Cytochrome P450 2E1: Its Role in Disease and Drug Metabolism

Ann K. Daly, Daly, Ann K.

Non-alcoholic fatty liver disease (NAFLD) and its progression to steatohepatitis (NASH) and cirrhosis is a growing problem in most developed countries. Increased hepatic expression of CYP2E1, which carries out omega hydroxylation of fatty acids, was first shown in a mouse model of NASH and this was later also reported for human NASH, though not all studies agree with this finding and further larger studies are still needed. In view of its role in fatty acid metabolism which leads to increased levels of toxic lipid peroxides and its possible increased expression in NASH, CYP2E1 is an attractive candidate for a role as a genetic risk factor for both NAFLD generally including progression to NASH. Two studies have focused on the variant allele CYP2E1*5, which may be associated with increased CYP2E1 expression. Both reported increased frequencies of this allele in NASH patients, though statistical significance was not achieved because of small sample sizes. Some more indirect data also suggests a relationship between high CYP2E1 activity and progression to NASH. However, three recent genome-wide association studies on NAFLD have failed to find any evidence that single nucleotide polymorphisms in or adjacent to the CYP2E1 gene contribute to susceptibility. Further studies are needed to investigate a possible role in disease progression in addition to susceptibility and the possibility that statistical power in the existing studies was insufficient to detect a relatively small contribution to disease susceptibility.