Abstract
CYP2E1 is an ethanol- and drug-metabolizing enzyme that can also activate procarcinogens and hepatotoxicants and generate reactive oxygen species; it has been implicated in the pathogenesis of liver diseases and cancer. Cigarette smoke increases CYP2E1 activity in rodents and in humans and we have shown that nicotine (0.1-1.0 mg/kg s.c. × 7 days) increases CYP2E1 protein and activity in the rat liver. In the current study, we have shown that the induction peaks at 4 h postnicotine (1 mg/kg s.c. × 7 days) treatment and recovers within 24 h. No induction was observed after a single injection, and 18 days of treatment did not increase the levels beyond that found at 7 days. We found that CYP2E1 is induced by very low doses of chronic (× 7 days) nicotine with an ED50 value of 0.01 mg/kg s.c.; 0.01 mg/kg in a rat model results in peak cotinine levels (nicotine metabolite) similar to those found in people exposed to environmental tobacco smoke (passive smokers; 2-7 ng/ml). Previously, we have shown no change in CYP2E1 mRNA, and our current mechanistic study indicates that nicotine does not regulate CYP2E1 expression by protein stabilization. We postulated that a nicotine metabolite could be causing the induction but found that cotinine (1 mg/kg × 7 days) did not increase CYP2E1. Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity in smokers, passive smokers, and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis or Parkinson's disease).
Footnotes
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Financial support for this study was provided by Canadian Institutes of Health Research (CIHR) grant MT 14173, a Canadian Research Chair in Pharmacogenetics and the Centre for Addiction and Mental Health. A preliminary report of this study was presented at the following conference and published in abstract form [Micu AM, Howard LA, Miksys S, Sellers EM, and Tyndale RF (2002) Induction of ethanol-inactivating and pro-carcinogen activating CYP2E1 by Nicotine. Proc Soc Res Nicotine Tob].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.052183.
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ABBREVIATIONS: CHO, Chinese hamster ovary; ETS, environmental tobacco smoke.
- Received March 27, 2003.
- Accepted May 13, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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