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Drug Metabolism and Disposition Fast Forward
First published on January 24, 2006; DOI: 10.1124/dmd.105.008029

0090-9556/06/3404-647-652$20.00
DMD 34:647-652, 2006

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INDUCTION AND RECOVERY TIME COURSE OF RAT BRAIN CYP2E1 AFTER NICOTINE TREATMENT

Meenal Joshi, and Rachel F. Tyndale

Centre for Addiction and Mental Health and Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada

CYP2E1, the primary ethanol-metabolizing cytochrome P450, metabolizes endogenous substrates (e.g., arachidonic acid) and drugs (e.g., acetaminophen, chlorzoxazone) and bioactivates procarcinogens (e.g., tobacco-specific nitrosamines) and toxins (e.g., carbon tetrachloride). Nicotine from tobacco smoke may contribute to the enhanced hepatic CYP2E1 activity in smokers. We have previously shown that chronic nicotine treatment can increase CYP2E1 in rat liver and brain. In this study, induction of brain CYP2E1 was assessed after a single acute or a 7-day chronic treatment with saline or nicotine (1 mg/kg s.c.), with sacrifice performed at various times after the last injection. Chronic 7-day nicotine treatment showed the highest levels of CYP2E1 12 h after the last injection in frontal cortex (1.4-fold, p < 0.05) versus 8 h in hippocampus (1.8-fold, p < 0.01) and cerebellum (1.4-fold, p < 0.05), returning to basal levels by 24 h. In contrast, acute nicotine treatment did not induce CYP2E1 in frontal cortex and hippocampus but increased CYP2E1 in cerebellum 8 h after treatment (1.6-fold, p < 0.01). Brain CYP2E1 mRNA levels did not increase after chronic nicotine treatment, suggesting nontranscriptional regulation. Thus, humans exposed to nicotine may have altered CYP2E1-mediated metabolism of centrally acting drugs and toxins as well as altered toxicity because of oxidative stress caused by CYP2E1. Those affected may include current and passive smokers and people that may be treated with nicotine such as smokers and, potentially, patients with Alzheimer's, Parkinson's disease, or ulcerative colitis.

Address correspondence to: Rachel F. Tyndale, Department of Pharmacology, 1 King's College Circle, Toronto, ON, Canada M5S 1A8. E-mail: r.tyndale{at}utoronto.ca




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F. J. Gonzalez
CYP2E1
Drug Metab. Dispos., January 1, 2007; 35(1): 1 - 8.
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