Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects

Guengerich, F. Peter; Kim, Dong-Hyun; Iwasaki, M.

doi:10.1021/tx00020a008

Cited by 1,121 publications

(586 citation statements)

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“…Cytochrome P450s (CYPs) are phase I xenobiotic metabolizing enzymes that modulate the biotransformation of endogenous and environmental toxicants including AOM 31 and CCl 4 . 32 Because CYPs are required to bioactivate both AOM and CCl 4 , the expression pattern of mRNAs encoding CYPs was examined. No differences were found between genotypes in the constitutive expression of CYP1A2, CYP2B10, CYP2E1, and CYP3A11 mRNA expression, albeit the expression of the latter mRNA was quite variable between individual mice.…”

Section: Ppar␤/␦ Protects Against Aom-induced Livermentioning

confidence: 99%

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

et al. 2008

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Potential functional roles for the peroxisome proliferator-activated receptor-␤/␦ (PPAR␤/␦) in skeletal muscle fatty acid catabolism and epithelial carcinogenesis have recently been described. Whereas PPAR␤/␦ is expressed in liver, its function in this tissue is less clear. To determine the role of PPAR␤/␦ in chemically induced liver toxicity, wild-type and PPAR␤/␦-null mice were treated with azoxymethane (AOM) and markers of liver toxicity examined. Bile duct hyperplasia, regenerative hyperplasia, and increased serum alanine aminotransferase (ALT) were found in AOM-treated PPAR␤/␦-null mice, and these effects were not observed in similarly treated wild-type mice. Exacerbated carbon tetrachloride (CCl 4 ) hepatoxicity was also observed in PPAR␤/␦-null as compared with wild-type mice. No differences in messenger RNAs (mRNAs) encoding cytochrome2E1 required for the metabolic activation of AOM and CCl 4 were observed between wild-type or PPAR␤/␦-null mice in response to CCl 4 . Significant differences in the expression of genes reflecting enhanced nuclear factor kappa B (NF-B) activity were noted in PPAR␤/␦-null mice. Conclusion:Results from these studies show that PPAR␤/␦ is protective against liver toxicity induced by AOM and CCl 4 , suggesting that this receptor is hepatoprotective against environmental chemicals that are metabolized in this tissue. (HEPATOLOGY 2008;47:225-235.)

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Section: Ppar␤/␦ Protects Against Aom-induced Livermentioning

confidence: 99%

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

et al. 2008

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“…The human enzyme CYP2E1 is a protein of about 62 kDa consisting of 493 amino acid residues, involved in the metabolism of more than 80 hydrophobic toxic compounds and contributing to the activation of many pro-carcinogens and certain drugs towards highly reactive forms (Guengerich et al, 1991). In particular the enzyme CYP2E1 activates the N-nitrosamines contained in tobacco cigarettes and in food (Wang et al, 2002), as well as in many carcinogens endogenous and/ or of industrial origin (Agundez, 2004).…”

Section: Introductionmentioning

confidence: 99%

Role and importance of polymorphisms with respect to DNA methylation for the expression of CYP2E1 enzyme

Naselli

Catanzaro

Bellavia

et al. 2014

Gene

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. Different individuals possess slightly different genetic information and show genetically-determined differences in several enzyme activities due to genetic variability. Following an integrated approach, we studied the polymorphisms and methylation of sites contained in the 5′ flanking region of the metabolizing enzyme CYP2E1 in correlation to its expression in both tumor and non-neoplastic liver cell lines, since to date little is known about the influence of these (epi)genetic elements in basal conditions and under induction by the specific inductor and a demethylating agent. In treated cells, reduced DNA methylation, assessed both at genomic and gene level, was not consistently associated with the increase of enzyme expression. Interestingly, the Rsa/Pst haplotype differentially influenced CYP2E1 enzyme expression. In addition, regarding the Variable Number of Tandem Repeats polymorphism, cells with A4/A4 genotype showed a greater expression inhibition (ranging from 20% to 30%) compared with others carrying the A2/A2 one, while those cells bringing A2/A3 genotype showed an increase of expression (of 25%, about). Finally, we demonstrated for the first time that the A2 and A3 CYP2E1 alleles play a more important role in the expression of the enzyme, compared with other (epi)genetic factors, since they are binding sites for trans-acting proteins.

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“…DDC has been shown to be an effective inhibitor of P4502E1-catalysed oxidation of substrates such as nitrosamines (Guengerich et al, 1991;Brady et al, 1991). Over the concentration range of 0.1-1.0 mM, DDC had only a small effect (10-30% inhibition) on the NADPH-dependent DNA strand cleavage catalysed by control microsomes, but inhibited the reaction with microsomes from ethanol-treated rats (Table 5).…”

Section: Introductionmentioning

confidence: 99%

DNA strand cleavage as a sensitive assay for the production of hydroxyl radicals by microsomes: role of cytochrome P4502E1 in the increased activity after ethanol treatment

Kukielka

Cederbaum

1994

Biochemical Journal

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There is increasing interest in the role of reactive oxygen radicals in the hepatotoxicity associated with ethanol consumption. Reactive oxygen intermediates interact with DNA and can cause single-strand breaks of supercoiled DNA. Experiments were carried out to evaluate the utility of this system as a sensitive assay for the detection of potent oxidants generated by rat liver microsomes isolated from pair-fed control rats and rats treated chronically-uwith ethanol. DNA strand cleavage was assayed by monitoring the migration of the supercoiled and open circular forms in agarose. Microsomes catalysed DNA strand breakage with either NADPH or NADH as cofactors; iron was required to catalyse the reaction and various ferric complexes were effective in promoting the reaction. DNA strand cleavage was prevented by catalase, superoxide dismutase, GSH and hydroxyl-radicalscavenging agents, suggesting that a hydroxyl-radical-like species was the oxidant responsible for the breakage. This assay system proved to be much more sensitive in detecting hydroxyl radicals than are other methods, such as e.s.r. spectroscopy or oxidation of chemical scavenging agents with respect to the amount of microsomal protein and the nature and concentration of the iron catalyst required. Microsomes from ethanol-treated rats were more reactive than control microsomes in catalysing the DNA strand cleavage with either NADPH or NADH; increased catalytic activity was observed with various ferric complexes and was sensitive to the above antioxidants. Compared with preimmune IgG, anti-(cytochrome P4502E1) IgG had no effect on DNA strand cleavage by the control microsomes, but completely prevented the NADPH-and the NADH-dependent increased activity found with microsomes from the ethanol-treated rats. Inhibitors of cytochrome P4502E1, such as diethyl dithiocarbamate and tryptamine, also lowered the extent of increase of DNA strand cleavage produced by microsomes from the ethanoltreated rats. These results indicate that DNA strand cleavage is a very sensitive assay for detecting the production of hydroxyl radicals by microsomes and to demonstrate increased activity by microsomes after chronic ethanol treatment. This increased activity with NADPH and NADH is due, at least in part, to induction of cytochrome P4502E1.

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Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects

Cited by 1,121 publications

References 55 publications

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

Role and importance of polymorphisms with respect to DNA methylation for the expression of CYP2E1 enzyme

DNA strand cleavage as a sensitive assay for the production of hydroxyl radicals by microsomes: role of cytochrome P4502E1 in the increased activity after ethanol treatment

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