Rat hepatic CYP2E1 is induced by very low nicotine doses: an investigation of induction, time course, dose response, and mechanism.
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).
Department of Pharmacology, University of Toronto, Canada.
Alina L
AL
Micu
Sharon
S
Miksys
Edward M
EM
Sellers
Dennis R
DR
Koop
Rachel F
RF
Tyndale
D000818:Animals; D003367:Cotinine / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004795:Enzyme Stability; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D018722:Nicotinic Agonists; D009538:Nicotine; D019392:Cytochrome P-450 CYP2E1; D003367:Cotinine