The role of cytochrome P-4502E1 in the development of hepatic fat, fibrosis and DNA lesions in patients with of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD)

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. In addition, CYP2E1 seems also responsible for the generation of carcinogenic DNA lesions in both ALD and NAFLD. The purpose of this study was to further investigate the role of CYP2E1 in hepatic steatosis, fibrosis and carcinogenesis in human livers.

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 NAFLD. Carcinogenic DNA lesions such as exocyclic etheno-DNA adducts (edA) and 8-OH desoxyguanidine (8-OHdG) were also measured.

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). The induction of CYP2E1 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.

DNA-adducts - cytochrome - fatty liver