Induction of CYP2B1/2 and nicotine metabolism by ethanol in rat liver but not rat brain22Abbreviations: CYP, cytochrome P450; C8 xanthate, potassium octylxanthate; NCO, nicotine C-oxidation; NDMA, N-nitrosodimethylamine; NMA, N-nitroso-N-methylaniline; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; and SSC, saline-sodium citrate buffer

Autor: Edward M. Sellers, Rachel F. Tyndale, Kerri A. Schoedel
Rok vydání: 2001
Předmět:
Zdroj: Biochemical Pharmacology. 62:1025-1036
ISSN: 0006-2952
DOI: 10.1016/s0006-2952(01)00744-4
Popis: A higher proportion of alcoholics than non-alcoholics smoke (>80 vs 30%). In animals, chronic administration of alcohol induces tolerance to some effects of nicotine. To investigate if chronic ethanol (EtOH) induces alterations 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 CYP2B1/2 protein expression significantly in six brain regions (olfactory bulbs, olfactory tubercles, frontal cortex, hippocampus, cerebellum, and brainstem). However, a dose-dependent induction of CYP2B1/2 protein expression was detected in the liver. Significant induction of 2-, 3-, and 2.7-fold were observed for the 0.3, 1.0, and 3.0 g/kg doses, respectively. Increases were also observed in CYP2B1 mRNA, which was induced by 14, 38, and 43% at the 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 relevant doses of EtOH induce CYP2B1/2 protein, mRNA, and nicotine C-oxidation activity in rat liver but not in rat brain, and these increases could contribute to cross-tolerance and co-abuse of ethanol and nicotine.
Databáze: OpenAIRE
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