Rat hepatic CYP2E1 is induced by very low nicotine doses: an investigation of induction, time course, dose response, and mechanism.
Article Details
- CitationCopy to clipboard
Micu AL, Miksys S, Sellers EM, Koop DR, Tyndale RF
Rat hepatic CYP2E1 is induced by very low nicotine doses: an investigation of induction, time course, dose response, and mechanism.
J Pharmacol Exp Ther. 2003 Sep;306(3):941-7. doi: 10.1124/jpet.103.052183. Epub 2003 May 15.
- PubMed ID
- 12750430 [ View in PubMed]
- 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. 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).
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Nicotine Cytochrome P450 2E1 Protein Humans UnknownSubstrateInhibitorInducerDetails