Alcoholic Liver Disease: from CYP2E1 to CYP2A5

Abstract

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.

Keywords: Alcohol; CYP2A5; CYP2E1; Nrf2; antioxidants; interactions; mouse liver; reactive oxygen species.

Fig. 1

Alcohol induces mRNA and activity of CYP2A5 in WT mice but not in cyp2e1^−/− mice. The WT mice and cyp2e1^−/− mice were fed ethanol-diet for 3 weeks. (A) CYP2A5 mRNA; (B) CYP2E1 mRNA; (C) CYP2A5 activity. *P<0.05, compared with WT Control; #P<0.05, compared with WT Ethanol.

Fig. 2

CMZ, an inhibitor of CYP2E1, also inhibited CYP2A5 activity. The WT mice were fed ethanol-diet for 2 weeks. *P<0.05, compared with Control; #P<0.05, compared with Ethanol.

Fig. 3

Alcohol-induced oxidative stress and hyperglycemia in cyp2a5^−/− mice. The WT mice and cyp2a5^−/− mice were fed ethanol-diet for 3 weeks. (A) GSH and TBARS. (B) HO-1, CYP2A5 and CYP2E1; (C) serum glucose; (D) glucose tolerance test. * P<0.05, compared with Control; #P<0.05, compared with WT Ethanol; & P<0.05, compared with KO.