Regional and cellular induction of nicotine-metabolizing CYP2B1 in rat brain by chronic nicotine treatment.
In the rat, nicotine is metabolized to cotinine primarily by hepatic cytochrome P450 (CYP) 2B1. This enzyme is also found in other organs such as the lung and the brain. Hepatic nicotine metabolism is unaltered after nicotine exposure; however, nicotine may regulate CYP2B1 in other tissues. We hypothesized that nicotine induces its own metabolism in brain by increasing CYP2B1. Male rats were treated with nicotine (0.0, 0.1, 0.3, or 1.0 mg base/kg in saline) s.c. daily for 7 days. CYP2B1 mRNA and protein were assayed in the brain and liver by reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting, and immunocytochemistry. In control rats, CYP2B1 mRNA and protein expression were brain region- and cell-specific. CYP2B1 was not induced in the liver, but CYP2B1 mRNA and protein showed dose-dependent, region- and cell-specific patterns of induction across brain regions. At 1.0 mg nicotine/kg, the largest increase in protein was in the brain stem (5.8-fold, P < 0.05) with a corresponding increase in CYP2B1 mRNA (7.6-fold, P < 0.05). Induction of CYP2B1 was also observed in the frontal cortex, striatum, and olfactory tubercle. Immunocytochemistry showed that induction was restricted principally to neurons. These data indicate that nicotine may alter its own metabolism in the brain through transcriptional regulation, perhaps contributing to central tolerance to the effects of nicotine. CYP2B1 and its human homologue CYP2B6 also activate tobacco smoke procarcinogens such as NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]. Highly localized increases in CYP2B could result in increased mutagenesis. These data suggest roles for nicotine-induced CYP2B in central metabolic tolerance, nicotine-induced neurotoxicity, neuroplasticity, and carcinogenesis.
Miksys
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Centre for Addiction and Mental Health and Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
Hoffmann
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Tyndale
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D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009538:Nicotine / Q000378:metabolism / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018722:Nicotinic Agonists; D009538:Nicotine; D019362:Cytochrome P-450 CYP2B1