The role of cytochrome P-4502E1 in the progression of alcoholic and non-alcoholic fatty liver

Aims: Although the pathogenesis of alcoholic liver disease (ALD) is still unclear, there is increasing evidence of the involvement of cytochrome P-4502E1 (CYP2E1) in its progression, since the inhibition of CYP2E1 in animal experiments prevents ALD. The purpose of this study was to further investigate the role of CYP2E1 in hepatic steatosis, fibrosis and carcinogenesis in human livers and various animal models. Methods: The degree of fat, fibrosis and CYP2E1 induction was determined in liver biopsies from 60 patients with various stages of ALD and 40 patients with non alcoholic fatty liver disease (NAFLD). In addition, carcinogenic DNA lesions such as exocyclic DNA adducts and 8-OH desoxyguanidine (8-OHdG) were measured in the livers of animals with hepatic steatosis induced by the administration of a high fat and a methionine/choline deficient diet with and without chronic ethanol co-administration. Results: CYP2E1 induction (p<0.01), steatosis (p<0.01) and fibrosis (p<0.01) were more pronounced in the livers of patients with ALD as compared to NAFLD. A significant correlation was found between CYP2E1 and hepatic steatosis as well as fibrosis (p<0.01). In animals, diet induced fatty livers reveal a significant induction of CYP2E1 (p<0.01) which was further enhanced by concomitant ethanol administration. This induction was associated with the generation of highly carcinogenic etheno DNA adducts (p<0.01), but not with 8-OHdG. Discussion and conclusion: The data emphasize the causal role of CYP2E1 in the progression of ALD. They further demonstrate that CYP2E1 is induced in fatty livers regardless of its cause resulting in the generation of carcinogenic DNA lesions. Thus, fatty liver may be a condition predisposing to cancer and additional alcohol intake may increase cancer risk.