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Alan Archibald - One of the best experts on this subject based on the ideXlab platform.
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cloning and mapping of the porcine Cytochrome P450 2E1 gene and its association with skatole levels in the domestic pig
Animal Genetics, 2005Co-Authors: T M Skinner, E. Doran, J.d. Mcgivan, Chris Haley, Alan ArchibaldAbstract:The porcine Cytochrome-P450 2E1 (CYP2E1) gene was isolated by screening a pig BAC library and partially sequenced. This sequence information was used to identify six single nucleotide polymorphisms (SNPs) within the CYP2E1 gene and its promoter. In addition, a microsatellite marker tightly linked to the CYP2E1 gene was subcloned from the BAC. One of these markers was used to map the CYP2E1 gene distal of SWC27 on SSC14, well outside reported quantitative trait loci on SSC14 for skatole, indole and taste test measures of boar taint. However, in a population of commercial pigs scored for backfat skatole levels, there was evidence of association between a SNP in the CYP2E1 promoter and skatole deposition, although there was no significant association between this SNP and skatole levels in the experimental cross.
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Cloning and mapping of the porcine Cytochrome‐P450 2E1 gene and its association with skatole levels in the domestic pig
Animal Genetics, 2005Co-Authors: T M Skinner, E. Doran, J.d. Mcgivan, Chris Haley, Alan ArchibaldAbstract:The porcine Cytochrome-P450 2E1 (CYP2E1) gene was isolated by screening a pig BAC library and partially sequenced. This sequence information was used to identify six single nucleotide polymorphisms (SNPs) within the CYP2E1 gene and its promoter. In addition, a microsatellite marker tightly linked to the CYP2E1 gene was subcloned from the BAC. One of these markers was used to map the CYP2E1 gene distal of SWC27 on SSC14, well outside reported quantitative trait loci on SSC14 for skatole, indole and taste test measures of boar taint. However, in a population of commercial pigs scored for backfat skatole levels, there was evidence of association between a SNP in the CYP2E1 promoter and skatole deposition, although there was no significant association between this SNP and skatole levels in the experimental cross.
Dennis R. Koop - One of the best experts on this subject based on the ideXlab platform.
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The effects of nitrogen-heme-iron coordination on substrate affinities for Cytochrome P450 2E1
Chemico-biological interactions, 2011Co-Authors: Jeffrey P. Jones, Carolyn A. Joswig-jones, Michelle Hebner, Yuzhuo Chu, Dennis R. KoopAbstract:Abstract A descriptor based computational model was developed for Cytochrome P450 2E1 (CYP2E1) based on inhibition constants determined for inhibition of chlorzoxazone, or 4-nitrophenol, metabolism. An empirical descriptor for type II binding was developed and tested for a series of CYP2E1 inhibitors. Inhibition constants where measured for 51 different compounds. A fast 2-dimensional predictive model was developed based on 40 compounds, and tested on 8 compounds of diverse structure. The trained model (n = 40) had an r2 value of 0.76 and an RMSE of 0.48. The correlation between the predicted and actual pKi values of the test set of compounds not included in the model gives an r2 value of 0.78. The features that described binding include heme coordination (type II binding), molecular volume, octanol/water partition coefficient, solvent accessible surface area, and the sum of the atomic polarizabilities. The heme coordination parameter assigns an integer between 0 and 6 depending on structure, and is a new descriptor, based on simple quantum chemical calculations with correction for steric effects. The type II binding parameter was found to be important in obtaining a good correlation between predicted and experimental inhibition constants increasing the r2 value from 0.38 to 0.77.
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Alcohol metabolism's damaging effects on the cell: a focus on reactive oxygen generation by the enzyme Cytochrome P450 2E1.
Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism, 2006Co-Authors: Dennis R. KoopAbstract:Alcohol metabolism's various processes create harmful compounds that contribute to cell and tissue damage. In particular, the enzyme Cytochrome P450 2E1 (CYP2E1) plays a role in creating a harmful condition known as oxidative stress. This condition is related to oxygen's ability to accept electrons and the subsequent highly reactive and harmful byproducts created by these chemical reactions. CYP2E1's use of oxygen in alcohol metabolism generates reactive oxygen species, ultimately leading to oxidative stress and tissue damage.
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Cytochrome P450 2E1 expression induces hepatocyte resistance to cell death from oxidative stress.
Antioxidants & redox signaling, 2002Co-Authors: Brett E. Jones, Dennis R. Koop, Hailing Liu, Mark J. CzajaAbstract:Increased expression of Cytochrome P450 2E1 (CYP2E1) occurs in alcoholic liver disease, and leads to the hepatocellular generation of toxic reactive oxygen intermediates (ROI). Oxidative stress created by CYP2E1 overexpression may promote liver cell injury by sensitizing hepatocytes to oxidant-induced damage from Kupffer cell-produced ROI or cytokines. To determine the effect of CYP2E1 expression on the hepatocellular response to injury, stably transfected hepatocytes expressing increased (S-CYP15) and decreased (AN-CYP10) levels of CYP2E1 were generated from the rat hepatocyte line RALA255-10G. S-CYP15 cells had increased levels of CYP2E1 as demonstrated by Northern blot analysis, immunoblotting, catalytic activity, and increased cell sensitivity to death from acetaminophen. Death in S-CYP15 cells was significantly decreased relative to that in AN-CYP10 cells following treatment with hydrogen peroxide and the superoxide generator menadione. S-CYP15 cells underwent apoptosis in response to these ROI, wher...
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Oxidation of 1,3-butadiene to (R)- and (S)-butadiene monoxide by purified recombinant Cytochrome P450 2E1 from rabbit, rat and human
Toxicology letters, 1998Co-Authors: Joe L. Nieusma, Dennis R. Koop, Weiqiao Chen, Raimund M. Peter, Sidney D. Nelson, David J. Claffey, James A. Ruth, David RossAbstract:1,3-Butadiene (BD) is a gas used widely in the rubber and plastics industry as an intermediate in production processes and has been detected in automobile exhaust and cigarette smoke. BD requires metabolic activation to exert toxicity and has been shown to be carcinogenic in rodents. IARC has classified BD as a group 2A (probably carcinogenic to humans) carcinogen. The initial oxidation of BD to butadiene monoxide (BMO) occurs primarily via Cytochrome P450 2E1 and two stereoisomers of BMO (R and S) can be formed. (R) and (S)-BMO are metabolized differently and demonstrate markedly different toxicities in isolated rat hepatocytes. This work examined the generation of (R) and (S)-BMO from BD by Cytochrome P450 2E1 from rabbit, rat and human. BMO level was measured by GC-MS analysis and enantiomeric composition was determined by GC-FID. The greatest rate of formation of BMO from BD was obtained with rabbit Cytochrome P4502E1 followed by human and then by rat. Enantiomeric distribution of R and S-BMO produced by the three species demonstrated no significant differences.
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Formation of 19(S)-, 19(R)-, and 18(R)-hydroxyeicosatetraenoic acids by alcohol-inducible Cytochrome P450 2E1
The Journal of biological chemistry, 1993Co-Authors: Ronald M. Laethem, Michael Balazy, John R. Falck, Carmen L. Laethem, Dennis R. KoopAbstract:Abstract When reconstituted with Cytochrome b5 and NADPH Cytochrome P450 oxidoreductase, Cytochrome P450 2E1 metabolized lauric, stearic, oleic, linoleic, linolenic, and arachidonic acid to multiple metabolites. Two major metabolites, accounting for 78% of the total metabolism, were produced with arachidonic acid. The Vmax for total metabolite formation from arachidonic acid was 5 nmol/min/nmol P450 with an apparent Km of 62 microM. Gas chromatography-mass spectrometry analysis identified the two major metabolites as monohydroxylated eicosatetraenoic acids (HETEs). The major HETE was 19-hydroxyeicosatetraenoic acid (19-HETE) and comprised 46% of the total metabolite produced. The second metabolite was the omega-2 hydroxylated metabolite (18-HETE) and comprised 32% of the total product formed. Chiral analysis demonstrated that 19-HETE was 70% 19(S)-HETE and 30% 19(R)-HETE. In contrast, 18-HETE was essentially 100% R isomer. Approximately 18% of the total metabolite produced from arachidonic acid coeluted with epoxyeicosatrienoic acid (EET) standards. The EET metabolites were 56.4% 14,15-EET and 43.6% as a mixture of 11,12-EET and 8,9-EET. 5,6-EET was not detected. Anti-P450 2E1 IgG inhibited arachidonic acid metabolism by renal and hepatic microsomes prepared from acetone-treated rabbits. With renal cortex microsomes, the formation of 18-HETE and 19-HETE was inhibited 67 and 25%, respectively, by the antibody. Liver microsomal formation of 18-HETE was inhibited by 87% and 19-HETE by 70%. Thus, under conditions where Cytochrome P450 2E1 is induced, the enzyme could contribute significantly to the formation of the omega-1 and omega-2 hydroxylated metabolites of arachidonic acid.
T M Skinner - One of the best experts on this subject based on the ideXlab platform.
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cloning and mapping of the porcine Cytochrome P450 2E1 gene and its association with skatole levels in the domestic pig
Animal Genetics, 2005Co-Authors: T M Skinner, E. Doran, J.d. Mcgivan, Chris Haley, Alan ArchibaldAbstract:The porcine Cytochrome-P450 2E1 (CYP2E1) gene was isolated by screening a pig BAC library and partially sequenced. This sequence information was used to identify six single nucleotide polymorphisms (SNPs) within the CYP2E1 gene and its promoter. In addition, a microsatellite marker tightly linked to the CYP2E1 gene was subcloned from the BAC. One of these markers was used to map the CYP2E1 gene distal of SWC27 on SSC14, well outside reported quantitative trait loci on SSC14 for skatole, indole and taste test measures of boar taint. However, in a population of commercial pigs scored for backfat skatole levels, there was evidence of association between a SNP in the CYP2E1 promoter and skatole deposition, although there was no significant association between this SNP and skatole levels in the experimental cross.
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Cloning and mapping of the porcine Cytochrome‐P450 2E1 gene and its association with skatole levels in the domestic pig
Animal Genetics, 2005Co-Authors: T M Skinner, E. Doran, J.d. Mcgivan, Chris Haley, Alan ArchibaldAbstract:The porcine Cytochrome-P450 2E1 (CYP2E1) gene was isolated by screening a pig BAC library and partially sequenced. This sequence information was used to identify six single nucleotide polymorphisms (SNPs) within the CYP2E1 gene and its promoter. In addition, a microsatellite marker tightly linked to the CYP2E1 gene was subcloned from the BAC. One of these markers was used to map the CYP2E1 gene distal of SWC27 on SSC14, well outside reported quantitative trait loci on SSC14 for skatole, indole and taste test measures of boar taint. However, in a population of commercial pigs scored for backfat skatole levels, there was evidence of association between a SNP in the CYP2E1 promoter and skatole deposition, although there was no significant association between this SNP and skatole levels in the experimental cross.
Arthur I. Cederbaum - One of the best experts on this subject based on the ideXlab platform.
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Hepatoprotective effects of S-adenosyl-L-methionine against alcohol- and Cytochrome P450 2E1-induced liver injury.
World journal of gastroenterology, 2010Co-Authors: Arthur I. CederbaumAbstract:S-adenosyl-L-methionine (SAM) acts as a methyl donor for methylation reactions and participates in the synthesis of glutathione. SAM is also a key metabolite that regulates hepatocyte growth, differentiation and death. Hepatic SAM levels are decreased in animal models of alcohol liver injury and in patients with alcohol liver disease or viral cirrhosis. This review describes the protection by SAM against alcohol and Cytochrome P450 2E1-dependent cytotoxicity both in vitro and in vivo and evaluates mechanisms for this protection.
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Cytochrome P450 2E1 contributes to ethanol induced fatty liver in mice
Hepatology, 2008Co-Authors: Jian Zhuge, Xiaodong Wang, Jingxiang Bai, Arthur I. CederbaumAbstract:Cytochrome P450 2E1 (CYP2E1) is suggested to play a role in alcoholic liver disease, which includes alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. In this study, we investigated whether CYP2E1 plays a role in experimental alcoholic fatty liver in an oral ethanol-feeding model. After 4 weeks of ethanol feeding, macrovesicular fat accumulation and accumulation of triglyceride in liver were observed in wild-type mice but not in CYP2E1-knockout mice. In contrast, free fatty acids (FFAs) were increased in CYP2E1-knockout mice but not in wild-type mice. CYP2E1 was induced by ethanol in wild-type mice, and oxidative stress induced by ethanol was higher in wild-type mice than in CYP2E1-knockout mice. Peroxisome proliferator-activated receptor α (PPARα), a regulator of fatty acid oxidation, was up-regulated in CYP2E1-knockout mice fed ethanol but not in wild-type mice. A PPARα target gene, acyl CoA oxidase, was decreased by ethanol in wild-type but not in CYP2E1-knockout mice. Chlormethiazole, an inhibitor of CYP2E1, lowered macrovesicular fat accumulation, inhibited oxidative stress, and up-regulated PPARα protein level in wild-type mice fed ethanol. The introduction of CYP2E1 to CYP2E1-knockout mice via an adenovirus restored macrovesicular fat accumulation. These results indicate that CYP2E1 contributes to experimental alcoholic fatty liver in this model and suggest that CYP2E1-derived oxidative stress may inhibit oxidation of fatty acids by preventing up-regulation of PPARα by ethanol, resulting in fatty liver. (HEPATOLOGY 2008.)
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Cytochrome P450 2E1-dependent oxidant stress and upregulation of anti-oxidant defense in liver cells.
Journal of Gastroenterology and Hepatology, 2006Co-Authors: Arthur I. CederbaumAbstract: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. Cytochrome P450 2E1 is induced under a variety of physiological and pathophysiological conditions. The laboratory at Mount Sinai School of Medicine established HepG2 cell lines that constitutively express human CYP2E1. Ethanol, polyunsaturated fatty acids and iron were toxic to the HepG2 cells that express CYP2E1 (E47 cells) but not control HepG2 cells. The E47 cells had higher glutathione levels than control HepG2 cells due to activation of the genes encoding the heavy and light subunits of gamma glutamyl cysteine synthetase (GCLC and GCLM). There was also a twofold increase in catalase, cytosolic and microsomal glutathione transferase, and heme oxygenase-1 (HO-1) in the E47 cells due to activation of their respective genes. These activations were prevented by anti-oxidants, suggesting that the upregulation of these anti-oxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. Increases in nuclear factor erythroid 2-related factor 2 (Nrf2) protein and mRNA were observed in livers of hepatocytes of chronic alcohol-fed and of pyrazole-treated rats or mice, conditions known to elevate CYP2E1. E47 cells showed increased Nrf2 mRNA and protein expression. Upregulation of GCLC and HO-1 in E47 cells is dependent on Nrf2. These results suggest that Nrf2 is activated and its levels are increased when CYP2E1 is elevated. It is suggested that Nrf2 plays a key role in the adaptive response against increased oxidative stress caused by CYP2E1.
E. Doran - One of the best experts on this subject based on the ideXlab platform.
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cloning and mapping of the porcine Cytochrome P450 2E1 gene and its association with skatole levels in the domestic pig
Animal Genetics, 2005Co-Authors: T M Skinner, E. Doran, J.d. Mcgivan, Chris Haley, Alan ArchibaldAbstract:The porcine Cytochrome-P450 2E1 (CYP2E1) gene was isolated by screening a pig BAC library and partially sequenced. This sequence information was used to identify six single nucleotide polymorphisms (SNPs) within the CYP2E1 gene and its promoter. In addition, a microsatellite marker tightly linked to the CYP2E1 gene was subcloned from the BAC. One of these markers was used to map the CYP2E1 gene distal of SWC27 on SSC14, well outside reported quantitative trait loci on SSC14 for skatole, indole and taste test measures of boar taint. However, in a population of commercial pigs scored for backfat skatole levels, there was evidence of association between a SNP in the CYP2E1 promoter and skatole deposition, although there was no significant association between this SNP and skatole levels in the experimental cross.
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Cloning and mapping of the porcine Cytochrome‐P450 2E1 gene and its association with skatole levels in the domestic pig
Animal Genetics, 2005Co-Authors: T M Skinner, E. Doran, J.d. Mcgivan, Chris Haley, Alan ArchibaldAbstract:The porcine Cytochrome-P450 2E1 (CYP2E1) gene was isolated by screening a pig BAC library and partially sequenced. This sequence information was used to identify six single nucleotide polymorphisms (SNPs) within the CYP2E1 gene and its promoter. In addition, a microsatellite marker tightly linked to the CYP2E1 gene was subcloned from the BAC. One of these markers was used to map the CYP2E1 gene distal of SWC27 on SSC14, well outside reported quantitative trait loci on SSC14 for skatole, indole and taste test measures of boar taint. However, in a population of commercial pigs scored for backfat skatole levels, there was evidence of association between a SNP in the CYP2E1 promoter and skatole deposition, although there was no significant association between this SNP and skatole levels in the experimental cross.
