Received for publication March 28, 2003.
Revised April 18, 2003.
Accepted for publication May 13, 2003.

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

Abstract

CYP2E1 is an ethanol- and drug-metabolizing enzyme that can also activate procarcinogens and hepatotoxins 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 studies we have shown that the induction peaks at 4 hours post nicotine (1 mg/kg s.c. X 7 days) treatment and recovers within 24 hrs. No induction was observed following 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 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 studies indicate 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).

Key words: Animal/drug effects, Cytochrome P-450 CYP2E1, Enzyme Induction/drug effects, Liver/drug effects, Nicotine/administration & dosage/blood, Western Blotting/Protein stabilization

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