Low doses of nicotine and ethanol induce CYP2E1 and chlorzoxazone metabolism in rat liver

The use of ethanol and nicotine is strongly linked; 80 to 95% of heavy alco hol users are also smokers. In humans, cigarette smoking significantly enha nces CYP2E1 activity, as measured by increased metabolism of chlorzoxazone in vivo. CYP2E1 metabolizes ethanol and can generate toxic intermediates. C YP2E1 also bioactivates tobacco smoke and other procarcinogens and several hepatotoxins. We hypothesized that, like ethanol, nicotine increases CYP2E1 activity. Rats were treated once daily with saline, ethanol (0.3, 1.0, and 3.0 g/kg p.o.), or nicotine bitartrate (0.1, 0.3, and 1.0 mg base/kg s.c.) for 7 days. After ethanol or nicotine administration, immunostaining for C YP2E1 was increased in the centrilobular regions of rat liver. Western blot analyses revealed that hepatic CYP2E1 levels were increased by ethanol (1. 6-2.4-fold) and nicotine (1.3-1.7-fold). In vitro chlorzoxazone 6-hydroxyla tion analyses demonstrated elevated V-max values (compared with saline-trea ted animals) by using hepatic microsomes from high-dose ethanol (2.27 +/- 0 .12 versus 1.18 +/- 0.23 nmol/mg/min, p < 0.001) or nicotine-treated rats ( 2.35 +/- 0.04 versus 1.32 +/- 0.55 nmol/mg/ min, p < 0.005), with no change in affinity. The magnitude of enhanced chlorzoxazone metabolism by microso mes from drug-treated animals is consistent with the observed increase in C YP2E1 protein by immunoblot. These data suggest that nicotine may increase CYP2E1-induced toxicity and contribute to cross-tolerance in smokers and pe ople treated with nicotine (e.g., smokers, patients with Alzheimer's diseas e, ulcerative colitis, neuropsychiatric motor disorders).