Cytochrome P450 CYP2E1, But Not Nicotinamide Adenine Dinucleotide Phosphate Oxidase, Is Required for Ethanol-Induced Oxidative DNA Damage in Rodent Liver

The occurrence ofmalignant tumors of the upper gastrointestinal tract and liver is, based largely on epidemiological evidence, causally related to the consumption of ethanol. It is widely recog-nized 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 dinucle-otide phosphate oxidase, cytochrome P450 CYP2E1, or both are responsible for the production ofDNAdamage.The rodentTsukamoto-Frenchmodel of intragastric ethanol infusionwasused. Wistar rats, Cyp2e1-, p47phox-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-typemice, 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 endpointswas observed in ethanol-treatedCyp2e1-nullmice, whereas themagnitude of response in p47phox-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 t