/i; AST 32.19 u/i; GGT 55,65 u/i; ALT/AST ratio: 0.77. Lactate dehydrogenase 255.30 u/L. Alkaline phosphatase 82.80 u/L and bilirubin 0.78 mg/dL Conclusions: We did not find correlation between liver steatosis and alteration

acute toxicity and effect of fenitrothion on liver esterase of fish

African Journals Online (AJOL)

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physiological state thereby changing the biochemi- cal constituent of aquatic organisms. It is well known that xenobiotics are enzymati- cally metabolised in the liver of fish. According to. Chambers et al. (1994), phosphrothionate insecti- cides and their active metabolites can be detoxified by a variety of hepatic mechanisms.

Effects of castration on expression of lipid metabolism genes in the liver of korean cattle.

Science.gov (United States)

Baik, Myunggi; Nguyen, Trang Hoa; Jeong, Jin Young; Piao, Min Yu; Kang, Hyeok Joong

2015-01-01

Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (pcastration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2) and fatty acid (FA) oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase) between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL) secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP) protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration.

Adipose Tissue Dysfunction and Altered Systemic Amino Acid Metabolism Are Associated with Non-Alcoholic Fatty Liver Disease

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Cheng, Sulin; Wiklund, Petri; Autio, Reija; Borra, Ronald; Ojanen, Xiaowei; Xu, Leiting; Törmäkangas, Timo; Alen, Markku

2015-01-01

BACKGROUND: Fatty liver is a major cause of obesity-related morbidity and mortality. The aim of this study was to identify early metabolic alterations associated with liver fat accumulation in 50- to 55-year-old men (n = 49) and women (n = 52) with and without NAFLD. METHODS: Hepatic fat content was

Transcriptome Analyses Reveal Lipid Metabolic Process in Liver Related to the Difference of Carcass Fat Content in Rainbow Trout (Oncorhynchus mykiss

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Guo Hu

2016-01-01

Full Text Available Excessive accumulation of carcass fat in farm animals, including fish, has a significant impact on meat quality and on the cost of feeding. Similar to farmed animals and humans, the liver can be considered one of the most important organs involved in lipid metabolism in rainbow trout (Oncorhynchus mykiss. RNA-seq based whole transcriptome sequencing was performed to liver tissue of rainbow trout with high and low carcass fat content in this study. In total 1,694 differentially expressed transcripts were identified, including many genes involved in lipid metabolism, such as L-FABP, adiponectin, PPAR-α, PPAR-β, and IGFBP1a. Evidence presented in this study indicated that lipid metabolic process in liver may be related to the difference of carcass fat content. The relevance of PPAR-α and PPAR-β as molecular markers for fat storage in liver should be worthy of further investigation.

Independent and supra-additive effects of alcohol consumption, cigarette smoking, and metabolic syndrome on the elevation of serum liver enzyme levels.

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Eun Young Park

Full Text Available We investigated the independent and combined effects of alcohol consumption, cigarette smoking and metabolic syndrome on abnormal liver function, i.e., the elevation of serum liver enzyme levels. Participants of a Korean population-based prospective cohort aged ≥30 years without liver disease, diabetes, or cardiovascular diseases were included. Information on alcohol consumption, smoking status, and metabolic syndrome, defined as per the criteria of the Adult Treatment Panel III, were applied to evaluate their impact on serum levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT, and gamma-glutamyl transferase (GGT. Alcohol consumption, cigarette smoking and metabolic syndrome were the significant individual factors that elevated serum liver enzyme levels. Supra-additive effects of metabolic syndrome and either alcohol consumption or cigarette smoking were also identified. The combination of heavy drinking (≥24 g/day and metabolic syndrome conferred an effect that was higher than the sum of the two individual effects (Synergic Index (SI: AST, 2.37 [1.20-4.67]; GGT, 1.91 [1.17-3.13]. Only GGT level (odds ratio 6.04 [3.68-9.94], SI 2.33 [1.24-4.41] was significantly elevated when the effect of moderate drinking (20 pack years, 1.80 for ≥24 g/day and ≤20 pack years, 2.03 for ≥24 g/day and >20 pack years, while only the combined effect of drinking ≥24 g/day and smoking >20 pack years elevated the AST level (SI 4.55 [3.12-6.61]. The combined effect of cigarette smoking and metabolic syndrome was not supra-additive. To prevent fatty liver disease and other related diseases, a multifactorial prevention strategy that includes limited alcohol consumption, smoking cessation and rectification of adverse metabolic profiles is required.

The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep.

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Hogg, Kirsten; Wood, Charlotte; McNeilly, Alan S; Duncan, W Colin

2011-01-01

Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS). We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin-like growth factor (IGF) and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5) or testosterone propionate (TP; n = 9) twice weekly (100 mg; i.m) from d62-102 (gestation 147 days). In a novel treatment paradigm, a second cohort received a direct C (n = 4) or TP (20 mg; n = 7) fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (Pfetal intervention (C and TP) led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK) was up-regulated in the fetal controls (Pfetal TP (Pfetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.

Induced hypoglycemia for 48 hours indicates differential glucose and insulin effects on liver metabolism in dairy cows.

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Kreipe, L; Vernay, M C M B; Oppliger, A; Wellnitz, O; Bruckmaier, R M; van Dorland, H A

2011-11-01

Hypoglycemia is a characteristic condition of early lactation dairy cows and is subsequently dependent on, and may affect, metabolism in the liver. The objective of the present study was to investigate the effects of induced hypoglycemia, maintained for 48 h, on metabolic parameters in plasma and liver of mid-lactation dairy cows. The experiment involved 3 treatments, including a hyperinsulinemic hypoglycemic clamp (HypoG, n=6) to obtain a glucose concentration of 2.5 mmol/L, a hyperinsulinemic euglycemic clamp (EuG, n=6) in which the effect of insulin was studied, and a control treatment with a 0.9% saline solution (NaCl, n=6). Blood samples for measurements of insulin, metabolites, and enzymes were taken at least once per hour. Milk yield was recorded and milk samples were collected before and after treatment. Liver biopsies were obtained before and after treatment to measure mRNA abundance by real-time, quantitative reverse transcription-PCR of 12 candidate genes involved in the main metabolic pathways. Milk yield decreased in HypoG and NaCl cows, whereas it remained unaffected in EuG cows. Energy-corrected milk yield (kg/d) was only decreased in HypoG cows. In plasma, concentration of β-hydroxybutyrate decreased in response to treatment in EuG cows and was lower (0.41±0.04 mmol/L) on d 2 of the treatment compared with that in HypoG and NaCl cows (on average 0.61±0.03 mmol/L, respectively). Nonesterified fatty acids remained unaffected in all treatments. In the liver, differences between treatments for their effects were only observed in case of mitochondrial phosphoenolpyruvate carboxykinase (PEPCKm) and glucose-6-phosphatase (G6PC). In HypoG, mRNA abundance of PEPCKm was upregulated, whereas in EuG and NaCl cows, it was downregulated. The EuG treatment downregulated mRNA expression of G6PC, a marked effect compared with the unchanged transcript expression in NaCl. The mRNA abundance of the insulin receptor remained unaffected in all treatments, and no

Polymorphisms of xenobiotic metabolizing enzymes in bladder cancer patients of the Semmelweis University Budapest, Hungary.

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Ebbinghaus, Dörte; Bánfi, Gergely; Selinski, Silvia; Blaszkewicz, Meinolf; Bürger, Hannah; Hengstler, Jan G; Nyirády, Péter; Golka, Klaus

2017-01-01

Polymorphic xenobiotic metabolizing enzymes such as N-acetyltransferase 2 (NAT2) or glutathione S-transferase M1 (GSTM1) are known to modulate bladder cancer risk. As no apparent data were available from Hungary, a former member of the eastern European economic organization, a study was performed in Budapest. In total, 182 bladder cancer cases and 78 cancer-free controls were investigated by questionnaire. Genotypes of NAT2, GSTM1, GSTT1, rs1058396 and rs17674580 were determined by standard methods. Current smokers' crude odds ratio (OR) (3.43) and former smokers crude OR (2.36) displayed a significantly increased bladder cancer risk. The risk rose by a factor of 1.56 per 10 pack years. Exposure to fumes was associated with an elevated bladder cancer risk (23% cases, 13% controls). Sixty-four % of the cases and 59% of controls were slow NAT2 acetylators. It was not possible to establish a particular impact of NAT2*6A and *7B genotypes (15 cases, 8%, 5 controls, 7%). GSTT1 exerted no marked influence on bladder cancer (negative 21% cases vs. 22% controls). The portion of GSTM1 negative bladder cancer patients was increased (63% cases vs. 54% controls). The SLC14A1 SNPs rs1058396[AG/GG] and the nearby rs17674580[CT/TT] occurred more frequently in cases (79% and 68%) than controls (77% and 55%). The portion of GSTM1 negative bladder cancer patients is comparable with portions reported from other industrialized areas like Lutherstadt Wittenberg/Germany (58%), Dortmund/Germany (70%), Brescia/Italy (66%) or an occupational case-control series in Germany (56%). Data indicate that GSTM1 is a susceptibility factor for environmentally triggered bladder cancer rather than for smoking-mediated bladder cancer.

Effects of a six-week intraduodenal supplementation with quercetin on liver lipid metabolism and oxidative stress in peripartal dairy cows.

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Stoldt, A-K; Mielenz, M; Nürnberg, G; Sauerwein, H; Esatbeyoglu, T; Wagner, A E; Rimbach, G; Starke, A; Wolffram, S; Metges, C C

2016-05-01

The purpose of this study was to evaluate possible effects of quercetin (Q) on liver lipid metabolism and antioxidative status in periparturient dairy cows. The periparturient period is associated with enormous metabolic changes for dairy cows. Energy needs for incipient lactation are too high to be balanced by feed intake, leading to negative energy balance and body fat mobilization. It has been estimated that this leads to the development of fatty liver in about 50% of cows, which are at high risk for disease. Furthermore, the antioxidative status of these cows may be impaired. Quercetin is a plant flavonoid having hepatoprotective and antioxidative potential and the ability to reduce liver lipid accumulation in monogastric animals. Little information is available in regard to these effects in ruminants. To prevent microbial Q degradation in the rumen, Q was administered via a duodenal fistula to improve systemic availability. Five cows of the Q-treated group received, daily, 100 mg of quercetin dehydrate/kg BW in a 0.9% sodium chloride solution from d -20 until d 20 relative to calving, whereas 5 control (CTR) cows received only a sodium chloride solution. Blood samples were taken weekly and liver biopsies were performed in wk -4, -2, and 3 relative to calving. Cows treated with Q showed a tendency ( = 0.082) for lower liver fat content compared with CTR cows. Liver glycogen, glutathione concentrations, and relative mRNA abundance of genes related to hepatic lipid metabolism and antioxidative status as well as parameters of antioxidative status in plasma were not affected ( > 0.1) by Q supplementation. In conclusion, liver fat content in dairy cows tended to be reduced by Q supplementation, but potential underlying mechanisms remain unclear because analyzed parameters related to hepatic lipid metabolism and antioxidative defense were not altered by Q supplementation.

Tc-99 m-GSA liver scintigraphy in alcoholic liver cirrhosis

International Nuclear Information System (INIS)

Itano, Satoshi; Harada, Masaru; Nagamatsu, Hiroaki

2003-01-01

We compared 15 alcoholic liver cirrhosis patients with 10 viral liver cirrhosis patients using technetium-99 m-galactosyl human serum albumin (Tc-99 m-GSA) liver scintigraphy and could clinically reveal the disorder of metabolism of asialoglycoprotein in alcoholic liver cirrhosis. Receptor index (LHL 15 = liver count divided by the sum of liver and heart counts at 15 minutes) was significantly (p <0.01) lower in patients with alcoholic cirrhosis (median: 0.821), compared with patients with viral cirrhosis (0.915). Grading score, which was an index showed by the difference in the isotope uptake patterns between liver and heart, was significantly (p <0.01) worse in patients with alcoholic cirrhosis, compared with patients with viral cirrhosis. These results suggested that alcoholic liver cirrhosis had a specific disorder of a metabolic function for asialoglycoprotein. (author)

The interaction of representative members from two classes of antimycotics--the azoles and the allylamines--with cytochromes P-450 in steroidogenic tissues and liver.

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Schuster, I

1985-06-01

Spectrophotometric studies with ketoconazole, clotrimazole and miconazole show strong type-II interactions with several cytochromes P-450, particularly (Ks greater than 10(7)M-1; pH7.4; 25 degrees C) with the 11 beta-hydroxylase of adrenal mitochondria, with the 17 alpha/20 lyase of testis microsomes and with some forms of cytochromes P-450 of liver. A tight binding of the azoles also occurs to the reduced cytochromes, giving rise to an impeded CO binding to the haem iron. The binding of the azoles to 11 beta-hydroxylase and 17 alpha/20 lyase is much tighter than the binding of endogenous substrates, and consequently inhibition of steroidogenesis will occur at these sites. The metabolism of xenobiotic substrates by the cytochromes P-450 of liver will also be severely impeded. In contrast, the allylamines naftifine and SF 86-327 are type-I substrates for a small portion of cytochromes P-450 of liver microsomes only and there is no spectral evidence for binding to the cytochromes P-450 involved in steroid biosynthesis.

Design and Performance of a Xenobiotic Metabolism Database Manager for Building Metabolic Pathway Databases

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A major challenge for scientists and regulators is accounting for the metabolic activation of chemicals that may lead to increased toxicity. Reliable forecasting of chemical metabolism is a critical factor in estimating a chemical’s toxic potential. Research is underway to develo...

Dietary Omega-3 Fatty Acid Deficiency and High Fructose Intake in the Development of Metabolic Syndrome, Brain Metabolic Abnormalities, and Non-Alcoholic Fatty Liver Disease

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Artemis P. Simopoulos

2013-07-01

Full Text Available Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS. Both a low intake of omega-3 fatty acids or a high fructose intake contribute to metabolic syndrome, liver steatosis or non-alcoholic fatty liver disease (NAFLD, promote brain insulin resistance, and increase the vulnerability to cognitive dysfunction. Insulin resistance is the core perturbation of metabolic syndrome. Multiple cognitive domains are affected by metabolic syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function. Fish oil supplementation maintains proper insulin signaling in the brain, ameliorates NAFLD and decreases the risk to metabolic syndrome suggesting that adequate levels of omega-3 fatty acids in the diet can cope with the metabolic challenges imposed by high fructose intake in Western diets which is of major public health importance. This review presents the current status of the mechanisms involved in the development of the metabolic syndrome, brain insulin resistance, and NAFLD a most promising area of research in Nutrition for the prevention of these conditions, chronic diseases, and improvement of Public Health.

Proteomic Profiles of Adipose and Liver Tissues from an Animal Model of Metabolic Syndrome Fed Purple Vegetables

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Hala M Ayoub

2018-04-01

Full Text Available Metabolic Syndrome (MetS is a complex disorder that predisposes an individual to Cardiovascular Diseases and type 2 Diabetes Mellitus. Proteomics and bioinformatics have proven to be an effective tool to study complex diseases and mechanisms of action of nutrients. We previously showed that substitution of the majority of carbohydrate in a high fat diet by purple potatoes (PP or purple carrots (PC improved insulin sensitivity and hypertension in an animal model of MetS (obese Zucker rats compared to a control sucrose-rich diet. In the current study, we used TMT 10plex mass tag combined with LC-MS/MS technique to study proteomic modulation in the liver (n = 3 samples/diet and adipose tissue (n = 3 samples/diet of high fat diet-fed rats with or without substituting sucrose for purple vegetables, followed by functional enrichment analysis, in an attempt to elucidate potential molecular mechanisms responsible for the phenotypic changes seen with purple vegetable feeding. Protein folding, lipid metabolism and cholesterol efflux were identified as the main modulated biological themes in adipose tissue, whereas lipid metabolism, carbohydrate metabolism and oxidative stress were the main modulated themes in liver. We propose that enhanced protein folding, increased cholesterol efflux and higher free fatty acid (FFA re-esterification are mechanisms by which PP and PC positively modulate MetS pathologies in adipose tissue, whereas, decreased de novo lipogenesis, oxidative stress and FFA uptake, are responsible for the beneficial effects in liver. In conclusion, we provide molecular evidence for the reported metabolic health benefits of purple carrots and potatoes and validate that these vegetables are good choices to replace other simple carbohydrate sources for better metabolic health.

Clinical features of male patients with alcoholic liver cirrhosis or hepatitis B cirrhosis complicated by abnormal glucose metabolism

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CHEN Qidan

2016-02-01

Full Text Available ObjectiveTo investigate the clinical features of male patients with alcoholic liver cirrhosis (ALC or hepatitis B cirrhosis (HBC complicated by abnormal glucose metabolism. MethodsA total of 287 patients with liver cirrhosis who were admitted to Guangzhou Panyu Central Hospital from January 2008 to September 2013 were selected. Among these patients, 74 had ALC and were all male, including 54 with abnormal glucose metabolism; the other 213 had HBC, including 97 with abnormal glucose metabolism (69 male patients and 28 female patients. A controlled study was performed for the clinical data of ALC and HBC patients with abnormal glucose metabolism, to investigate the association of patients′ clinical manifestations with the indices for laboratory examination, insulin resistance index, incidence rate of abnormal glucose metabolism, and Child-Pugh class. The t-test was applied for comparison of continuous data between groups, the chi-square test was applied for comparison of categorical data between groups, and the Spearman rank correlation was applied for correlation analysis. ResultsCompared with HBC patients, ALC patients had significantly higher incidence rates of abnormal glucose metabolism (730% vs 32.4%, hepatogenous diabetes (35.1% vs 14.6%, fasting hypoglycemia (27.0% vs 10.3%, and impaired glucose tolerance (31.1% vs 14.1% (χ2=4.371, 3.274, 4.784, and 1.633, all P＜0.05. The Spearman correlation analysis showed that in ALC and HBC patients, the incidence rate of abnormal glucose metabolism was positively correlated with Child-Pugh class (rs=0.41, P＜005. Compared with the HBC patients with abnormal glucose metabolism, the ALC patients with abnormal glucose metabolism had a significantly higher incidence rate of Child-Pugh class A (χ2=7.520, P=0.001, and a significantly lower incidence rate of Child-Pugh class C (χ2=6.542, P=0.003. There were significant differences in the incidence rates of dim complexion, telangiectasia of the

The role of the autonomic nervous liver innervation in the control of energy metabolism

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Yi, Chun-Xia; la Fleur, Susanne E.; Fliers, Eric; Kalsbeek, Andries

2010-01-01

Despite a longstanding research interest ever since the early work by Claude Bernard, the functional significance of autonomic liver innervation, either sympathetic or parasympathetic, is still ill defined. This scarcity of information not only holds for the brain control of hepatic metabolism, but

A study of standardized extracts of Picrorhiza kurroa Royle ex Benth in experimental nonalcoholic fatty liver disease

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Sapna N Shetty

2010-01-01

Full Text Available As a major organ of intermediary metabolism, the liver is exposed to a variety of metabolic insults due to diseases and xenobiotics viz., insulin resistance (IR drugs, toxins, microbial products, etc. One of the consequences of these metabolic insults including obesity and type 2 diabetes mellitus is the development of non-alcoholic fatty liver disease (NAFLD. The recent alarming increase in the prevalence of NAFLD compels the need to develop an appropriate animal model of the disease so as to evolve effective interventions. In this study, we have developed, in the rat, a new model of NAFLD showing several key features akin to the disease in humans. Male Wistar rats were challenged with 30% high fat diet (HFD - butter, for 2 weeks to induce NAFLD. A hydroalcoholic extract of Picrorhiza kurroa was administered to study the possible reversal of fatty changes in the liver. The extract was given in two doses viz., 200mg/kg and 400 mg/kg b.i.d., p.o. for a period of 4 weeks. There were three control groups (n = 6/group - vehicle with a regular diet, vehicle with HFD, and HFD with silymarin - a known hepatoprotective. Histopathology showed that the P. kurroa extract brought about a reversal of the fatty infiltration of the liver (mg/g and a lowering of the quantity of hepatic lipids (mg/g compared to that in the HFD control group (38.33 ± 5.35 for 200mg/kg; 29.44 ± 8.49 for 400mg/kg of P. kurroa vs.130.07 ± 6.36mg/g of liver tissue in the HFD control group; P<0.001. Compared to the standard dose of the known hepatoprotective silymarin, P. kurroa reduced the lipid content (mg/g of the liver more significantly at the dose of 400mg/kg (57.71 ± 12.45mg/kg vs. 29.44 ± 8.49 for the silymarin group vs. 400mg/kg of P. kurroa, P<0.001. In view of the increasing prevalence of metabolic syndrome and NAFLD, P. kurroa should be investigated by the reverse pharmacology path as a potential drug for the treatment of NAFLD, and essential safety studies and

Metabolic changes associated with the long winter fast dominate the liver proteome in 13-lined ground squirrels

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Hindle, Allyson G.; Grabek, Katharine R.; Epperson, L. Elaine; Karimpour-Fard, Anis

2014-01-01

Small-bodied hibernators partition the year between active homeothermy and hibernating heterothermy accompanied by fasting. To define molecular events underlying hibernation that are both dependent and independent of fasting, we analyzed the liver proteome among two active and four hibernation states in 13-lined ground squirrels. We also examined fall animals transitioning between fed homeothermy and fasting heterothermy. Significantly enriched pathways differing between activity and hibernation were biased toward metabolic enzymes, concordant with the fuel shifts accompanying fasting physiology. Although metabolic reprogramming to support fasting dominated these data, arousing (rewarming) animals had the most distinct proteome among the hibernation states. Instead of a dominant metabolic enzyme signature, torpor-arousal cycles featured differences in plasma proteins and intracellular membrane traffic and its regulation. Phosphorylated NSFL1C, a membrane regulator, exhibited this torpor-arousal cycle pattern; its role in autophagosome formation may promote utilization of local substrates upon metabolic reactivation in arousal. Fall animals transitioning to hibernation lagged in their proteomic adjustment, indicating that the liver is more responsive than preparatory to the metabolic reprogramming of hibernation. Specifically, torpor use had little impact on the fall liver proteome, consistent with a dominant role of nutritional status. In contrast to our prediction of reprogramming the transition between activity and hibernation by gene expression and then within-hibernation transitions by posttranslational modification (PTM), we found extremely limited evidence of reversible PTMs within torpor-arousal cycles. Rather, acetylation contributed to seasonal differences, being highest in winter (specifically in torpor), consistent with fasting physiology and decreased abundance of the mitochondrial deacetylase, SIRT3. PMID:24642758

Partition and metabolic fate of dietary glycerol in muscles and liver of juvenile tilapia.

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da Costa, Diego Vicente; Dias, Jorge; Colen, Rita; Rosa, Priscila Vieira; Engrola, Sofia

2017-04-01

This study investigated the effect of dietary glycerol on the metabolism of juvenile tilapia (Oreochromis mossambicus) and to determine its metabolic fate. The experimental diets contained 0% (Group CON), 5% (Group G5) and 15% glycerol (Group G15) and were fed for 40 d to apparent satiation, three times a day. For the metabolism trials, six fish from each treatment were randomly chosen and tube-fed with five pellets labelled with 14 C-glycerol [ 14 C(U)] in order to evaluate the absorption, catabolism, retention and partition of glycerol in muscle and liver. Group G5 presented the highest 14 C-glycerol retention and the lowest catabolism, with no significant differences between Groups CON and G15. In Group CON, the highest percentage of 14 C was incorporated in muscle lipids; with no significant differences between Groups G5 and G15. Furthermore, no treatment effects were found for hepatic 14 C-lipid and for 14 C in hepatic and muscle non-lipid extract. In the non-lipid and non-protein fraction, the highest radioactivity was measured in livers of Group G5, however no significant differences were found for this fraction between Groups CON and G15 in liver and for all treatments in muscle. The results of the present study can have practical implications in diet formulations for tilapia and for other aquaculture species with similar feeding pattern since juvenile tilapia are able to metabolise dietary glycerol into lipids, protein and/or carbohydrates and to use it as energy source.

Aerobic interval exercise improves parameters of nonalcoholic fatty liver disease (NAFLD) and other alterations of metabolic syndrome in obese Zucker rats.

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Kapravelou, Garyfallia; Martínez, Rosario; Andrade, Ana M; Nebot, Elena; Camiletti-Moirón, Daniel; Aparicio, Virginia A; Lopez-Jurado, Maria; Aranda, Pilar; Arrebola, Francisco; Fernandez-Segura, Eduardo; Bermano, Giovanna; Goua, Marie; Galisteo, Milagros; Porres, Jesus M

2015-12-01

Metabolic syndrome (MS) is a group of metabolic alterations that increase the susceptibility to cardiovascular disease and type 2 diabetes. Nonalcoholic fatty liver disease has been described as the liver manifestation of MS. We aimed to test the beneficial effects of an aerobic interval training (AIT) protocol on different biochemical, microscopic, and functional liver alterations related to the MS in the experimental model of obese Zucker rat. Two groups of lean and obese animals (6 weeks old) followed a protocol of AIT (4 min at 65%-80% of maximal oxygen uptake, followed by 3 min at 50%-65% of maximal oxygen uptake for 45-60 min, 5 days/week, 8 weeks of experimental period), whereas 2 control groups remained sedentary. Obese rats had higher food intake and body weight (P metabolism and increased the liver protein expression of PPARγ, as well as the gene expression of glutathione peroxidase 4 (P < 0.001). The training protocol also showed significant effects on the activity of hepatic antioxidant enzymes, although this action was greatly influenced by rat phenotype. The present data suggest that AIT protocol is a feasible strategy to improve some of the plasma and liver alterations featured by the MS.

Cytochrome P450 humanised mice

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Gonzalez Frank J

2004-05-01

Full Text Available Abstract Humans are exposed to countless foreign compounds, typically referred to as xenobiotics. These can include clinically used drugs, environmental pollutants, food additives, pesticides, herbicides and even natural plant compounds. Xenobiotics are metabolised primarily in the liver, but also in the gut and other organs, to derivatives that are more easily eliminated from the body. In some cases, however, a compound is converted to an electrophile that can cause cell toxicity and transformation leading to cancer. Among the most important xenobiotic-metabolising enzymes are the cytochromes P450 (P450s. These enzymes represent a superfamily of multiple forms that exhibit marked species differences in their expression and catalytic activities. To predict how humans will metabolise xenobiotics, including drugs, human liver extracts and recombinant P450s have been used. New humanised mouse models are being developed which will be of great value in the study of drug metabolism, pharmacokinetics and pharmacodynamics in vivo, and in carrying out human risk assessment of xenobiotics. Humanised mice expressing CYP2D6 and CYP3A4, two major drug-metabolising P450s, have revealed the feasibility of this approach.

Cytochrome P450 humanised mice

Science.gov (United States)

2004-01-01

Humans are exposed to countless foreign compounds, typically referred to as xenobiotics. These can include clinically used drugs, environmental pollutants, food additives, pesticides, herbicides and even natural plant compounds. Xenobiotics are metabolised primarily in the liver, but also in the gut and other organs, to derivatives that are more easily eliminated from the body. In some cases, however, a compound is converted to an electrophile that can cause cell toxicity and transformation leading to cancer. Among the most important xenobiotic-metabolising enzymes are the cytochromes P450 (P450s). These enzymes represent a superfamily of multiple forms that exhibit marked species differences in their expression and catalytic activities. To predict how humans will metabolise xenobiotics, including drugs, human liver extracts and recombinant P450s have been used. New humanised mouse models are being developed which will be of great value in the study of drug metabolism, pharmacokinetics and pharmacodynamics in vivo, and in carrying out human risk assessment of xenobiotics. Humanised mice expressing CYP2D6 and CYP3A4, two major drug-metabolising P450s, have revealed the feasibility of this approach. PMID:15588489

Application of localized 31P MRS saturation transfer at 7 T for measurement of ATP metabolism in the liver: reproducibility and initial clinical application in patients with non-alcoholic fatty liver disease

International Nuclear Information System (INIS)

Valkovic, Ladislav; Gajdosik, Martin; Chmelik, Marek; Trattnig, Siegfried; Traussnigg, Stefan; Kienbacher, Christian; Trauner, Michael; Wolf, Peter; Krebs, Michael; Bogner, Wolfgang; Krssak, Martin

2014-01-01

Saturation transfer (ST) phosphorus MR spectroscopy ( 31 P MRS) enables in vivo insight into energy metabolism and thus could identify liver conditions currently diagnosed only by biopsy. This study assesses the reproducibility of the localized 31 P MRS ST in liver at 7 T and tests its potential for noninvasive differentiation of non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). After the ethics committee approval, reproducibility of the localized 31 P MRS ST at 7 T and the biological variation of acquired hepato-metabolic parameters were assessed in healthy volunteers. Subsequently, 16 suspected NAFL/NASH patients underwent MRS measurements and diagnostic liver biopsy. The Pi-to-ATP exchange parameters were compared between the groups by a Mann-Whitney U test and related to the liver fat content estimated by a single-voxel proton ( 1 H) MRS, measured at 3 T. The mean exchange rate constant (k) in healthy volunteers was 0.31 ± 0.03 s -1 with a coefficient of variation of 9.0 %. Significantly lower exchange rates (p -1 ) when compared to healthy volunteers, and NAFL patients (k = 0.30 ± 0.05 s -1 ). Significant correlation was found between the k value and the liver fat content (r = 0.824, p 31 P MRS ST technique provides a tool for gaining insight into hepatic ATP metabolism and could contribute to the differentiation of NAFL and NASH. (orig.)

Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1β-induced chronic inflammation.

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Liang, Wen; Lindeman, Jan H; Menke, Aswin L; Koonen, Debby P; Morrison, Martine; Havekes, Louis M; van den Hoek, Anita M; Kleemann, Robert

2014-05-01

The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1β (IL-1β), administered by slow-release minipumps) and metabolic dietary triggers (carbohydrate, cholesterol) of inflammation on the progression of bland liver steatosis (BS) to NASH. Transgenic APOE3*Leiden.huCETP (APOE3L.CETP) mice fed a high-fat diet (HFD) developed BS after 10 weeks. Then, inflammatory triggers were superimposed or not (control) for six more weeks. Mouse livers were analyzed with particular emphasis on hallmarks of inflammation which were defined in human liver biopsies with and without NASH. Livers of HFD-treated control mice remained steatotic and did not progress to NASH. All four inflammatory triggers activated hepatic nuclear factor-κB (NF-κB) significantly and comparably (≥5-fold). However, HFD+LPS or HFD+IL-1β did not induce a NASH-like phenotype and caused intrahepatic accumulation of almost exclusively mononuclear cells. By contrast, mice treated with metabolic triggers developed NASH, characterized by enhanced steatosis, hepatocellular hypertrophy, and formation of mixed-type inflammatory foci containing myeloperoxidase-positive granulocytes (neutrophils) as well as mononuclear cells, essentially as observed in human NASH. Specific for the metabolic inducers was an activation of the proinflammatory transcription factor activator protein-1 (AP-1), neutrophil infiltration, and induction of risk factors associated with human NASH, that is, dyslipidemia (by cholesterol) and insulin resistance (by carbohydrate). In conclusion, HFD feeding followed by NF-κB activation per se (LPS, IL-1β) does not promote the transition from BS to NASH. HFD feeding followed by metabolically evoked inflammation induces additional inflammatory components

Metabolic Characterization of Peripheral Host Responses to Drainage-Resistant Klebsiella pneumoniae Liver Abscesses by Serum 1H-NMR Spectroscopy

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Zhihui Chang

2018-06-01

Full Text Available Purpose: To explore the metabolic characterization of host responses to drainage-resistant Klebsiella pneumoniae liver abscesses (DRKPLAs with serum 1H-nuclear magnetic resonance (NMR spectroscopy.Materials and Methods: The hospital records of all patients with a diagnosis of a liver abscess between June 2015 and December 2016 were retrieved from an electronic hospital database. Eighty-six patients with Klebsiella pneumoniae (K. pneumoniae liver abscesses who underwent percutaneous drainage were identified. Twenty patients with confirmed DRKPLAs were studied. Moreover, we identified 20 consecutive patients with drainage-sensitive Klebsiella pneumoniae liver abscesses (DSKPLAs as controls. Serum samples from the two groups were analyzed with 1H NMR spectroscopy. Partial least squares discriminant analysis (PLS-DA was used to perform 1H NMR metabolic profiling. Metabolites were identified using the Human Metabolome Database, and pathway analysis was performed with MetaboAnalyst 3.0.Results: The PLS-DA test was able to discriminate between the two groups. Five key metabolites that contributed to their discrimination were identified. Glucose, lactate, and 3-hydroxybutyrate were found to be upregulated in DRKPLAs, whereas glutamine and alanine were downregulated compared with the DSKPLAs. Pathway analysis indicated that amino acid metabolisms were significantly different between the DRKPLAs and the DSKPLAs. The D-glutamine and D-glutamate metabolisms exhibited the greatest influences.Conclusions: The five key metabolites identified in our study may be potential targets for guiding novel therapeutics of DRKPLAs and are worthy of additional investigation.

Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment

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Vila, Laia; Rebollo, Alba; Adalsteisson, Gunnar S [Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona (Spain); Alegret, Marta; Merlos, Manuel; Roglans, Nuria [Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona (Spain); IBUB - Institute of Biomedicine, University of Barcelona, Barcelona (Spain); CIBERobn, [Center for Biomedical Investigation Network in Obesity and Nutrition Physiopathology; Spain; Laguna, Juan C., E-mail: jclagunae@ub.edu [Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona (Spain); IBUB -Institute of Biomedicine, University of Barcelona, Barcelona (Spain); CIBERobn, [Center for Biomedical Investigation Network in Obesity and Nutrition Physiopathology; Spain

2011-02-15

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose + atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid {beta}-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x0.45) and its target genes, and increased the hepatic activity of the fatty acid {beta}-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion. - Graphical Abstract: Display Omitted Research Highlights

Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment

International Nuclear Information System (INIS)

Vila, Laia; Rebollo, Alba; Adalsteisson, Gunnar S.; Alegret, Marta; Merlos, Manuel; Roglans, Nuria; Laguna, Juan C.

2011-01-01

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose + atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid β-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x0.45) and its target genes, and increased the hepatic activity of the fatty acid β-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion. - Graphical Abstract: Display Omitted Research Highlights: �

BIOCHEMICAL MARKERS OF BONE RESORPTION AND HORMONAL REGULATION OF BONE METABOLISM FOLLOWING LIVER TRANSPLANTATION

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V. P. Buzulina

2013-01-01

Full Text Available Aim. Comparative evaluation of two biochemical markers of bone resorption and hormonal regulation of bone metabolism in liver recipients. Methods and results. Bоne densitometry of L2–L4 and neck of femur, serum level of some hormones (PTH, vitamin D3, estradiol, testosterone regulating osteoclastogenesis as well as com- parative analyses of two bone resorption markers β-crosslaps and tartrate-resistant acid phosphatase type 5b (TRAP-5b were fulfilled in patients after orthotopic liver transplantation (OLT. In 1 month after OLT bone density reduction of L2–L4 and neck of femur; decrease of vitamin D3, estradiol in women, testosterone in men and increase levels of bone resorption markers were observed. In 1 and 2 years after OLT the rise of bone density, increased levels of PTH, estradiol, testosterone and decreased β-crosslaps levels were revealed, while vitamin D3 and TRAP-5b levels remained stable. Conclusion. TRAP-5b was found to be a more speciffic marker of bone resorption, independent from collagen metabolism in liver. Osteoporosis defined in long-term period after OLT was associated with higher TRAP-5b and revialed in women with low estradiol level. 

Metabolic profiles are principally different between cancers of the liver, pancreas and breast.

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Budhu, Anuradha; Terunuma, Atsushi; Zhang, Geng; Hussain, S Perwez; Ambs, Stefan; Wang, Xin Wei

2014-01-01

Molecular profiling of primary tumors may facilitate the classification of patients with cancer into more homogenous biological groups to aid clinical management. Metabolomic profiling has been shown to be a powerful tool in characterizing the biological mechanisms underlying a disease but has not been evaluated for its ability to classify cancers by their tissue of origin. Thus, we assessed metabolomic profiling as a novel tool for multiclass cancer characterization. Global metabolic profiling was employed to identify metabolites in paired tumor and non-tumor liver (n=60), breast (n=130) and pancreatic (n=76) tissue specimens. Unsupervised principal component analysis showed that metabolites are principally unique to each tissue and cancer type. Such a difference can also be observed even among early stage cancers, suggesting a significant and unique alteration of global metabolic pathways associated with each cancer type. Our global high-throughput metabolomic profiling study shows that specific biochemical alterations distinguish liver, pancreatic and breast cancer and could be applied as cancer classification tools to differentiate tumors based on tissue of origin.

Protective effect of genetic deletion of pannexin1 in experimental mouse models of acute and chronic liver disease.

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Willebrords, Joost; Maes, Michaël; Pereira, Isabel Veloso Alves; da Silva, Tereza Cristina; Govoni, Veronica Mollica; Lopes, Valéria Veras; Crespo Yanguas, Sara; Shestopalov, Valery I; Nogueira, Marina Sayuri; de Castro, Inar Alves; Farhood, Anwar; Mannaerts, Inge; van Grunsven, Leo; Akakpo, Jephte; Lebofsky, Margitta; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

2018-03-01

Pannexins are transmembrane proteins that form communication channels connecting the cytosol of an individual cell with its extracellular environment. A number of studies have documented the presence of pannexin1 in liver as well as its involvement in inflammatory responses. In this study, it was investigated whether pannexin1 plays a role in acute liver failure and non-alcoholic steatohepatitis, being prototypical acute and chronic liver pathologies, respectively, both featured by liver damage, oxidative stress and inflammation. To this end, wild-type and pannexin1 -/- mice were overdosed with acetaminophen for 1, 6, 24 or 48h or were fed a choline-deficient high-fat diet for 8weeks. Evaluation of the effects of genetic pannexin1 deletion was based on a number of clinically relevant read-outs, including markers of liver damage, histopathological analysis, lipid accumulation, protein adduct formation, oxidative stress and inflammation. In parallel, in order to elucidate molecular pathways affected by pannexin1 deletion as well as to mechanistically anchor the clinical observations, whole transcriptome analysis of liver tissue was performed. The results of this study show that pannexin1 -/- diseased mice present less liver damage and oxidative stress, while inflammation was only decreased in pannexin1 -/- mice in which non-alcoholic steatohepatitis was induced. A multitude of genes related to inflammation, oxidative stress and xenobiotic metabolism were differentially modulated in both liver disease models in wild-type and in pannexin1 -/- mice. Overall, the results of this study suggest that pannexin1 may play a role in the pathogenesis of liver disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Phenylalanine metabolism in isolated rat liver cells. Effects of glucagon and diabetes.

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Carr, F P; Pogson, C I

1981-01-01

1. Methods are described for monitoring the metabolic flux through phenylalanine hydroxylase, the tyrosine catabolic pathway and phenylalanine: pyruvate transaminase in isolated liver cell incubations. 2. The relationship between hydroxylase flux and phenylalanine concentration is sigmoidal. 3. Glucagon increases hydroxylase activity at low, near-physiological, substrate concentrations only. The hormone does not affect the rate of formation of phenylpyruvate. 4. Experimental diabetes (for 10 ...

Ananas comosus L. Leaf Phenols and p-Coumaric Acid Regulate Liver Fat Metabolism by Upregulating CPT-1 Expression

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Weidong Xie

2014-01-01

Full Text Available In this study, we aimed to investigate the effect and action mechanisms of pineapple leaf phenols (PLPs on liver fat metabolism in high-fat diet-fed mice. Results show that PLP significantly reduced abdominal fat and liver lipid accumulation in high-fat diet-fed mice. The effects of PLP were comparable with those of FB. Furthermore, at the protein level, PLP upregulated the expression of carnitine palmitoyltransferase 1 (CPT-1, whereas FB had no effects on CPT-1 compared with the HFD controls. Regarding mRNA expression, PLP mainly promoted the expression of CPT-1, PGC1a, UCP-1, and AMPK in the mitochondria, whereas FB mostly enhanced the expression of Ech1, Acox1, Acaa1, and Ehhadh in peroxisomes. PLP seemed to enhance fat metabolism in the mitochondria, whereas FB mainly exerted the effect in peroxisomes. In addition, p-coumaric acid (CA, one of the main components from PLP, significantly inhibited fat accumulation in oleic acid-induced HepG2 cells. CA also significantly upregulated CPT-1 mRNA and protein expressions in HepG2 cells. We, firstly, found that PLP enhanced liver fat metabolism by upregulating CPT-1 expression in the mitochondria and might be promising in treatment of fatty liver diseases as alternative natural products. CA may be one of the active components of PLP.

Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a High-throughput Targeted Metabolomics Approach

Science.gov (United States)

Yu, Nanyang; Wei, Si; Li, Meiying; Yang, Jingping; Li, Kan; Jin, Ling; Xie, Yuwei; Giesy, John P.; Zhang, Xiaowei; Yu, Hongxia

2016-04-01

Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.

In vivo 19F-MRS observation of 5-FU metabolism in fatty liver induced by choline-deficient diet

International Nuclear Information System (INIS)

Otsuka, Hideki; Harada, Masafumi; Nishitani, Hiromu; Koga, Keiko.

1996-01-01

Using 19 F-MRS, 5-FU metabolism was investigated in rat fatty liver. Fatty liver was induced by choline-deficient diet (CD diet). This study showed differences in 5-FU metabolism between normal and fatty liver. After laparotomy, a surface coil was placed directly on the liver surface. Spectra were continuously obtained after injection of 5-FU 100 mg/kg body weight via a catheter inserted into femoral vein. We made MRI and 1 H-MRS study to examine the lipid accumulation. Histological study was also performed using HE (hematoxylin-eosin) and oil red stain. The livers of rats fed a CD diet showed very high intensity on T 1 -WI. 1 H-MRS was very useful in deteminating the fat content because the fat ratio demonstrated by 1 H-MRS is well correlated to histological findings. In 19 F-MRS, we recognized the following four peaks: 5-FU, FBAL, Fnct (fluoronucleotide) and FUPA. The decrease of 5-FU was not very apparent, but compared to the normal liver, the formation of Fnct increased and the formation of FBAL was suppressed in fatty liver. The rats fed a CD diet for four weeks showed a higher Fnct peak and lower FBAL peak compared with the results of rats fed a CD diet for two weeks. In a CD diet group, liver cell degeneration and necrotic changes were observed histologically. It is reported that cell degeneration is followed by cell proliferation in fatty liver induced by a choline deficient diet, and the high Fnct peak found in our study may reflect this phenomenon. The high Fnct peak on 19 F-MRS may correspond to recovering reaction from liver injury like fatty liver. (author)

Metabolic effects of the iodothyronine functional analogue TRC150094 on the liver and skeletal muscle of high-fat diet fed overweight rats: an integrated proteomic study.

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Silvestri, Elena; Glinni, Daniela; Cioffi, Federica; Moreno, Maria; Lombardi, Assunta; de Lange, Pieter; Senese, Rosalba; Ceccarelli, Michele; Salzano, Anna Maria; Scaloni, Andrea; Lanni, Antonia; Goglia, Fernando

2012-07-06

A novel functional iodothyronine analogue, TRC150094, which has a much lower potency toward thyroid hormone receptor (α1/β1) activation than triiodothyronine, has been shown to be effective at reducing adiposity in rats simultaneously receiving a high-fat diet (HFD). Here, by combining metabolic, functional and proteomic analysis, we studied how the hepatic and skeletal muscle phenotypes might respond to TRC150094 treatment in HFD-fed overweight rats. Drug treatment increased both the liver and skeletal muscle mitochondrial oxidative capacities without altering mitochondrial efficiency. Coherently, in terms of individual respiratory in-gel activity, blue-native analysis revealed an increased activity of complex V in the liver and of complexes II and V in tibialis muscle in TCR150094-treated animals. Subsequently, the identification of differentially expressed proteins and the analysis of their interrelations gave an integrated view of the phenotypic/metabolic adaptations occurring in the liver and muscle proteomes during drug treatment. TRC150094 significantly altered the expression of several proteins involved in key liver metabolic pathways, including amino acid and nitrogen metabolism, and fructose and mannose metabolism. The canonical pathways most strongly influenced by TRC150094 in tibialis muscle included glycolysis and gluconeogenesis, amino acid, fructose and mannose metabolism, and cell signaling. The phenotypic/metabolic influence of TRC150094 on the liver and skeletal muscle of HFD-fed overweight rats suggests the potential clinical application of this iodothyronine analogue in ameliorating metabolic risk parameters altered by diet regimens.

Metabolism of polybrominated diphenyl ethers and tetrabromobisphenol A by fish liver subcellular fractions in vitro.

Science.gov (United States)

Shen, Mengnan; Cheng, Jie; Wu, Ruohan; Zhang, Shenghu; Mao, Liang; Gao, Shixiang

2012-06-15

Polybrominated diphenyl ethers (PBDEs) and tetrabromobisphenol A (TBBPA) are two major flame retardants that accumulate in fish tissues and are potentially toxic. Their debrominated and oxidated derivatives were also reported in fish tissues although the sources of theses derivatives were unidentified. Our study was to determine whether PBDEs and TBBPA could be metabolized by fish liver subcellular fractions in vitro and to identify what types of metabolites were formed. Liver microsomes and S9 fractions of crucian carp (Carassius auratus) were exposed to 4,4'-dibromodiphenyl ether (BDE 15), 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) or TBBPA solutions for 4h. Exposure of liver subcellular fractions to BDE 15 resulted in the formation of bromophenol and two monohydroxylated dibromodiphenyl ether metabolites. Neither in microsomes nor in S9 studies has revealed the presence of hydroxylated metabolites with BDE 47 exposure which indicated that the oxidation reactions in vitro were hindered by the increased number of bromine substituents on the PBDEs. TBBPA underwent an oxidative cleavage near the central carbon of the molecule, which led to the production of 2,6-dibromo-4-isopropyl-phenol and three unidentified metabolites. Another metabolite of TBBPA characterized as a hexa-brominated compound with three aromatic rings was also found in the liver subcellular fractions. These results suggest that the biotransformation of BDE 15 and TBBPA in fish liver is mediated by cytochrome P450 (CYP450) enzymes, as revealed by the formation of hydroxylated metabolites and oxidative bond cleavage products. Moreover, further studies on the identification of specific CYP450 isozymes involved in the biotransformation revealed that CYP1A was the major enzyme responsible for the biotransformation of BDE 15 and TBBPA in fish liver subcellular fractions and CYP3A4 also played a major role in metabolism of TBBPA. Copyright © 2012 Elsevier B.V. All rights reserved.

Contribution of liver alcohol dehydrogenase to metabolism of alcohols in rats.

Science.gov (United States)

Plapp, Bryce V; Leidal, Kevin G; Murch, Bruce P; Green, David W

2015-06-05

The kinetics of oxidation of various alcohols by purified rat liver alcohol dehydrogenase (ADH) were compared with the kinetics of elimination of the alcohols in rats in order to investigate the roles of ADH and other factors that contribute to the rates of metabolism of alcohols. Primary alcohols (ethanol, 1-propanol, 1-butanol, 2-methyl-1-propanol, 3-methyl-1-butanol) and diols (1,3-propanediol, 1,3-butanediol, 1,4-butanediol, 1,5-pentanediol) were eliminated in rats with zero-order kinetics at doses of 5-20 mmol/kg. Ethanol was eliminated most rapidly, at 7.9 mmol/kgh. Secondary alcohols (2-propanol-d7, 2-propanol, 2-butanol, 3-pentanol, cyclopentanol, cyclohexanol) were eliminated with first order kinetics at doses of 5-10 mmol/kg, and the corresponding ketones were formed and slowly eliminated with zero or first order kinetics. The rates of elimination of various alcohols were inhibited on average 73% (55% for 2-propanol to 90% for ethanol) by 1 mmol/kg of 4-methylpyrazole, a good inhibitor of ADH, indicating a major role for ADH in the metabolism of the alcohols. The Michaelis kinetic constants from in vitro studies (pH 7.3, 37 °C) with isolated rat liver enzyme were used to calculate the expected relative rates of metabolism in rats. The rates of elimination generally increased with increased activity of ADH, but a maximum rate of 6±1 mmol/kg h was observed for the best substrates, suggesting that ADH activity is not solely rate-limiting. Because secondary alcohols only require one NAD(+) for the conversion to ketones whereas primary alcohols require two equivalents of NAD(+) for oxidation to the carboxylic acids, it appears that the rate of oxidation of NADH to NAD(+) is not a major limiting factor for metabolism of these alcohols, but the rate-limiting factors are yet to be identified. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient.

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Ling Ye

Full Text Available BACKGROUND: Sorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC, is metabolized by cytochrome P450 (CYP 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients. METHODS: Sorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs and adjacent normal hepatic microsomes (NHLMs of HCC patients (n = 18. Commercial hepatic microsomes (CHLMs were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting. RESULTS: The mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients' samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs. CONCLUSIONS: Sorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

Metabolic changes associated with the long winter fast dominate the liver proteome in 13-lined ground squirrels.

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Hindle, Allyson G; Grabek, Katharine R; Epperson, L Elaine; Karimpour-Fard, Anis; Martin, Sandra L

2014-05-15

Small-bodied hibernators partition the year between active homeothermy and hibernating heterothermy accompanied by fasting. To define molecular events underlying hibernation that are both dependent and independent of fasting, we analyzed the liver proteome among two active and four hibernation states in 13-lined ground squirrels. We also examined fall animals transitioning between fed homeothermy and fasting heterothermy. Significantly enriched pathways differing between activity and hibernation were biased toward metabolic enzymes, concordant with the fuel shifts accompanying fasting physiology. Although metabolic reprogramming to support fasting dominated these data, arousing (rewarming) animals had the most distinct proteome among the hibernation states. Instead of a dominant metabolic enzyme signature, torpor-arousal cycles featured differences in plasma proteins and intracellular membrane traffic and its regulation. Phosphorylated NSFL1C, a membrane regulator, exhibited this torpor-arousal cycle pattern; its role in autophagosome formation may promote utilization of local substrates upon metabolic reactivation in arousal. Fall animals transitioning to hibernation lagged in their proteomic adjustment, indicating that the liver is more responsive than preparatory to the metabolic reprogramming of hibernation. Specifically, torpor use had little impact on the fall liver proteome, consistent with a dominant role of nutritional status. In contrast to our prediction of reprogramming the transition between activity and hibernation by gene expression and then within-hibernation transitions by posttranslational modification (PTM), we found extremely limited evidence of reversible PTMs within torpor-arousal cycles. Rather, acetylation contributed to seasonal differences, being highest in winter (specifically in torpor), consistent with fasting physiology and decreased abundance of the mitochondrial deacetylase, SIRT3. Copyright © 2014 the American Physiological Society.

Effect of thiamine deficiency, pyrithiamine and oxythiamine on pyruvate metabolism in rat liver and brain in vivo

International Nuclear Information System (INIS)

Meghal, S.K.; O'Neal, R.M.; Koeppe, R.E.

1977-01-01

Rats were fed either a thiamine-deficient diet or diets containing pyrithiamine or oxythiamine. When symptoms of thiamine deficiency appeared, the animals were injected intraperitoneally with [2- 14 C] pyruvate six to twelve minutes prior to sacrifice. Free glutamic and aspartic acids were isolated from liver and brain and degraded. The results indicate that, in thiamine-deficient or oxythiamine-treated rats, pyruvate metabolism in liver and brain is similar to that in normal animals. In contrast, pyrithinamine drastically decreases the oxidative decarboxylation of pyruvate by rat liver. (auth.)

Dysfunctional Muscle and Liver Glycogen Metabolism in mdx Dystrophic Mice

Science.gov (United States)

Stapleton, David I.; Lau, Xianzhong; Flores, Marcelo; Trieu, Jennifer; Gehrig, Stefan M.; Chee, Annabel; Naim, Timur; Lynch, Gordon S.; Koopman, René

2014-01-01

Background Duchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD patients and mdx mice (an animal model of DMD) exhibit altered metabolic disturbances that cannot be attributed to the loss of dystrophin directly. We tested the hypothesis that glycogen metabolism is defective in mdx dystrophic mice. Results Dystrophic mdx mice had increased skeletal muscle glycogen (79%, (Pglycogen synthesis is initiated by glycogenin, the expression of which was increased by 50% in mdx mice (PGlycogen synthase activity was 12% higher (Pglycogen branching enzyme activity was 70% lower (Pglycogen breakdown, glycogen phosphorylase, had 62% lower activity (Pglycogen debranching enzyme expression was 50% higher (Pglycogen (Pglycogen metabolism in mdx mice identified reduced glycogenin protein expression (46% less; Pglycogen but reduced amounts of liver glycogen. PMID:24626262

Salecan protected against concanavalin A-induced acute liver injury by modulating T cell immune responses and NMR-based metabolic profiles

Energy Technology Data Exchange (ETDEWEB)

Sun, Qi; Xu, Xi, E-mail: xuxi@njust.edu.cn; Yang, Xiao; Weng, Dan; Wang, Junsong; Zhang, Jianfa

2017-02-15

Salecan, a water-soluble extracellular β-glucan produced by Agrobacterium sp. ZX09, has been reported to exhibit a wide range of biological effects. The aims of the present study were to investigate the protective effect of salecan against Concanavalin A (ConA)-induced hepatitis, a well-established animal model of immune-mediated liver injury, and to search for possible mechanisms. C57BL/6 mice were pretreated with salecan followed by ConA injection. Salecan treatment significantly reduced ConA-induced acute liver injury, and suppressed the expression and secretion of inflammatory cytokines including interferon (IFN)-γ, interleukin (IL)-6 and IL-1β in ConA-induced liver injury model. The high expression levels of chemokines and adhesion molecules such as MIP-1α, MIP-1β, ICAM-1, MCP-1 and RANTES in the liver induced by ConA were also down-regulated after salecan treatment. Salecan inhibited the infiltration and activation of inflammatory cells, especially T cells, in the liver induced by ConA. Moreover, salecan reversed the metabolic profiles of ConA-treated mice towards the control group by partly recovering the metabolic perturbations induced by ConA. Our results suggest the preventive and therapeutic potential of salecan in immune-mediated hepatitis. - Highlights: • Salecan treatment significantly reduced ConA-induced liver injury. • Salecan suppressed the expression and secretion of inflammatory cytokines. • Salecan decreased the expression of chemokines and adhesion molecules in liver. • Salecan inhibited the infiltration and activation of T cells induced by ConA. • Salecan partly recovered the metabolic perturbations induced by ConA.

Metabolic changes in the pig liver during warm ischemia and reperfusion measured by microdialysis

DEFF Research Database (Denmark)

Kannerup, Anne-Sofie; Funch-Jensen, Peter; Grønbaek, Henning

2008-01-01

AIM: Portal triad clamping can cause ischemia-reperfusion injury. The aim of the study was to monitor metabolic changes by microdialysis before, during, and after warm ischemia in the pigliver. MATERIAL AND METHODS: Eight pigs underwent laparotomy followed by ischemia by Pringle's maneuver. One...... in transaminase levels was observed. CONCLUSIONS: During and after warm ischemia, there were profound metabolic changes in the pigliver observed with an increase in lactate, glucose, glycerol, and the lactate-pyruvate ratio. There were no differences between the four liver lobes, indicating the piglivers...

Metabolic Profiling of Liver Tissue in Diabetic Mice Treated with Artemisia Capillaris and Alisma Rhizome Using LC-MS and CE-MS.

Science.gov (United States)

Kim, Yumi; Lee, In-Seung; Kim, Kang-Hoon; Park, Jiyoung; Lee, Ji-Hyun; Bang, Eunjung; Jang, Hyeung-Jin; Na, Yun-Cheol

2016-01-01

Artemisia Capillaris (AC) and Alisma Rhizome (AR) are natural products for the treatment of liver disorders in oriental medicine clinics. Here, we report metabolomic changes in the evaluation of the treatment effects of AC and AR on fatty livers in diabetic mice, along with a proposition of the underlying metabolic pathway. Hydrophobic and hydrophilic metabolites extracted from mouse livers were analyzed using HPLC-QTOF and CE-QTOF, respectively, to generate metabolic profiles. Statistical analysis of the metabolites by PLS-DA and OPLA-DA fairly discriminated between the diabetic, and the AC- and AR-treated mice groups. Various PEs mostly contributed to the discrimination of the diabetic mice from the normal mice, and besides, DG (18:1/16:0), TG (16:1/16:1/20:1), PE (21:0/20:5), and PA (18:0/21:0) were also associated with discrimination by s-plot. Nevertheless, the effects of AC and AR treatment were indistinct with respect to lipid metabolites. Of the 97 polar metabolites extracted from the CE-MS data, 40 compounds related to amino acid, central carbon, lipid, purine, and pyrimidine metabolism, with [Formula: see text] values less than 0.05, were shown to contribute to liver dysregulation. Following treatment with AC and AR, the metabolites belonging to purine metabolism preferentially recovered to the metabolic state of the normal mice. The AMP/ATP ratio of cellular energy homeostasis in AR-treated mice was more apparently increased ([Formula: see text]) than that of AC-treated mice. On the other hand, amino acids, which showed the main alterations in diabetic mice, did not return to the normal levels upon treatment with AR or AC. In terms of metabolomics, AR was a more effective natural product in the treatment of liver dysfunction than AC. These results may provide putative biomarkers for the prognosis of fatty liver disorder following treatment with AC and AR extracts.

Non-alcoholic fatty liver disease and subclinical atherosclerosis: A comparison of metabolically- versus genetically-driven excess fat hepatic storage.

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Di Costanzo, Alessia; D'Erasmo, Laura; Polimeni, Licia; Baratta, Francesco; Coletta, Paola; Di Martino, Michele; Loffredo, Lorenzo; Perri, Ludovica; Ceci, Fabrizio; Montali, Anna; Girelli, Gabriella; De Masi, Bruna; Angeloni, Antonio; Catalano, Carlo; Maranghi, Marianna; Del Ben, Maria; Angelico, Francesco; Arca, Marcello

2017-02-01

Non-alcoholic fatty liver disease (NAFLD) is frequently associated with atherosclerosis. However, it is unclear whether this association is related to excess fat liver storage per se or to metabolic abnormalities that typically accompany NAFLD. To investigate this, we compared individuals with hepatic steatosis driven by metabolic disturbances to those with hepatic steatosis associated with the rs738409 GG genotype in the patatin-like phospholipase domain-containing 3 gene (PNPLA3). Carotid intima-media thickness (CIMT), as a surrogate marker of subclinical atherosclerosis, was measured in 83 blood donors with the mutant GG genotype (group G), 100 patients with features of metabolic syndrome (MetS) but the wildtype CC genotype (group M), and 74 blood donors with the wildtype CC genotype (controls). Fatty liver was evaluated by ultrasonography and hepatic fat fraction (HFF) was measured using magnetic resonance (MRS/MRI) in 157 subjects. Compared with group G and controls, group M subjects were older and had increased adiposity indices, dyslipidemia, insulin resistance and elevated transaminase levels (all p hepatic steatosis), the median CIMT in group M (0.84 [0.70-0.95] mm) was significantly greater than that in group G (0.66 [0.55-0.74] mm; p < 0.001), which was similar to that in controls (0.70 [0.64-0.81] mm). Results were similar in the subgroup evaluated using MRS/MRI. Excess liver fat accumulation appeared to increase the burden of subclinical atherosclerosis only when it is associated with metabolic abnormalities. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver

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Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver D.B. Johnson, 1 W.O. Ward, 2 V.L. Bass, 2 M.C.J. Schladweiler, 2A.D. Ledbetter, 2 D. Andrews, and U.P. Kodavanti 2 1 Curriculum in Toxicology, UNC School of Medicine, Cha...

Multi-omic network-based interrogation of rat liver metabolism following gastric bypass surgery featuring SWATH proteomics.

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Sridharan, Gautham Vivek; D'Alessandro, Matthew; Bale, Shyam Sundhar; Bhagat, Vicky; Gagnon, Hugo; Asara, John M; Uygun, Korkut; Yarmush, Martin L; Saeidi, Nima

2017-09-01

Morbidly obese patients often elect for Roux-en-Y gastric bypass (RYGB), a form of bariatric surgery that triggers a remarkable 30% reduction in excess body weight and reversal of insulin resistance for those who are type II diabetic. A more complete understanding of the underlying molecular mechanisms that drive the complex metabolic reprogramming post-RYGB could lead to innovative non-invasive therapeutics that mimic the beneficial effects of the surgery, namely weight loss, achievement of glycemic control, or reversal of non-alcoholic steatohepatitis (NASH). To facilitate these discoveries, we hereby demonstrate the first multi-omic interrogation of a rodent RYGB model to reveal tissue-specific pathway modules implicated in the control of body weight regulation and energy homeostasis. In this study, we focus on and evaluate liver metabolism three months following RYGB in rats using both SWATH proteomics, a burgeoning label free approach using high resolution mass spectrometry to quantify protein levels in biological samples, as well as MRM metabolomics. The SWATH analysis enabled the quantification of 1378 proteins in liver tissue extracts, of which we report the significant down-regulation of Thrsp and Acot13 in RYGB as putative targets of lipid metabolism for weight loss. Furthermore, we develop a computational graph-based metabolic network module detection algorithm for the discovery of non-canonical pathways, or sub-networks, enriched with significantly elevated or depleted metabolites and proteins in RYGB-treated rat livers. The analysis revealed a network connection between the depleted protein Baat and the depleted metabolite taurine, corroborating the clinical observation that taurine-conjugated bile acid levels are perturbed post-RYGB.

Integrated modelling of two xenobiotic organic compounds

DEFF Research Database (Denmark)

Lindblom, Erik Ulfson; Gernaey, K.V.; Henze, Mogens

2006-01-01

This paper presents a dynamic mathematical model that describes the fate and transport of two selected xenobiotic organic compounds (XOCs) in a simplified representation. of an integrated urban wastewater system. A simulation study, where the xenobiotics bisphenol A and pyrene are used as reference...... compounds, is carried out. Sorption and specific biological degradation processes are integrated with standardised water process models to model the fate of both compounds. Simulated mass flows of the two compounds during one dry weather day and one wet weather day are compared for realistic influent flow...... rate and concentration profiles. The wet weather day induces resuspension of stored sediments, which increases the pollutant load on the downstream system. The potential of the model to elucidate important phenomena related to origin and fate of the model compounds is demonstrated....

Shift work or food intake during the rest phase promotes metabolic disruption and desynchrony of liver genes in male rats.

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Salgado-Delgado, Roberto C; Saderi, Nadia; Basualdo, María del Carmen; Guerrero-Vargas, Natali N; Escobar, Carolina; Buijs, Ruud M

2013-01-01

In the liver, clock genes are proposed to drive metabolic rhythms. These gene rhythms are driven by the suprachiasmatic nucleus (SCN) mainly by food intake and via autonomic and hormonal pathways. Forced activity during the normal rest phase, induces also food intake, thus neglecting the signals of the SCN, leading to conflicting time signals to target tissues of the SCN. The present study explored in a rodent model of night-work the influence of food during the normal sleep period on the synchrony of gene expression between clock genes and metabolic genes in the liver. Male Wistar rats were exposed to forced activity for 8 h either during the rest phase (day) or during the active phase (night) by using a slow rotating wheel. In this shift work model food intake shifts spontaneously to the forced activity period, therefore the influence of food alone without induced activity was tested in other groups of animals that were fed ad libitum, or fed during their rest or active phase. Rats forced to be active and/or eating during their rest phase, inverted their daily peak of Per1, Bmal1 and Clock and lost the rhythm of Per2 in the liver, moreover NAMPT and metabolic genes such as Pparα lost their rhythm and thus their synchrony with clock genes. We conclude that shift work or food intake in the rest phase leads to desynchronization within the liver, characterized by misaligned temporal patterns of clock genes and metabolic genes. This may be the cause of the development of the metabolic syndrome and obesity in individuals engaged in shift work.

The biochemistry and molecular biology of xenobiotic polymer degradation by microorganisms.

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Kawai, Fusako

2010-01-01

Research on microbial degradation of xenobiotic polymers has been underway for more than 40 years. It has exploited a new field not only in applied microbiology but also in environmental microbiology, and has greatly contributed to polymer science by initiating the design of biodegradable polymers. Owing to the development of analytical tools and technology, molecular biological and biochemical advances have made it possible to prospect for degrading microorganisms in the environment and to determine the mechanisms involved in biodegradation when xenobiotic polymers are introduced into the environment and are exposed to microbial attack. In this review, the molecular biological and biochemical aspects of the microbial degradation of xenobiotic polymers are summarized, and possible applications of potent microorganisms, enzymes, and genes in environmental biotechnology are suggested.

Association of the components of the metabolic syndrome with non- alcoholic fatty liver disease among normal-weight, overweight and obese children and adolescents

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Kelishadi Roya

2009-12-01

Full Text Available Abstract Objectives This study aimed to determine the prevalence of the metabolic syndrome, abnormalities of liver enzymes and sonographic fatty liver, as well as the inter-related associations in normal weight, overweight and obese children and adolescents. Methods This cross-sectional study was conducted among a sample of 1107 students (56.1% girls, aged 6-18 years in Isfahan, Iran. In addition to physical examination, fasting blood glucose, serum lipid profile and liver enzymes were determined. Liver sonography was performed among 931 participants. These variables were compared among participants with different body mass index (BMI categories. Results From lower to higher BMI category, alanine aminotransferase (ALT, total cholesterol, LDL-cholesterol, triglycerides and systolic blood pressure increased, and HDL-cholesterol decreased significantly. Elevated ALT, aspartate aminotransferase (AST and alkaline phosphatase (ALP were documented in respectively 4.1%, 6.6% and 9.8% of normal weight group. The corresponding figure was 9.5%, 9.8% and 9.1% in overweight group, and 16.9%, 14.9% and 10.8% in obese group, respectively. In all BMI categories, ALT increased significantly by increasing the number of the components of the metabolic syndrome. Odds ratio for elevated liver enzymes and sonographic fatty liver increased significantly with higher number of the components of the metabolic syndrome and higher BMI categories before and after adjustment for age. Conclusions Because of the interrelationship of biochemical and sonographic indexes of fatty liver with the components of the metabolic syndrome, and with increase in their number, it is suggested to determine the clinical impact of such association in future longitudinal studies.

On-line HPLC Analysis System for Metabolism and Inhibition Studies in Precision-Cut Liver Slices

NARCIS (Netherlands)

van Midwoud, Paul M.; Janssen, Joost; Merema, M.T.; de Graaf, Inge A. M.; Groothuis, Geny M. M.; Verpoorte, Elisabeth

2011-01-01

A novel approach for on-line monitoring of drug metabolism in continuously perifused, precision-cut liver slices (PCLS) in a microfluidic system has been developed using high-performance liquid chromatography with UV detection (HPLC-UV). In this approach, PCLS are incubated in a microfluidic device

Investigation on liver fast metabolism with CT

International Nuclear Information System (INIS)

Huebener, K.H.; Schmitt, W.G.H.

1981-01-01

Measurements of the density of normal and diffusely diseased liver parenchyma show a significant difference only in fatty liver. A linear relationship between the fat content and physical density has been demonstrated. Computed tomographic densitometry of liver tissue correlates well with physical in vitro measurements of fat content and is sufficiently accurate for clinical use. Other types of liver diseases cannot be differentiated by densitometry, Lipolisis in fatty liver in chronic alcoholism alcohol withdrawal has been investigated. It has been found that a rate of decrease of the fatty degeneration of the liver equals to 1 percent/day. Fatty degeneration of the liver in acute pancreatitis and other diseases have been also investigated. CT densitometry of the liver should be considered as a useful routine clinical method to determine the fat content of liver. (author)

Investigation on liver fast metabolism with CT

Energy Technology Data Exchange (ETDEWEB)

Huebener, K.H.; Schmitt, W.G.H. (Heidelberg Univ. (Germany, F.R.). Pathologisches Inst.)

1981-01-01

Measurements of the density of normal and diffusely diseased liver parenchyma show a significant difference only in fatty liver. A linear relationship between the fat content and physical density has been demonstrated. Computed tomographic densitometry of liver tissue correlates well with physical in vitro measurements of fat content and is sufficiently accurate for clinical use. Other types of liver diseases cannot be differentiated by densitometry, Lipolisis in fatty liver in chronic alcoholism alcohol withdrawal has been investigated. It has been found that a rate of decrease of the fatty degeneration of the liver equals to 1 percent/day. Fatty degeneration of the liver in acute pancreatitis and other diseases have been also investigated. CT densitometry of the liver should be considered as a useful routine clinical method to determine the fat content of liver.

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

Science.gov (United States)

Oesch, F; Fabian, E; Landsiedel, Robert

2018-06-18

Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which-taken with great caution because of the still very limited data-the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive

Xenobiotics that affect oxidative phosphorylation alter differentiation of human adipose-derived stem cells at concentrations that are found in human blood

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Laura Llobet

2015-11-01

Full Text Available Adipogenesis is accompanied by differentiation of adipose tissue-derived stem cells to adipocytes. As part of this differentiation, biogenesis of the oxidative phosphorylation system occurs. Many chemical compounds used in medicine, agriculture or other human activities affect oxidative phosphorylation function. Therefore, these xenobiotics could alter adipogenesis. We have analyzed the effects on adipocyte differentiation of some xenobiotics that act on the oxidative phosphorylation system. The tested concentrations have been previously reported in human blood. Our results show that pharmaceutical drugs that decrease mitochondrial DNA replication, such as nucleoside reverse transcriptase inhibitors, or inhibitors of mitochondrial protein synthesis, such as ribosomal antibiotics, diminish adipocyte differentiation and leptin secretion. By contrast, the environmental chemical pollutant tributyltin chloride, which inhibits the ATP synthase of the oxidative phosphorylation system, can promote adipocyte differentiation and leptin secretion, leading to obesity and metabolic syndrome as postulated by the obesogen hypothesis.

Effects of insulin-like growth factor-I on bone metabolism in patients with liver cirrhosis

International Nuclear Information System (INIS)

Li Xiaohong; Gao Wenjin; Wang Mingtao; Hu Haiqiang

2006-01-01

To study the effects of serum insulin-like growth factor-I (IGF-I) on bone metabolism in liver cirrhosis, 44 patients with hepatic cirrhosis were divided into 3 groups according to disease severity (Child Pugh Score) and 38 healthy subjects served as controls. Serum levels of IGF-I and osteocalcin(BGP) were measured in all patients and controls. Results showed that levels of IGF-I, BGP, and BMD were lower significantly in patients with liver cirrhosis than that in controls. When the condition of cirrhosis more deteriorated, these changes became much lower significantly. Serum levels of BGP and BMD were positively correlated with IGF-I. The decreasing level of IGF-I might be an important factor causing osteoporosis in patients with liver cirrhosis. (authors)

Effects of Castration on Expression of Lipid Metabolism Genes in the Liver of Korean Cattle

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Myunggi Baik

2015-01-01

Full Text Available Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p<0.001 hepatic lipids contents and higher (p<0.01 mRNA levels of lipogenic acetyl-CoA carboxylase. This differential gene expression may, in part, contribute to increased hepatic lipid content following the castration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2 and fatty acid (FA oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration.

The effect of experimental diabetes on phenylalanine metabolism in isolated liver cells.

OpenAIRE

Santana, M A; Fisher, M J; Bate, A J; Pogson, C I

1985-01-01

Chronic (10-day) diabetes was associated with increased metabolic flux through phenylalanine hydroxylase in isolated liver cells. This flux was stimulated by 0.1 microM-glucagon, but not by 10 microM-noradrenaline; 0.1 microM-insulin affected neither basal nor glucagon-stimulated flux. The increased rate of phenylalanine hydroxylation in diabetes was accompanied by parallel increases in enzyme activity (as measured with artificial cofactor) and immunoreactive-enzyme-protein content. In contra...

IFPA meeting 2015 workshop report III: nanomedicine applications and exosome biology, xenobiotics and endocrine disruptors and pregnancy, and lipid.

Science.gov (United States)

Albrecht, C; Caniggia, I; Clifton, V; Göhner, C; Harris, L; Hemmings, D; Jawerbaum, A; Johnstone, E; Jones, H; Keelan, J; Lewis, R; Mitchell, M; Murthi, P; Powell, T; Saffery, R; Smith, R; Vaillancourt, C; Wadsack, C; Salomon, C

2016-12-01

Workshops are an important part of the IFPA annual meeting, as they allow for discussion of specialized topics. At the IFPA meeting 2015 there were twelve themed workshops, three of which are summarized in this report. These workshops were related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) nanomedicine applications and exosome biology; 2) xenobiotics and endocrine disruptors and pregnancy; 3) lipid mediators and placental function. Copyright © 2016. Published by Elsevier Ltd.

Failure of Chemotherapy in Hepatocellular Carcinoma Due to Impaired and Dysregulated Primary Liver Drug Metabolizing Enzymes and Drug Transport Proteins: What to Do?

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Ul Islam, Salman; Ahmed, Muhammad Bilal; Shehzad, Adeeb; Ul-Islam, Mazhar; Lee, Young Sup

2018-05-28

Most of the drugs are metabolized in the liver by the action of drug metabolizing enzymes. In hepatocellular carcinoma (HCC), primary drug metabolizing enzymes are severely dysregulated, leading to failure of chemotherapy. Sorafenib is the only standard systemic drug available, but it still presents certain limitations, and much effort is required to understand who is responsive and who is refractory to the drug. Preventive and therapeutic approaches other than systemic chemotherapy include vaccination, chemoprevention, liver transplantation, surgical resection, and locoregional therapies. This review details the dysregulation of primary drug metabolizing enzymes and drug transport proteins of the liver in HCC and their influence on chemotherapeutic drugs. Furthermore, it emphasizes the adoption of safe alternative therapeutic strategies to chemotherapy. The future of HCC treatment should emphasize the understanding of resistance mechanisms and the finding of novel, safe, and efficacious therapeutic strategies, which will surely benefit patients affected by advanced HCC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Animal experiments to study the connection between the radioreaction of the RNA metabolism of the liver and the activity of the protein metabolism

Energy Technology Data Exchange (ETDEWEB)

Peters, E

1973-02-05

After selective deep X-ray irradiation of rat livers with 200 KeV X-rays, an enhanced incorporation of tritium uridine into various RNA species is observed. The extent and the rate of the radioreaction could be modified by experimentally changing the metabolic status of the liver cells. Partial deproteinisation of the plasma by means of an exchange function lead to a marked rise in the RNA synthesis rate of the liver for a short period of time. Additional irradiation had an inhibiting and delaying effect on the induction-dependent increase in tritium uridine incorporation in the case of transfer-RNA and m-RNA, while there was an enhanced incorporation in the messenger RNA of the heavy ribosome and polymer fraction.

Measurements of radioactive and xenobiotic substances in the biosphere in the Netherlands 1983

International Nuclear Information System (INIS)

1983-01-01

In this annual report the results and conclusions are given of measurements of radioactive and xenobiotic substances in the biosphere of the Netherlands. The measurements are coordinated by the Coordinating Committee for the Monitoring of Radioactive and Xenobiotic Substances (CCRX)

The Metabolism of Separase Inhibitor Sepin-1 in Human, Mouse, and Rat Liver Microsomes

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Feng Li

2018-05-01

Full Text Available Separase, a known oncogene, is widely overexpressed in numerous human tumors of breast, bone, brain, blood, and prostate. Separase is an emerging target for cancer therapy, and separase enzymatic inhibitors such as sepin-1 are currently being developed to treat separase-overexpressed tumors. Drug metabolism plays a critical role in the efficacy and safety of drug development, as well as possible drug–drug interactions. In this study, we investigated the in vitro metabolism of sepin-1 in human, mouse, and rat liver microsomes (RLM using metabolomic approaches. In human liver microsomes (HLM, we identified seven metabolites including one cysteine–sepin-1 adduct and one glutathione–sepin-1 adduct. All the sepin-1 metabolites in HLM were also found in both mouse and RLM. Using recombinant CYP450 isoenzymes, we demonstrated that multiple enzymes contributed to the metabolism of sepin-1, including CYP2D6 and CYP3A4 as the major metabolizing enzymes. Inhibitory effects of sepin-1 on seven major CYP450s were also evaluated using the corresponding substrates recommended by the US Food and Drug Administration. Our studies indicated that sepin-1 moderately inhibits CYP1A2, CYP2C19, and CYP3A4 with IC50 < 10 μM but weakly inhibits CYP2B6, CYP2C8/9, and CYP2D6 with IC50 > 10 μM. This information can be used to optimize the structures of sepin-1 for more suitable pharmacological properties and to predict the possible sepin-1 interactions with other chemotherapeutic drugs.

Metabolism Retrofit Strategies for ToxCast Assays (BOSC)

Science.gov (United States)

The EPA’s ToxCast program utilizes a wide variety of high-throughput screening assays (HTS) to assess chemical perturbations of molecular and cellular endpoints. A limitation of many HTS assays used for toxicity assessment is the lack of xenobiotic metabolism (XM) which precludes...

Green tea polyphenols alter lipid metabolism in the livers of broiler chickens through increased phosphorylation of AMP-activated protein kinase.

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Jinbao Huang

Full Text Available Our previous results showed that green tea polyphenols (GTPs significantly altered the expression of lipid-metabolizing genes in the liver of chickens. However, the underlying mechanism was not elucidated. In this study, we further characterized how GTPs influence AMP-activated protein kinase (AMPK in the regulation of hepatic fat metabolism. Thirty-six male chickens were fed GTPs at a daily dose of 0, 80 or 160 mg/kg of body weight for 4 weeks. The results demonstrated that oral administration of GTPs significantly reduced hepatic lipid content and abdominal fat mass, enhanced the phosphorylation levels of AMPKα and ACACA, and altered the mRNA levels and enzymatic activities of lipid-metabolizing enzymes in the liver. These results suggested that the activation of AMPK is a potential mechanism by which GTPs regulate hepatic lipid metabolism in such a way that lipid synthesis is reduced and fat oxidation is stimulated.

Eicosapentaenoic Acid-Enriched Phosphatidylcholine Attenuated Hepatic Steatosis Through Regulation of Cholesterol Metabolism in Rats with Nonalcoholic Fatty Liver Disease.

Science.gov (United States)

Liu, Yanjun; Shi, Di; Tian, Yingying; Liu, Yuntao; Zhan, Qiping; Xu, Jie; Wang, Jingfeng; Xue, Changhu

2017-02-01

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Disturbed cholesterol metabolism plays a crucial role in the development of NAFLD. The present study was conducted to evaluate the effects of EPA-PC extracted from sea cucumber on liver steatosis and cholesterol metabolism in NAFLD. Male Wistar rats were randomly divided into seven groups (normal control group, model group, lovastatin group, low- and high-dose EPA groups, and low- and high-dose EPA-PC groups). Model rats were established by administering a diet containing 1% orotic acid. To determine the possible cholesterol metabolism promoting mechanism of EPA-PC, we analyzed the transcription of key genes and transcriptional factors involved in hepatic cholesterol metabolism. EPA-PC dramatically alleviated hepatic lipid accumulation, reduced the serum TC concentration, and elevated HDLC levels in NAFLD rats. Fecal neutral cholesterol excretion was also promoted by EPA-PC administration. Additionally, EPA-PC decreased the mRNA expression of hydroxymethyl glutaric acid acyl (HMGR) and cholesterol 7α-hydroxylase (CYP7A), and increased the transcription of sterol carrying protein 2 (SCP2). Moreover, EPA-PC stimulated the transcription of peroxisome proliferators-activated receptor α (PPARα) and adenosine monophosphate activated protein kinase (AMPK) as well as its modulators, liver kinase B1 (LKB1) and Ca 2+ /calmodulin-dependent kinase kinase (CAMKK). Based on the results, the promoting effects of EPA-PC on NAFLD may be partly associated with the suppression of cholesterol synthesis via HMGR inhibition and the enhancement of fecal cholesterol excretion through increased SCP2 transcription. The underlying mechanism may involve stimulation of PPARα and AMPK.

The Metabolic Role of Gut Microbiota in the Development of Nonalcoholic Fatty Liver Disease and Cardiovascular Disease

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Marco Sanduzzi Zamparelli

2016-07-01

Full Text Available The prevalence of metabolic disorders, such as type 2 diabetes (T2D, obesity, and non-alcoholic fatty liver disease (NAFLD, which are common risk factors for cardiovascular disease (CVD, has dramatically increased worldwide over the last decades. Although dietary habit is the main etiologic factor, there is an imperfect correlation between dietary habits and the development of metabolic disease. Recently, research has focused on the role of the microbiome in the development of these disorders. Indeed, gut microbiota is implicated in many metabolic functions and an altered gut microbiota is reported in metabolic disorders. Here we provide evidence linking gut microbiota and metabolic diseases, focusing on the pathogenetic mechanisms underlying this association.

The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep.

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Kirsten Hogg

Full Text Available Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS. We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin-like growth factor (IGF and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5 or testosterone propionate (TP; n = 9 twice weekly (100 mg; i.m from d62-102 (gestation 147 days. In a novel treatment paradigm, a second cohort received a direct C (n = 4 or TP (20 mg; n = 7 fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (P<0.05 and the histological presence of fatty liver (P<0.05 independent of central obesity. Additionally, hepatic androgen receptor (AR; P<0.05, glucocorticoid receptor (GR; P<0.05, UDP- glucose ceramide glucosyltransferase (UGCG; P<0.05 and IGF1 (P<0.01 expression were upregulated. The direct fetal intervention (C and TP led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK was up-regulated in the fetal controls (P<0.05 and this was opposed by fetal TP (P<0.05. Hepatic estrogen receptor (ERα; P<0.05 and mitogen activated protein kinase kinase 4 (MAP2K4; P<0.05 were increased following fetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.

Hepatotoxicity and the present herbal hepatoprotective scenario

OpenAIRE

Priyankar Dey; Manas Ranjan Saha; Arnab Sen

2013-01-01

Most of the metabolic and physiological processes of our body as well as the detoxification of various drugs and xenobiotic chemicals occur in the liver. During this detoxification process, the reactive chemical intermediates damage the liver severely. There are several commercially available drugs, consumption of which results in idiosyncratic drug reaction mediated hepatotoxicity. Drug induced hepatotoxicity is a burning problem in this regard and several drugs are withdrawn from the market...

Metabolism of ginger component [6]-shogaol in liver microsomes from mouse, rat, dog, monkey, and human.

Science.gov (United States)

Chen, Huadong; Soroka, Dominique; Zhu, Yingdong; Sang, Shengmin

2013-05-01

There are limited data on the metabolism of [6]-shogaol (6S), a major bioactive component of ginger. This study demonstrates metabolism of 6S in liver microsomes from mouse, rat, dog, monkey, and human. The in vitro metabolism of 6S was compared among five species using liver microsomes from mouse, rat, dog, monkey, and human. Following incubations with 6S, three major reductive metabolites 1-(4'-hydroxy-3'-methoxyphenyl)-4-decen-3-ol (M6), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9), and 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11), as well as two new oxidative metabolites (1E,4E)-1-(4'-hydroxy-3'-methoxyphenyl)-deca-1,4-dien-3-one (M14) and (E)-1-(4'-hydroxy-3'-methoxyphenyl)-dec-1-en-3-one (M15) were found in all species. The kinetic parameters of M6 in liver microsomes from each respective species were quantified using Michaelis-Menten theory. A broad CYP-450 inhibitor, 1-aminobenzotriazole, precluded the formation of oxidative metabolites, M14 and M15, and 18β-glycyrrhetinic acid, an aldo-keto reductase inhibitor, eradicated the formation of the reductive metabolites M6, M9, and M11 in all species. Metabolites M14 and M15 were tested for cancer cell growth inhibition and induction of apoptosis and both showed substantial activity, with M14 displaying greater potency than 6S. We conclude that 6S is metabolized extensively in mammalian species mouse, rat, dog, monkey, and human, and that there are significant interspecies differences to consider when planning preclinical trials toward 6S chemoprevention. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Non-targeted, high resolution mass spectrometry strategy for simultaneous monitoring of xenobiotics and endogenous compounds in green sea turtles on the Great Barrier Reef.

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Heffernan, Amy L; Gómez-Ramos, Maria M; Gaus, Caroline; Vijayasarathy, Soumini; Bell, Ian; Hof, Christine; Mueller, Jochen F; Gómez-Ramos, Maria J

2017-12-01

Chemical contamination poses a threat to ecosystem, biota and human health, and identifying these hazards is a complex challenge. Traditional hazard identification relies on a priori-defined targets of limited chemical scope, and is generally inappropriate for exploratory studies such as explaining toxicological effects in environmental systems. Here we present a non-target high resolution mass spectrometry environmental monitoring study with multivariate statistical analysis to simultaneously detect biomarkers of exposure (e.g. xenobiotics) and biomarkers of effect in whole turtle blood. Borrowing the concept from clinical chemistry, a case-control sampling approach was used to investigate the potential influence of xenobiotics of anthropogenic origin on free-ranging green sea turtles (Chelonia mydas) from a remote, offshore 'control' site; and two coastal 'case' sites influenced by urban/industrial and agricultural activities, respectively, on the Great Barrier Reef in North Queensland, Australia. Multiple biomarkers of exposure, including sulfonic acids (n=9), a carbamate insecticide metabolite, and other industrial chemicals; and five biomarkers of effect (lipid peroxidation products), were detected in case sites. Additionally, two endogenous biomarkers of neuroinflammation and oxidative stress were identified, and showed moderate-to-strong correlations with clinical measures of inflammation and liver dysfunction. Our data filtering strategy overcomes limitations of traditional a priori selection of target compounds, and adds to the limited environmental xenobiotic metabolomics literature. To our knowledge this is the first case-control study of xenobiotics in marine megafauna, and demonstrates the utility of green sea turtles to link internal and external exposure, to explain potential toxicological effects in environmental systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Characteristics and significance of D-tagatose-induced liver enlargement in rats: An interpretative review.

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Bär, A

1999-04-01

This review addresses the issue of asymptomatic liver enlargement in rats. It was necessitated by the observation of significantly increased liver weights in rats fed diets with 10 to 20% D-tagatose, a potential new bulk sweetener, for between 28 and 90 days. Increases of liver size without accompanying histopathological changes or impairment of organ function have been observed in rats in response to the ingestion of various xenobiotic compounds (including some food additives), changes of dietary composition (e.g. , high doses of fructose and sucrose), metabolic aberrations (e.g., diabetes), as well as normal pregnancy and lactation. The underlying mechanism(s) are not yet understood in detail but peroxisome proliferation, microsomal enzyme induction, increased storage of glycogen or lipids, and hyperfunction due to an excessive workload are well-established causes of hepatomegaly in rats. In D-tagatose- and fructose-fed rats, a treatment-related increase of hepatic glycogen storage was identified as a likely cause of the liver enlargement. Dietary levels of 5% and about 15-20% were determined as no-effect levels (NOEL) for D-tagatose- and fructose-induced liver enlargement, respectively. At doses above the NOEL, D-tagatose is about four times more efficient than fructose in inducing liver enlargement. On the other hand, the estimated intake of D-tagatose from its intended uses in food is about four times lower than the actual fructose intake. Consequently, a similar safety margin would apply for both sugars. Considering the similarity of the liver effects in rats of fructose, a safe food ingredient, and D-tagatose, the absence of histopathological changes in rats fed a diet with 20% D-tagatose for 90 days, and the absence of adverse long-term consequences of glycogen-induced liver enlargement in rats, it is concluded that the observed liver enlargement in D-tagatose-fed rats has no relevance for the assessment of human safety of this substance. Copyright 1999

Changes in cytochrome P450 gene expression and enzyme activity induced by xenobiotics in rabbits in vivo and in vitro

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Orsolya Palócz

2017-06-01

Full Text Available As considerable inter-species differences exist in xenobiotic metabolism, developing new pharmaceutical therapies for use in different species is fraught with difficulties. For this reason, very few medicines have been registered for use in rabbits, despite their importance in inter alia meat and fur production. We have developed a rapid and sensitive screening system for drug safety in rabbits based on cytochrome P450 enzyme assays, specifically CYP1A1, CYP1A2 and CYP3A6, employing an adaptation of the luciferin-based clinical assay currently used in human drug screening. Short-term (4-h cultured rabbit primary hepatocytes were treated with a cytochrome inducer (phenobarbital and 2 inhibitors (alpha-naphthoflavone and ketoconazole. In parallel, and to provide verification, New Zealand white rabbits were dosed with 80 mg/kg phenobarbital or 40 mg/kg ketoconazole for 3 d. Ketoconazole significantly increased CYP3A6 gene expression and decreased CYP3A6 activity both in vitro and in vivo. CYP1A1 activity was decreased by ketoconazole in vitro and increased in vivo. This is the first report of the inducer effect of ketoconazole on rabbit cytochrome isoenzymes in vivo. Our data support the use of a luciferin-based assay in short-term primary hepatocytes as an appropriate tool for xenobiotic metabolism assays and short-term toxicity testing in rabbits.

Long-Lasting Improvements in Liver Fat and Metabolism Despite Body Weight Regain After Dietary Weight Loss

OpenAIRE

Haufe, Sven; Haas, Verena; Utz, Wolfgang; Birkenfeld, Andreas L.; Jeran, Stephanie; Böhnke, Jana; Mähler, Anja; Luft, Friedrich C.; Schulz-Menger, Jeanette; Boschmann, Michael; Jordan, Jens; Engeli, Stefan

2013-01-01

OBJECTIVE Weight loss reduces abdominal and intrahepatic fat, thereby improving metabolic and cardiovascular risk. Yet, many patients regain weight after successful diet-induced weight loss. Long-term changes in abdominal and liver fat, along with liver test results and insulin resistance, are not known. RESEARCH DESIGN AND METHODS We analyzed 50 overweight to obese subjects (46 ± 9 years of age; BMI, 32.5 ± 3.3 kg/m2; women, 77%) who had participated in a 6-month hypocaloric diet and were ra...

[The effect of halothane on the fructose metabolism in the liver].

Science.gov (United States)

Götz, E; Scholz, R

1975-10-01

Glucose production from frutose (2 mmol) and fructolysis was studied in perfused rat liver. In the presence of halothane (0.5, 1.5, and 4.0 vol%) glucose production was inhibited, whereas lactate production was stimulated. Total fructose metabolism was unchanged. Since halogenated hydrocarbon compounds are known to inhibit the mitochondrial respiratory chain, it is concluded that glucose synthesis is inhibited due to decreased supply of energy-rich phosphates from oxidative phosphorylation. On the other hand, this depletion of energy may be partially compensated for by an increased extramitochondrial energy production due to fructolysis.

Oxidative Inactivation of Liver Mitochondria in High Fructose Diet-Induced Metabolic Syndrome in Rats: Effect of Glycyrrhizin Treatment.

Science.gov (United States)

Sil, Rajarshi; Chakraborti, Abhay Sankar

2016-09-01

Metabolic syndrome is a serious health problem in the present world. Glycyrrhizin, a triterpenoid saponin of licorice (Glycyrrhiza glabra) root, has been reported to ameliorate the primary complications and hepatocellular damage in rats with the syndrome. In this study, we have explored metabolic syndrome-induced changes in liver mitochondrial function and effect of glycyrrhizin against the changes. Metabolic syndrome was induced in rats by high fructose (60%) diet for 6 weeks. The rats were then treated with glycyrrhizin (50 mg/kg body weight) by single intra-peritoneal injection. After 2 weeks of the treatment, the rats were sacrificed to collect liver tissue. Elevated mitochondrial ROS, lipid peroxidation and protein carbonyl, and decreased reduced glutathione content indicated oxidative stress in metabolic syndrome. Loss of mitochondrial inner membrane cardiolipin was observed. Mitochondrial complex I activity did not change but complex IV activity decreased significantly. Mitochondrial MTT reduction ability, membrane potential, phosphate utilisation and oxygen consumption decreased in metabolic syndrome. Reduced mitochondrial aconitase activity and increased aconitase carbonyl content suggested oxidative damage of the enzyme. Elevated Fe(2+) ion level in mitochondria might be associated with increased ROS generation in metabolic syndrome. Glycyrrhizin effectively attenuated mitochondrial oxidative stress and aconitase degradation, and improved electron transport chain activity. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Application of localized {sup 31}P MRS saturation transfer at 7 T for measurement of ATP metabolism in the liver: reproducibility and initial clinical application in patients with non-alcoholic fatty liver disease

Energy Technology Data Exchange (ETDEWEB)

Valkovic, Ladislav [Medical University of Vienna, High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Slovak Academy of Sciences, Department of Imaging Methods, Institute of Measurement Science, Bratislava (Slovakia); Gajdosik, Martin; Chmelik, Marek; Trattnig, Siegfried [Medical University of Vienna, High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Traussnigg, Stefan; Kienbacher, Christian; Trauner, Michael [Medical University of Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Vienna (Austria); Wolf, Peter; Krebs, Michael [Medical University of Vienna, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Vienna (Austria); Bogner, Wolfgang [Medical University of Vienna, High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA (United States); Krssak, Martin [Medical University of Vienna, High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Medical University of Vienna, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Vienna (Austria)

2014-07-15

Saturation transfer (ST) phosphorus MR spectroscopy ({sup 31}P MRS) enables in vivo insight into energy metabolism and thus could identify liver conditions currently diagnosed only by biopsy. This study assesses the reproducibility of the localized {sup 31}P MRS ST in liver at 7 T and tests its potential for noninvasive differentiation of non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). After the ethics committee approval, reproducibility of the localized {sup 31}P MRS ST at 7 T and the biological variation of acquired hepato-metabolic parameters were assessed in healthy volunteers. Subsequently, 16 suspected NAFL/NASH patients underwent MRS measurements and diagnostic liver biopsy. The Pi-to-ATP exchange parameters were compared between the groups by a Mann-Whitney U test and related to the liver fat content estimated by a single-voxel proton ({sup 1}H) MRS, measured at 3 T. The mean exchange rate constant (k) in healthy volunteers was 0.31 ± 0.03 s{sup -1} with a coefficient of variation of 9.0 %. Significantly lower exchange rates (p < 0.01) were found in NASH patients (k = 0.17 ± 0.04 s{sup -1}) when compared to healthy volunteers, and NAFL patients (k = 0.30 ± 0.05 s{sup -1}). Significant correlation was found between the k value and the liver fat content (r = 0.824, p < 0.01). Our data suggest that the {sup 31}P MRS ST technique provides a tool for gaining insight into hepatic ATP metabolism and could contribute to the differentiation of NAFL and NASH. (orig.)

Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome

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Marta Borges-Canha

Full Text Available Background: The non-alcoholic fatty liver disease is the hepatic counterpart of the metabolic syndrome. ZSF1 rats are a metabolic syndrome animal model in which liver changes have not been described yet. Aim: The characterization of liver histological and innate immunity changes in ZSF1 rats. Methods: Five groups of rats were included (n = 7 each group: healthy Wistar-Kyoto control rats (Ctrl, hypertensive ZSF1 lean (Ln, ZSF1 obese rats with a normal diet (Ob, ZSF1 obese rates with a high-fat diet (Ob-HFD, and ZSF1 obese rats with low-intensity exercise training (Ob-Ex. The animals were sacrificed at 20 weeks of age, their livers were collected for: a measurements of the area of steatosis, fibrosis and inflammation (histomorphological analysis; and b innate immunity (toll-like receptor [TLR] 2, TLR4, peroxisome proliferator-activated receptor γ [PPARγ], toll interacting protein [TOLLIP] and inflammatory marker (tumor necrosis factor-alpha [TNFvs], interleukin 1 [IL-1] expression analysis by real-time PCR. Results: Ob, Ob-HFD and Ob-Ex were significantly heavier than Ln and Ctrl animals. Ob, Ob-HFD and Ob-Ex animals had impaired glucose tolerance and insulin resistance. ZSF1 Ob, Ob-HFD and Ob-Ex presented a higher degree of steatosis (3,5x; p < 0.05 than Ctrl or ZSF1 Ln rats. Steatohepatitis and fibrosis were not observed in any of the groups. No differences in expression were observed between Ctrl, Ln and Ob animals (except for the significantly higher expression of TOLLIP observed in the Ob vs Ln comparison. Ob-HFD and Ob-Ex rats showed increased expression of PPARγ and TOLLIP as compared to other groups. However, both groups also showed increased expression of TLR2 and TLR4. Nevertheless, this did not translate into a differential expression of TNFα or IL-1 in any of the groups. Conclusion: The ZSF1 model is associated with liver steatosis but not with steatohepatitis or a significantly increased expression of innate immunity or

Metabolism of lysergic acid diethylamide (LSD) to 2-oxo-3-hydroxy LSD (O-H-LSD) in human liver microsomes and cryopreserved human hepatocytes.

Science.gov (United States)

Klette, K L; Anderson, C J; Poch, G K; Nimrod, A C; ElSohly, M A

2000-10-01

The metabolism of lysergic acid diethylamide (LSD) to 2-oxo-3-hydroxy lysergic acid diethylamide (O-H-LSD) was investigated in liver microsomes and cyropreserved hepatocytes from humans. Previous studies have demonstrated that O-H-LSD is present in human urine at concentrations 16-43 times greater than LSD, the parent compound. Additionally, these studies have determined that O-H-LSD is not generated during the specimen extraction and analytical processes or due to parent compound degradation in aqueous urine samples. However, these studies have not been conclusive in demonstrating that O-H-LSD is uniquely produced during in vivo metabolism. Phase I drug metabolism was investigated by incubating human liver microsomes and cryopreserved human hepatocytes with LSD. The reaction was quenched at various time points, and the aliquots were extracted using liquid partitioning and analyzed by liquid chromatography-mass spectrometry. O-H-LSD was positively identified in all human liver microsomal and human hepatocyte fractions incubated with LSD. In addition, O-H-LSD was not detected in any microsomal or hepatocyte fraction not treated with LSD nor in LSD specimens devoid of microsomes or hepatocytes. This study provides definitive evidence that O-H-LSD is produced as a metabolic product following incubation of human liver microsomes and hepatocytes with LSD.

Differential induction of enzymes and genes involved in lipid metabolism in liver and visceral adipose tissue of juvenile yellow catfish Pelteobagrus fulvidraco exposed to copper

International Nuclear Information System (INIS)

Chen, Qi-Liang; Luo, Zhi; Pan, Ya-Xiong; Zheng, Jia-Lang; Zhu, Qing-Ling; Sun, Lin-Dan; Zhuo, Mei-Qin; Hu, Wei

2013-01-01

Highlights: •Cu downregulates lipogenesis and reduces lipid deposition in liver and adipose tissue. •Mechanism of Cu affecting lipid metabolism is determined at the enzymatic and molecular levels. •Cu exposure differentially influences lipid metabolism between liver and adipose tissue. -- Abstract: The present study was conducted to determine the mechanism of waterborne Cu exposure influencing lipid metabolism in liver and visceral adipose tissue (VAT) of juvenile yellow catfish Pelteobagrus fulvidraco. Yellow catfish were exposed to four waterborne copper (Cu) concentrations (2 (control), 24 (low), 71 (medium), 198 (high) μg Cu/l, respectively) for 6 weeks. Waterborne Cu exposure had a negative effect on growth and several condition indices (condition factor, viscerosomatic index, hepatosomatic index and visceral adipose index). In liver, lipid content, activities of lipogenic enzymes (6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), isocitrate dehydrogenase (ICDH), and fatty acid synthase (FAS)) as well as mRNA levels of 6PGD, G6PD, FAS and sterol-regulator element-binding protein-1 (SREBP-1) genes decreased with increasing Cu concentrations. However, activity and mRNA level of lipoprotein lipase (LPL) gene in liver increased. In VAT, G6PD, ME and LPL activities as well as the mRNA levels of FAS, LPL and PPARγ genes decreased in fish exposed to higher Cu concentrations. The differential Pearson correlations between transcription factors (SREBP-1 and peroxisome proliferators-activated receptor-γ (PPARγ)), and the activities and mRNA expression of lipogenic enzymes and their genes were observed between liver and VAT. Thus, our study indicated that reduced lipid contents in liver and VAT after Cu exposure were attributable to the reduced activities and mRNA expression of lipogenic enzymes and their genes in these tissues. Different response patterns of several tested enzymes and genes to waterborne Cu

Differential induction of enzymes and genes involved in lipid metabolism in liver and visceral adipose tissue of juvenile yellow catfish Pelteobagrus fulvidraco exposed to copper

Energy Technology Data Exchange (ETDEWEB)

Chen, Qi-Liang; Luo, Zhi, E-mail: luozhi99@yahoo.com.cn; Pan, Ya-Xiong; Zheng, Jia-Lang; Zhu, Qing-Ling; Sun, Lin-Dan; Zhuo, Mei-Qin; Hu, Wei

2013-07-15

Highlights: •Cu downregulates lipogenesis and reduces lipid deposition in liver and adipose tissue. •Mechanism of Cu affecting lipid metabolism is determined at the enzymatic and molecular levels. •Cu exposure differentially influences lipid metabolism between liver and adipose tissue. -- Abstract: The present study was conducted to determine the mechanism of waterborne Cu exposure influencing lipid metabolism in liver and visceral adipose tissue (VAT) of juvenile yellow catfish Pelteobagrus fulvidraco. Yellow catfish were exposed to four waterborne copper (Cu) concentrations (2 (control), 24 (low), 71 (medium), 198 (high) μg Cu/l, respectively) for 6 weeks. Waterborne Cu exposure had a negative effect on growth and several condition indices (condition factor, viscerosomatic index, hepatosomatic index and visceral adipose index). In liver, lipid content, activities of lipogenic enzymes (6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), isocitrate dehydrogenase (ICDH), and fatty acid synthase (FAS)) as well as mRNA levels of 6PGD, G6PD, FAS and sterol-regulator element-binding protein-1 (SREBP-1) genes decreased with increasing Cu concentrations. However, activity and mRNA level of lipoprotein lipase (LPL) gene in liver increased. In VAT, G6PD, ME and LPL activities as well as the mRNA levels of FAS, LPL and PPARγ genes decreased in fish exposed to higher Cu concentrations. The differential Pearson correlations between transcription factors (SREBP-1 and peroxisome proliferators-activated receptor-γ (PPARγ)), and the activities and mRNA expression of lipogenic enzymes and their genes were observed between liver and VAT. Thus, our study indicated that reduced lipid contents in liver and VAT after Cu exposure were attributable to the reduced activities and mRNA expression of lipogenic enzymes and their genes in these tissues. Different response patterns of several tested enzymes and genes to waterborne Cu

MicroRNA-mediated regulation of glutathione and methionine metabolism and its relevance for liver disease.

Science.gov (United States)

Lu, Shelly C; Mato, José M; Espinosa-Diez, Cristina; Lamas, Santiago

2016-11-01

The discovery of the microRNA (miRNA) family of small RNAs as fundamental regulators of post-transcriptional gene expression has fostered research on their importance in every area of biology and clinical medicine. In the particular area of liver metabolism and disease, miRNAs are gaining increasing importance. By focusing on two fundamental hepatic biosynthetic pathways, glutathione and methionine, we review recent advances on the comprehension of the role of miRNAs in liver pathophysiology and more specifically of models of hepatic cholestasis/fibrosis and hepatocellular carcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease.

Directory of Open Access Journals (Sweden)

Adeeba Ahmed

Full Text Available Non alcoholic fatty liver disease (NAFLD is the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of liver disease ranging from reversible hepatic steatosis, to non alcoholic steato-hepatitis (NASH and cirrhosis. The potential role of glucocorticoids (GC in the pathogenesis of NAFLD is highlighted in patients with GC excess, Cushing's syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, hepatic cortisol availability is controlled by enzymes that regenerate cortisol (F from inactive cortisone (E (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1, or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR.In vitro studies defined 11β-HSD1 expression in normal and NASH liver samples. We then characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD compared to 32 obese controls using gas chromatographic analysis of 24 hour urine collection and plasma cortisol generation profile following oral cortisone.In patients with steatosis 5αR activity was increased, with a decrease in hepatic 11β-HSD1 activity. Total cortisol metabolites were increased in this group consistent with increased GC production rate. In contrast, in patients with NASH, 11β-HSD1 activity was increased both in comparison to patients with steatosis, and controls. Endorsing these findings, 11β-HSD1 mRNA and immunostaining was markedly increased in NASH patients in peri septal hepatocytes and within CD68 positive macrophages within inflamed cirrhotic septa.Patients with hepatic steatosis have increased clearance and decreased hepatic regeneration of cortisol and we propose that this may represent a protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11β-HSD1 activity and consequent cortisol regeneration may

A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease.

Science.gov (United States)

Ahmed, Adeeba; Rabbitt, Elizabeth; Brady, Theresa; Brown, Claire; Guest, Peter; Bujalska, Iwona J; Doig, Craig; Newsome, Philip N; Hubscher, Stefan; Elias, Elwyn; Adams, David H; Tomlinson, Jeremy W; Stewart, Paul M

2012-01-01

Non alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of liver disease ranging from reversible hepatic steatosis, to non alcoholic steato-hepatitis (NASH) and cirrhosis. The potential role of glucocorticoids (GC) in the pathogenesis of NAFLD is highlighted in patients with GC excess, Cushing's syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, hepatic cortisol availability is controlled by enzymes that regenerate cortisol (F) from inactive cortisone (E) (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1), or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR). In vitro studies defined 11β-HSD1 expression in normal and NASH liver samples. We then characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD compared to 32 obese controls using gas chromatographic analysis of 24 hour urine collection and plasma cortisol generation profile following oral cortisone. In patients with steatosis 5αR activity was increased, with a decrease in hepatic 11β-HSD1 activity. Total cortisol metabolites were increased in this group consistent with increased GC production rate. In contrast, in patients with NASH, 11β-HSD1 activity was increased both in comparison to patients with steatosis, and controls. Endorsing these findings, 11β-HSD1 mRNA and immunostaining was markedly increased in NASH patients in peri septal hepatocytes and within CD68 positive macrophages within inflamed cirrhotic septa. Patients with hepatic steatosis have increased clearance and decreased hepatic regeneration of cortisol and we propose that this may represent a protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11β-HSD1 activity and consequent cortisol regeneration may serve to

Biofabrication of a three-dimensional liver micro-organ as an in vitro drug metabolism model.

Science.gov (United States)

Chang, Robert; Emami, Kamal; Wu, Honglu; Sun, Wei

2010-12-01

In their normal in vivo matrix milieu, tissues assume complex well-organized three-dimensional architectures. Therefore, the primary aim in the tissue engineering design process is to fabricate an optimal analog of the in vivo scenario. This challenge can be addressed by applying emerging layered biofabrication approaches in which the precise configuration and composition of cells and bioactive matrix components can recapitulate the well-defined three-dimensional biomimetic microenvironments that promote cell-cell and cell-matrix interactions. Furthermore, the advent of and refinements in microfabricated systems can present physical and chemical cues to cells in a controllable and reproducible fashion unmatched with conventional cultures, resulting in the precise construction of engineered biomimetic microenvironments on the cellular length scale in geometries that are readily parallelized for high throughput in vitro models. As such, the convergence of layered solid freeform fabrication (SFF) technologies along with microfabrication techniques enables the creation of a three-dimensional micro-organ device to serve as an in vitro platform for cell culture, drug screening or to elicit further biological insights, particularly for NASA's interest in a flight-suitable high-fidelity microscale platform to study drug metabolism in space and planetary environments. The proposed model in this paper involves the combinatorial setup of an automated syringe-based, layered direct cell writing bioprinting process with micro-patterning techniques to fabricate a microscale in vitro device housing a chamber of bioprinted three-dimensional liver cell-encapsulated hydrogel-based tissue constructs in defined design patterns that biomimic the cell's natural microenvironment for enhanced biological functionality. In order to assess the structural formability and biological feasibility of such a micro-organ, reproducibly fabricated tissue constructs were biologically characterized for

Biofabrication of a three-dimensional liver micro-organ as an in vitro drug metabolism model

International Nuclear Information System (INIS)

Chang, Robert; Sun Wei; Emami, Kamal; Wu Honglu

2010-01-01

In their normal in vivo matrix milieu, tissues assume complex well-organized three-dimensional architectures. Therefore, the primary aim in the tissue engineering design process is to fabricate an optimal analog of the in vivo scenario. This challenge can be addressed by applying emerging layered biofabrication approaches in which the precise configuration and composition of cells and bioactive matrix components can recapitulate the well-defined three-dimensional biomimetic microenvironments that promote cell-cell and cell-matrix interactions. Furthermore, the advent of and refinements in microfabricated systems can present physical and chemical cues to cells in a controllable and reproducible fashion unmatched with conventional cultures, resulting in the precise construction of engineered biomimetic microenvironments on the cellular length scale in geometries that are readily parallelized for high throughput in vitro models. As such, the convergence of layered solid freeform fabrication (SFF) technologies along with microfabrication techniques enables the creation of a three-dimensional micro-organ device to serve as an in vitro platform for cell culture, drug screening or to elicit further biological insights, particularly for NASA's interest in a flight-suitable high-fidelity microscale platform to study drug metabolism in space and planetary environments. The proposed model in this paper involves the combinatorial setup of an automated syringe-based, layered direct cell writing bioprinting process with micro-patterning techniques to fabricate a microscale in vitro device housing a chamber of bioprinted three-dimensional liver cell-encapsulated hydrogel-based tissue constructs in defined design patterns that biomimic the cell's natural microenvironment for enhanced biological functionality. In order to assess the structural formability and biological feasibility of such a micro-organ, reproducibly fabricated tissue constructs were biologically characterized for

Biofabrication of a three-dimensional liver micro-organ as an in vitro drug metabolism model

Energy Technology Data Exchange (ETDEWEB)

Chang, Robert; Sun Wei [Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA (United States); Emami, Kamal; Wu Honglu, E-mail: rcc34@drexel.ed, E-mail: sunwei@drexel.ed, E-mail: kamal.emami-1@nasa.go, E-mail: honglu.wu-1@nasa.go [Radiation Biophysics Laboratory, Human Adaptation and Countermeasures Office, NASA Johnson Space Center, Houston, TX (United States)

2010-12-15

In their normal in vivo matrix milieu, tissues assume complex well-organized three-dimensional architectures. Therefore, the primary aim in the tissue engineering design process is to fabricate an optimal analog of the in vivo scenario. This challenge can be addressed by applying emerging layered biofabrication approaches in which the precise configuration and composition of cells and bioactive matrix components can recapitulate the well-defined three-dimensional biomimetic microenvironments that promote cell-cell and cell-matrix interactions. Furthermore, the advent of and refinements in microfabricated systems can present physical and chemical cues to cells in a controllable and reproducible fashion unmatched with conventional cultures, resulting in the precise construction of engineered biomimetic microenvironments on the cellular length scale in geometries that are readily parallelized for high throughput in vitro models. As such, the convergence of layered solid freeform fabrication (SFF) technologies along with microfabrication techniques enables the creation of a three-dimensional micro-organ device to serve as an in vitro platform for cell culture, drug screening or to elicit further biological insights, particularly for NASA's interest in a flight-suitable high-fidelity microscale platform to study drug metabolism in space and planetary environments. The proposed model in this paper involves the combinatorial setup of an automated syringe-based, layered direct cell writing bioprinting process with micro-patterning techniques to fabricate a microscale in vitro device housing a chamber of bioprinted three-dimensional liver cell-encapsulated hydrogel-based tissue constructs in defined design patterns that biomimic the cell's natural microenvironment for enhanced biological functionality. In order to assess the structural formability and biological feasibility of such a micro-organ, reproducibly fabricated tissue constructs were biologically

Symposium overview: alterations in cytokine receptors by xenobiotics.

Science.gov (United States)

Cohen, M D; Schook, L B; Oppenheim, J J; Freed, B M; Rodgers, K E

1999-04-01

A symposium entitled Alterations in Cytokine Receptors by Xenobiotics was held at the 37th Annual Meeting of the Society of Toxicology (SOT) in Seattle, Washington. The symposium was sponsored by the Immunotoxicology Specialty Section of SOT and was designed to present information on the effect of several different classes of xenobiotics on various aspects of receptor function (i.e., post-receptor signal transduction of receptor expression), or the involvement of cytokine receptors in the action of the toxicant under consideration. This symposium brought together scientists in the area of receptor immunobiology whose expertise in receptor modulation encompassed those major signaling agents involved in the normal immune response, i.e., proinflammatory cytokines, chemokines, interleukins, and interferons. The following is a summary of each of the individual presentations.