How can CYP2E1-dependent CYP2A5 induction inhibit oxidative stress? Besides generating oxidants including ROS, CYP2E1 can also up-regulate antioxidants, a function that may reflect an adaptive mechanism to remove CYP2E1-derived oxidants (24). In CYP2E1 over-expressing HepG2 cells, antioxidants including GSH, catalase, and GST are up-regulated (25, 26). Due to the increase in ROS produced by the elevated levels of CYP2E1, Nrf2 is up-regulated in CYP2E1 over-expressing HepG2 cells and in livers from ethanol-fed rodents (27, 28). It is generally accepted that Nrf2 up-regulates antioxidant enzymes, such as heme oxygenase 1(HO-1) and glutamyl cysteinylglycine synthase (a rate-limiting enzyme for GSH synthesis), to antagonize CYP2E1-mediated liver injury (13). Ethanol-induced liver injury was more severe in Nrf2 knockout (Nrf2−/−) mice than WT mice, suggesting that the up-regulation of Nrf2 protects against alcoholic liver disease (14). It was also reported that chronic ethanol feeding does not induce HO-1 in rodents (29). In the present study, a similar decrease in GSH levels was observed in ethanol-treated WT mice and cyp2a5−/− mice; thus, other Nrf2-regulated mechanisms may be involved. CYP2A6, the human orthologue to CYP2A5, is regulated
