Induction of CYP2B1/2 and nicotine metabolism by ethanol in rat liver but not rat brain

A higher proportion of alcoholics than non-alcoholics smoke (>80 vs 30%). I n animals, chronic administration of alcohol induces tolerance to some effe cts of nicotine. To investigate if chronic ethanol (EtOH) induces alteratio ns in CYP2B1/2 and nicotine C-oxidation activity, male rats (N = 4-6/group) were treated once daily with saline or EtOH (0.3, 1.0, and 3.0 g/kg, p.o./ by gavage) for 7 days. A quantitative immunoblotting assay was developed to detect CYP2B1/2 in the brain, where constitutive expression is low, and in the liver. Using this method, it was determined that EtOH did not alter CY P2B1/2 protein expression significantly in six brain regions (olfactory bul bs, olfactory tubercles, frontal cortex, hippocampus, cerebellum, and brain stem). However, a dose-dependent induction of CYP2B1/2 protein expression w as detected in the liver. Significant induction of 2-, 3-, and 2.7-fold wer e observed for the 0.3, 1.0, and 3.0 g/kg doses, respectively. Increases we re also observed in CYP2B1 mRNA, which was induced by 14, 38, and 43% at th e same doses. Liver microsomal nicotine C-oxidation also was increased (1.3 to 4.5-fold). CYP2B selective inactivators demonstrated that approximately 70% of nicotine C-oxidation was mediated by CYP2B1/2 in both EtOH-induced and uninduced hepatic microsomes. In summary, chronic, behaviorally relevan t doses of EtOH induce CYP2B1/2 protein, mRNA, and nicotine C-oxidation act ivity in rat liver but not in rat brain, and these increases could contribu te to cross-tolerance and co-abuse of ethanol and nicotine. (C) 2001 Elsevi er Science Inc. All rights reserved.