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TOXICOLOGY

Rat Hepatic CYP2E1 Is Induced by Very Low Nicotine Doses: An Investigation of Induction, Time Course, Dose Response, and Mechanism

Departments of Pharmacology (A.L.M., E.M.S., R.F.T.) Medicine (E.M.S.), and Psychiatry (E.M.S.), and the Centre for Addiction and Mental Health (S.M., E.M.S., R.F.T.), University of Toronto, Toronto, Ontario, Canada; and Department of Physiology and Pharmacology (D.R.K), Oregon Health Sciences University, Portland, Oregon

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. x 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. x 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 (x 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 x 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).

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

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