title: Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanol-induced oxidative DNA damage in rodent liver.
abstract: The occurrence of malignant tumors of the upper gastrointestinal tract and liver is, based largely on epidemiological evidence, causally related to the consumption of ethanol. It is widely recognized that oxidants play a key role in alcohol-induced liver injury; however, it is unclear how oxidants may be involved in DNA damage. We asked whether nicotinamide adenine dinucleotide phosphate oxidase, cytochrome P450 CYP2E1, or both are responsible for the production of DNA damage. The rodent Tsukamoto-French model of intragastric ethanol infusion was used. Wistar rats, Cyp2e1-, p47(phox)-null, and hCyp2e1 transgenic mice were used. The abundance of oxidative DNA adducts, mutagenic apurinic/apyrimidinic sites, and expression of base excision DNA repair genes was determined. In rats and wild-type mice, ethanol treatment for 4 weeks led to an increase in oxidative DNA damage and induction of expression of the base excision DNA repair genes that are known to remove oxidative DNA lesions. No increase in either of the endpoints was observed in ethanol-treated Cyp2e1-null mice, whereas the magnitude of response in p47(phox)-null mice and transgenic hCyp2e1 was identical to that in wild types. The increase in expression of DNA repair genes was completely abolished by treatment with the P450 inhibitor 1-aminobenzotriazole. In conclusion, the data support the hypothesis that oxidative stress to DNA is induced in liver by ethanol. Furthermore, although it was shown that nicotinamide adenine dinucleotide phosphate oxidase-derived oxidants are critical for the development of ethanol-induced liver injury, CYP2E1 is required for the induction of oxidative stress to DNA, and thus may play a key role in ethanol-associated hepatocarcinogenesis.
authors.affiliation: Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7431, USA.
authors.forename: Blair U
authors.initials: BU
authors.lastname: Bradford
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kono
authors.forename: Fuyumi
authors.initials: F
authors.lastname: Isayama
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wheeler
authors.forename: Taro E
authors.initials: TE
authors.lastname: Akiyama
authors.forename: Lisa
authors.initials: L
authors.lastname: Bleye
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Koop
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D015870:Gene Expression; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D019255:NADPH Oxidases