58 results match your criteria liver pyrazole-treated


CYP2E1 potentiates toxicity in obesity and after chronic ethanol treatment.

Drug Metabol Drug Interact 2012 ;27(3):125-44

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY, USA.

CYP2E1 activates several hepatotoxins and contributes to alcoholic liver damage. In this report, we review our studies on whether induction of CYP2E1 can potentiate liver injury in obesity. Acetone- or pyrazole-induced severe liver injury in obese mice as compared to obese controls and lean mice. Read More

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November 2012

Peroxiredoxin III and sulfiredoxin together protect mice from pyrazole-induced oxidative liver injury.

Antioxid Redox Signal 2012 Nov 31;17(10):1351-61. Epub 2012 May 31.

Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.

Aims: To define the mechanisms underlying pyrazole-induced oxidative stress and the protective role of peroxiredoxins (Prxs) and sulfiredoxin (Srx) against such stress.

Results: Pyrazole increased Srx expression in the liver of mice in a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent manner and induced Srx translocation from the cytosol to the endoplasmic reticulum (ER) and mitochondria. Pyrazole also induced the expression of CYP2E1, a primary reactive oxygen species (ROS) source for ethanol-induced liver injury, in ER and mitochondria. Read More

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November 2012

Pyrazole induced oxidative liver injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency.

Toxicology 2008 Oct 3;252(1-3):9-16. Epub 2008 Aug 3.

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Pyrazole can induce CYP2E1 and 2A5, which produce reactive oxygen species (ROS). Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates important antioxidant enzymes to remove ROS. In this study, we applied Nrf2 knockout mice to test the hypothesis that pyrazole will cause hepatotoxicity and elevate oxidative stress to a greater extent in Nrf2 knockout mice compared to wild type mice. Read More

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October 2008

A decrease in S-adenosyl-L-methionine potentiates arachidonic acid cytotoxicity in primary rat hepatocytes enriched in CYP2E1.

Authors:
Jian Zhuge

Mol Cell Biochem 2008 Jul 15;314(1-2):105-12. Epub 2008 Apr 15.

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Previous studies show that treatment with a polyunsaturated fatty acid, arachidonic acid (AA), or high concentrations of cycloleucine, an inhibitor of methionine adenosyltransferase (MAT), which lowers levels of S-adenosyl-L-methionine (SAM), increased toxicity in hepatocytes from pyrazole-treated rats which expressed high levels of cytochrome P450 2E1 (CYP2E1). In this study, I used concentrations of cycloleucine or AA, which by themselves do not produce any toxicity, to evaluate whether a decrease in SAM sensitizes hepatocytes to AA toxicity, especially in hepatocytes enriched in CYP2E1. Levels of SAM were lower by 50% in hepatocytes from pyrazole- compared to saline-treated rats. Read More

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Depletion of S-adenosyl-l-methionine with cycloleucine potentiates cytochrome P450 2E1 toxicity in primary rat hepatocytes.

Arch Biochem Biophys 2007 Oct 15;466(2):177-85. Epub 2007 Jun 15.

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.

S-Adenosyl-l-methionine (SAM) is the principal biological methyl donor. Methionine adenosyltransferase (MAT) catalyzes the only reaction that generates SAM. Hepatocytes were treated with cycloleucine, an inhibitor of MAT, to evaluate whether hepatocytes enriched in cytochrome P450 2E1 (CYP2E1) were more sensitive to a decline in SAM. Read More

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October 2007

Induction of cytochrome P450 2E1 [corrected] promotes liver injury in ob/ob mice.

Hepatology 2007 Jun;45(6):1355-65

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

Unlabelled: Cytochrome P450 2E1 (CYP2E1) activates several hepatotoxins and contributes to alcoholic liver damage. Obesity is a growing health problem in the United States. The aim of the present study was to evaluate whether acetone- or pyrazole-mediated induction of CYP2E1 can potentiate liver injury in obesity. Read More

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Increased toxicity by transforming growth factor-beta 1 in liver cells overexpressing CYP2E1.

Free Radic Biol Med 2006 Oct 4;41(7):1100-12. Epub 2006 Jul 4.

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Place, New York, NY 10029, USA.

Ethanol treatment causes an increase in expression of TGF-beta1 and CYP2E1 in the centrilobular area. Alcoholic liver disease is usually initiated in the centrilobular region of the liver. We hypothesized that the combination of TGF-beta1 and CYP2E1 produces increased oxidative stress and liver cell toxicity. Read More

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October 2006

Cytochrome P450 2E1-dependent oxidant stress and upregulation of anti-oxidant defense in liver cells.

J Gastroenterol Hepatol 2006 Oct;21 Suppl 3:S22-5

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York 10029, USA.

Induction of cytochrome P450 2E1 (CYP2E1) is a central pathway by which ethanol generates oxidative stress. Cytochrome P450 2E1 metabolizes many other toxicologic compounds. Toxicity of these agents is enhanced by ethanol, due to induction of CYP2E1. Read More

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October 2006

Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1.

Hepatology 2006 Jan;43(1):144-53

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.

Induction of CYP2E1 by ethanol is one pathway through which ethanol generates oxidative stress. Nrf2 is a transcription factor that regulates important antioxidant and phase II detoxification genes. Nrf2 induction by CYP2E1 and its importance in the adaptive response to increased oxidative stress caused by CYP2E1 was studied. Read More

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January 2006

Opposite action of S-adenosyl methionine and its metabolites on CYP2E1-mediated toxicity in pyrazole-induced rat hepatocytes and HepG2 E47 cells.

Am J Physiol Gastrointest Liver Physiol 2006 Apr 23;290(4):G674-84. Epub 2005 Nov 23.

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.

S-adenosyl-L-methionine (SAMe) is protective against a variety of hepatotoxins, including ethanol. The ability of SAMe to protect against cytochrome P-450 2E1 (CYP2E1)-dependent toxicity was studied in hepatocytes from pyrazole-treated rats and HepG2 E47 cells, both of which actively express CYP2E1. Toxicity was initiated by the addition of arachidonic acid (AA) or by depletion of glutathione after treatment with L-buthionine sulfoximine (BSO). Read More

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Glutathione depletion in CYP2E1-expressing liver cells induces toxicity due to the activation of p38 mitogen-activated protein kinase and reduction of nuclear factor-kappaB DNA binding activity.

Mol Pharmacol 2004 Sep;66(3):749-60

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

Depletion of glutathione (GSH) from CYP2E1-expressing cells by treatment with l-buthionine sulfoximine (BSO) causes decreased cell viability. The possible role of mitogen-activated protein kinases (MAPK) in this toxicity was evaluated. SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], an inhibitor of p38 MAPK decreased the BSO-dependent toxicity in HepG2 E47 cells, which express CYP2E1 and in hepatocytes from pyrazole-treated rats. Read More

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September 2004

Endoplasmic reticulum stress due to altered cellular redox status positively regulates murine hepatic CYP2A5 expression.

J Pharmacol Exp Ther 2004 Feb 10;308(2):600-8. Epub 2003 Nov 10.

Department of Biomedical Sciences, University of Guelph, ON, Canada.

Murine hepatic cytochrome P450 2A5 (CYP2A5) is uniquely induced by a variety of agents that cause liver injury and inflammation, conditions that are typically associated with downregulation of P450s. We hypothesized that induction of CYP2A5 occurs in response to hepatocellular damage resulting in endoplasmic reticulum (ER) stress. Treatment of mice in vivo and mouse hepatocytes in primary culture with the CYP2A5 inducer pyrazole resulted in overexpression of the ER stress biomarker glucose-regulated protein (GRP) 78. Read More

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February 2004

Predictive value of comparative molecular field analysis modelling of naphthalene inhibition of human CYP2A6 and mouse CYP2A5 enzymes.

Toxicol In Vitro 2003 Aug;17(4):449-55

Department of Environmental Sciences, University of Kuopio, Box 1627, 70211, Kuopio, Finland.

The objects of this study were first to compare how well the recently constructed structure-inhibition activity relationship models of mouse CYP2A5 and human CYP2A6 predict the interaction of naphthalene in liver microsomes and secondly to study if these CYP enzymes actually oxidize naphthalene. The CoMFA model of CYP2A5 predicted the IC(50) value of naphthalene to be 42 microM (18-115 microM 95% CL) whereas in the in vitro experiment the result was 74 microM (65-83 microM) with the corresponding values for CYP2A6 being 41 microM (18-112 microM) and 25 microM (21-30 microM), respectively. Naphthalene appeared to be a competitive inhibitor both for mouse and human liver microsomal coumarin 7-hydroxylase, which is the specific probe activity for CYP2A5 and CYP2A6. Read More

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Increased expression of cytochrome P450 2E1 induces heme oxygenase-1 through ERK MAPK pathway.

J Biol Chem 2003 Aug 30;278(32):29693-700. Epub 2003 May 30.

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.

The inducible form of heme oxygenase (HO-1) is increased during oxidative injury, and this may be an important defense mechanism against such injury. Cytochrome P450 2E1 (CYP2E1) generates reactive oxygen species and promotes lipid peroxidation. In this study induction of HO-1 by CYP2E1 and the possible role of mitogen-activated protein kinase (MAPK) in this process were evaluated. Read More

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Proteasome inhibition potentiates CYP2E1-mediated toxicity in HepG2 cells.

Hepatology 2003 Jun;37(6):1395-404

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.

Chronic ethanol consumption causes increased oxidative damage in the liver. Induction of CYP2E1 is one pathway involved in how ethanol produces oxidative stress. Ethanol can cause protein accumulation, decreased proteolysis, and decreased proteasome activity. Read More

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Increased Sp1-dependent transactivation of the LAMgamma 1 promoter in hepatic stellate cells co-cultured with HepG2 cells overexpressing cytochrome P450 2E1.

J Biol Chem 2003 Apr 15;278(17):15360-72. Epub 2003 Jan 15.

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.

Laminin is a basement-membrane protein that increases in liver fibrosis. To study the role of oxidative stress on laminin expression, hepatic stellate cells (HSC) were co-cultured with HepG2 cells that do or do not express (E47 or C34 cells, respectively) CYP2E1, a potent generator of oxygen radicals. Co-incubation of HSC with E47 cells increased laminin beta1 and gamma1 proteins compared with co-incubation with C34 cells; this increase was prevented by antioxidants and CYP2E1 inhibitors. Read More

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Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression.

Toxicology 2003 Mar;184(2-3):211-26

Department of Biomedical Sciences, University of Guelph, Ont., Canada.

Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused by the hepatotoxin pyrazole on hepatic Cyp2a5 expression in mice. Pyrazole treatment resulted in statistically significant increases in levels of Cyp2a5 mRNA, protein and catalytic activity by 540, 273 and 711%, respectively (P<0. Read More

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Cyclosporine A protects against arachidonic acid toxicity in rat hepatocytes: role of CYP2E1 and mitochondria.

Hepatology 2002 Jun;35(6):1420-30

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA.

Diets high in polyunsaturated fatty acids (PUFA) are important for the development of alcoholic liver injury. The goal of this report was to characterize toxicity by arachidonic acid (AA), its enhancement by salicylate, and the role of mitochondrial injury in the pathway leading to toxicity in hepatocytes from pyrazole-treated rats. AA caused toxicity that was increased by sodium salicylate. Read More

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Synergistic toxicity of iron and arachidonic acid in HepG2 cells overexpressing CYP2E1.

Mol Pharmacol 2001 Oct;60(4):742-52

Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.

Priming of the liver for ethanol-induced injury, by nutrients such as polyunsaturated fat and iron, plays a key role in alcoholic liver disease. The objective of this work was to evaluate the effect of the combination of Fe-nitrilotriacetic acid (Fe-NTA) and arachidonic acid (AA) on the viability of HepG2 cells (E47 cells) transfected to express human CYP2E1. Cells were plated, preloaded with arachidonic acid, washed, and exposed to Fe-NTA for variable periods. Read More

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October 2001

Sodium salicylate increases CYP2E1 levels and enhances arachidonic acid toxicity in HepG2 cells and cultured rat hepatocytes.

Authors:
D Wu A I Cederbaum

Mol Pharmacol 2001 Apr;59(4):795-805

Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine of New York University, New York, New York 10029, USA.

Sodium salicylate and acetylsalicylic acid are drugs used as anti-inflammatory agents. Salicylate prevents nuclear factor-kappa B activation and can cause apoptosis. However, salicylate, a substrate of CYP2E1, is also an antioxidant and can scavenge reactive oxygen species. Read More

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Induction of mouse CYP2J by pyrazole in the eye, kidney, liver, lung, olfactory mucosa, and small intestine, but not in the heart.

Drug Metab Dispos 2000 Nov;28(11):1311-6

Wadsworth Center, New York State Department of Health and School of Public Health, State University of New York at Albany, Albany, New York 12201-0509, USA.

We have recently shown that rat CYP2J4 is inducible by pyrazole in liver, small intestine, and olfactory mucosa. The aim of the present study was to determine whether mouse CYP2Js are also inducible by pyrazole, which was known to induce CYP2A5 in mouse liver and kidney, but not in lung or olfactory mucosa. CYP2J proteins were detected in mouse liver, lung, kidney, heart, eye, olfactory mucosa, and small intestine by immunoblot analysis with an anti-CYP2J4 antibody. Read More

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November 2000

Ethanol and arachidonic acid produce toxicity in hepatocytes from pyrazole-treated rats with high levels of CYP2E1.

Authors:
D Wu A I Cederbaum

Mol Cell Biochem 2000 Jan;204(1-2):157-67

Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Ethanol and polyunsaturated fatty acids such as arachidonic acid were shown to be toxic and cause apoptosis in HepG2 cells which express CYP2E1 but not in control HepG2 cell lines. The goal of the current study was to extend the observations made with the HepG2 cells to non-transformed, intact hepatocytes. Rats were treated with pyrazole to increase CYP2E1 levels, hepatocytes were isolated and placed into culture and treated for varying time points with ethanol or arachidonic acid. Read More

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January 2000

Pronounced differences in inhibition potency of lactone and non-lactone compounds for mouse and human coumarin 7-hydroxylases (CYP2A5 and CYP2A6).

Xenobiotica 2000 Jan;30(1):81-92

Department of Pharmacology, University of Kuopio, Finland.

1. The structural requirements for a compound to be a potent inhibitor for mouse CYP2A5 and human CYP2A6 enzymes catalysing coumarin 7-hydroxylase activity have been studied. 2. Read More

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January 2000

ESR and HPLC-EC analysis of ethanol oxidation to 1-hydroxyethyl radical: rapid reduction and quantification of POBN and PBN nitroxides.

Free Radic Biol Med 1998 Sep;25(4-5):536-45

Department of Biochemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.

Extensive ESR spin-trapping studies have shown that ethanol is oxidized to 1-hydroxyethyl radical (HER) by rat and deer mice liver microsomal systems. The ESR detection of POBN/HER nitroxide in bile, and formation of antibodies, which recognize HER adducts in alcoholics, suggest that HER is produced in vivo. In liver, where ethanol is primarily metabolized, only traces of PBN/HER nitroxide are documented. Read More

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September 1998

Differential xenobiotic induction of CYP2A5 in mouse liver, kidney, lung, and olfactory mucosa.

Drug Metab Dispos 1998 Aug;26(8):822-4

Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509, USA.

The effects of pyrazole, which is known to induce hepatic cytochrome P4502A5 (CYP2A5) through posttranscriptional mechanisms, on the level of CYP2A5 in liver and extrahepatic tissues were examined in this study. Intraperitoneal administration of pyrazole at 200 mg/kg for 3 days induced CYP2A4/5 mRNAs and proteins and microsomal coumarin 7-hydroxylation activity in liver and kidney of C57BL/6 mice. A marginal increase (30%) in CYP2A4/5 mRNAs was also observed in the olfactory mucosa but not in the lung, and no increase in CYP2A4/5 proteins or microsomal coumarin 7-hydroxylation activity was observed in either the olfactory mucosa or lung. Read More

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Both cytochromes P450 2E1 and 3A are involved in the O-hydroxylation of p-nitrophenol, a catalytic activity known to be specific for P450 2E1.

Chem Res Toxicol 1997 Oct;10(10):1205-12

Equipe de recherche EA-948, Faculté de Médecine, UBO, Brest, France.

4-Nitrophenol 2-hydroxylation activity was previously shown to be mainly catalyzed by P450 2E1 in animal species and humans. As this chemical compound is widely used as an in vitro probe for P450 2E1, this study was carried out to test its catalytic specificity. First, experiments were carried out on liver microsomes and hepatocyte cultures of rat treated with different inducers. Read More

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October 1997

Thiol oxidation and cytochrome P450-dependent metabolism of CCl4 triggers Ca2+ release from liver microsomes.

Biochemistry 1996 Dec;35(49):15839-45

Department of Biochemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.

Elevation of cytosolic calcium levels has been shown to occur after exposure to hepatotoxins such as CCl4. This has been associated with inhibition of the Ca2+, Mg(2+)-ATPase which pumps calcium into the endoplasmic reticulum. Elevated cytosolic Ca2+ may also result from activation of calcium releasing channels. Read More

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December 1996

The relationship between N-nitrosodimethylamine metabolism and DNA methylation in isolated rat hepatocytes.

Carcinogenesis 1996 May;17(5):1127-34

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-6805, USA.

The metabolism of N-nitrosodimethylamine (NDMA) and its methylation of DNA were simultaneously determined in hepatocytes isolated from untreated and saline- and pyrazole-treated male Sprague-Dawley rats. Metabolism of NDMA was directly measured by monitoring its disappearance via gas chromatography coupled with a sensitive and specific detector for N-nitrosamines. DNA methylation was determined in the same cells employed in the metabolism studies using a monoclonal antibody-based competitive ELISA procedure specific for O6-methyldeoxyguanosine (6-Me-dG). Read More

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Increased production of hydroxyl radical by pericentral microsomes compared to periportal microsomes after pyrazole induction of cytochrome P4502E1.

Biochem Biophys Res Commun 1995 Oct;215(2):698-705

Department of Biochemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.

Cytochrome P4502E1 is localized in the pericentral (PC) zone of the liver acinus to a greater extent than in the periportal (PP) zone. After pyrazole treatment, PC microsomes were more active in oxidizing typical substrates of CYP2E1 than PP microsomes and had an increased content of CYP2E1. The ability of PC and PP microsomes from pyrazole-treated rats to interact with iron and generate reactive oxygen species such as the hydroxyl radical (. Read More

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October 1995

Role of alcohol dehydrogenase in rat ethanol elimination kinetics.

Alcohol Alcohol Suppl 1994 ;29(1):15-20

Department of Legal Medicine, Kyoto University Faculty of Medicine, Kyoto 606-01, Japan.

Ethanol elimination in rats following bolus intravenous administration (0.5, 1, 2, 3 g/kg body weight) was investigated with and without pyrazole pretreatment. Elimination time was significantly longer in the pyrazole-pretreated group than in the control. Read More

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