The role of cytochrome P450 2E1 in ethanol-mediated carcinogenesis.

We and others have shown that chronic alcohol consumption results in the induction of CYP2E1 in the liver. We have also detected for the first time such an induction in the mucosa of the small intestine and the colon. The overall induction of CYP2E1 shows interindividual variations and occurs already following a daily ingestion of 40 g of ethanol after 1 week. CYP2E1 induction is associated with an increased metabolism of ethanol resulting in the generation of reactive oxygen species (ROS) with direct and indirect carcinogenic action. ROS generated by CYP2E1 may lead to lipid peroxidation and lipid peroxidation products such as 4-hydroxynonenal bind to DNA forming highly carcinogenic exocyclic etheno DNA-adducts. The generation of these adducts has been shown in cell cultures in animal experiments as well as in human liver biopsies. CYP2E1 also metabolizes various procarcinogens present in diets and in tobacco smoke to their carcinogenic metabolites. Among these, nitrosamines seem to be the most important carcinogens. CYP2E1 also degrades retinoic acid and retinol to polar metabolites. Metabolism of retinoic acid not only results in the loss of retinoic acid promoting carcinogenesis through an increase in cell proliferation and dedifferentiation but also in generation of polar metabolites with apoptotic properties. We have shown that chlormethiazole is a specific CYP2E1 inhibitor in humans. Chlormethiazole inhibits CYP2E1 activity and thus blocks the formation of DNA adducts in cell cultures, restores retinoic acids in alcohol fed animals and inhibits chemical induced ethanol mediated hepatocarcinogenesis. Thus, there is increasing evidence that CYP2E1 induced by chronic alcohol consumption plays an important role in alcohol mediated carcinogenesis.