This article reviews recent studies on CYP2E1-mediated alcoholic liver injury, the induction
of CYP2A5 by alcohol and the mechanism for this upregulation, especially the permissive role of
CYP2E1 in the induction of CYP2A5 by alcohol and the CYP2E1-ROS-Nrf2 pathway, and protective
effects of CYP2A5 against ethanol-induced oxidative liver injury. Ethanol can induce CYP2E1, an
active generator of reactive oxygen species (ROS), and CYP2E1 is a contributing factor for alcoholinduced
oxidative liver injury. CYP2A5, another isoform of cytochrome P450, can also be induced by
ethanol. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity, protein and
mRNA levels as compared to pair-fed controls. This induction was blunted in CYP2E1 knockout
(cyp2e1-/-) mice but was restored when human CYP2E1 was reintroduced and expressed in cyp2e1-/-
mice. Ethanol-induced CYP2E1 co-localized with CYP2A5 and preceded the elevation of CYP2A5.
The antioxidants N-acetyl cysteine and vitamin C lowered the alcohol elevation of ROS and blunted the
alcohol induction of CYP2A5, but not CYP2E1, suggesting ROS play a novel role in the crosstalk between
CYP2E1 and CYP2A5. The antioxidants blocked the activation of Nrf2, a transcription factor
known to upregulate expression of CYP2A5. When alcohol-induced liver injury was enhanced in Nrf2
knockout (Nrf2-/-) mice, alcohol elevation of CYP2A5 but not CYP2E1 was also lower in Nrf2-/- mice.
CYP2A5 knockout (cyp2a5-/-) mice exhibited an enhanced alcoholic liver injury compared with WT
mice as indicated by serum ALT, steatosis and necroinflammation. Alcohol-induced hyperglycemia
were observed in cyp2a5-/- mice but not in WT mice.