Ethanol Induction of CYP2A5: Permissive Role for CYP2E1

Abstract

ABSTRACT:CYP2A5 metabolizes xenobiotics and activates hepatocarcinogens, and induction occurs in response to hepatic damage and cellular stress. We evaluated whether ethanol can elevate CYP2A5 and whether CYP2E1 plays a role in the ethanol induction of CYP2A5. Wild-type (WT), CYP2E1 knockout (KO), and CYP2E1 knockin (KI) mice were fed ethanol for 3 weeks. Ethanol increased CYP2E1 and CYP2A5 protein and activity in WT mice but not in the KO mice. Induction of CYP2A5 (and CYP2E1) was restored in the KI mice. Ethanol induction of CYP2A5 occurred only after CYP2E1 was first induced. Immunohistochemical staining revealed that CYP2E1 and CYP2A5 colocalize to the same zones in the liver. Ethanol also elevated CYP2A5 mRNA levels in WT and KI mice but not in KO mice. Induction of CYP2A5 by cadmium was partially decreased in KO mice compared with WT or KI mice. Ethanol elevated CYP2A4 mRNA levels in all mice although the extent of induction was lowest in the KO mice. In summary, ethanol elevated mouse hepatic CYP2A5 levels, which may be of toxicological significance because CYP2A5 metabolizes nicotine and other drugs and activates hepatocarcinogens. Induction of CYP2A5 by ethanol is potentiated by the induction of CYP2E1. We speculate that ethanol induction of CYP2E1 followed by increases in reactive oxygen species and activation of Nrf2 are important steps in the mechanism by which ethanol induces CYP2A5. The possibility that induction of CYP2E1 is permissive for the induction of CYP2A5 may reflect a new contribution by CYP2E1 to the actions of ethanol.

Differential Effects of Nicotine Treatment and Ethanol Self-Administration on CYP2A6, CYP2B6 and Nicotine Pharmacokinetics in African Green Monkeys

“…Our findings are consistent with a human study that showed no association between the level of alcohol intake and in vivo CYP2A6 activity in a population of moderate alcohol consumers (Mwenifumbo et al, 2007). It has been proposed that hepatic CYP2A6 may be induced in response to ethanolmediated oxidative stress and/or liver damage (Lu et al, 2011). Treatment with 100 mM ethanol induced CYP2A6 in a human monocytic cell line, and this induction was blocked by pretreatment with the antioxidant vitamin C, suggesting a role for oxidative stress in the regulation of CYP2A6 (Jin et al, 2012).…”

“…Elevated levels of CYP2A6 and CYP2B6 protein have been reported in livers from alcoholics (Niemelä et al, 2000;Hesse et al, 2004). Chronic ethanol administration induces protein levels of hepatic CYP2A5 (orthologue to human CYP2A6) in mice (Lu et al, 2011) and hepatic CYP2B1/2 (orthologue to human CYP2B6) in rats (Howard et al, 2001), suggesting that ethanol exposure may be responsible for the higher levels of CYP2A6 and CYP2B6 in alcoholics; however, the induction of these hepatic enzymes by ethanol has not yet been demonstrated in primates.…”

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…Furthermore, CYP2E1-dependent ROS was needed for CYP2A5 induction through activation of the NRF2 (Lu et al, 2012). Since CYP2A5 can also metabolize many cancer causing agents, such as aflatoxin B1 and nitrosamines, the induction of CYP2A5 in rodents by alcohol (Lu et al, 2011) or HFD and CYP2A6 in alcoholic individuals is likely to contribute to increased oxidative stress and hepatic injury in ALD and NALD.…”

“…In mice, alcohol feeding induces CYP2A5 in a CYP2E1-dependent manner (Lu et al, 2011), possibly through the CYP2E1-ROS-Nrf2 axis (Lu, Zhang, & Cederbaum, 2012). Elevated levels of hepatic CYP2A6 (the human ortholog of the mouse CYP2A5) were also observed in some patients with ALD or cirrhosis than the control, despite the small sample size (Lu et al, 2011). In the mouse model, ethanol-mediated CYP2A5 induction was dependent on the presence of CYP2E1, while ethanol induction of CYP2E1 was not CYP2A5 dependent.…”

“…Chronic alcohol intake is known to increase the levels of CYP2A5, which can metabolize nicotine, a major ingredient of tobacco (Lu, Zhuge, Wu, & Cederbaum, 2011;Niemelä et al, 2000). In mice, alcohol feeding induces CYP2A5 in a CYP2E1-dependent manner (Lu et al, 2011), possibly through the CYP2E1-ROS-Nrf2 axis (Lu, Zhang, & Cederbaum, 2012).…”