Effects of nicotine on cytochrome P450 2A6 and 2E1 activities.
OBJECTIVE
Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone, which are probe reactions for cytochrome P450 2A6 (CYP2A6) and CYP2E1 activities, respectively. We aimed to determine the role of nicotine in these metabolic effects of cigarette smoking.


METHODS
The study had a single-blind, randomized, crossover two-arm design. Twelve healthy smokers were given two transdermal patches with 42-mg nicotine a day or placebo patches, each for 10 days. The subjects abstained from smoking during the study arms. Oral chlorzoxazone was given on day 7 and deuterium-labelled nicotine-d(2) and cotinine-d(4) infusion on day 8.


RESULTS
There was no significant influence of transdermal nicotine administration on pharmacokinetic parameters of nicotine-d(2) or on the formation of cotinine-d(2). Nicotine decreased the volume of distribution (62.6 vs. 67.7 l, 95% confidence interval of the difference -9.7, -0.6, P= 0.047) of infused cotinine-d(4). There were no significant differences in disposition kinetics of chlorzoxazone between the treatments.


CONCLUSIONS
CYP2A6 and CYP2E1 activities are not affected by nicotine. The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities remain unknown.
Hukkanen
Janne
J
Department of Internal Medicine, University of Oulu, Oulu, Finland.
Jacob Iii
Peyton
P
Peng
Margaret
M
Dempsey
Delia
D
Benowitz
Neal L
NL
D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002753:Chlorzoxazone / Q000378:metabolism / Q000493:pharmacokinetics*; D003367:Cotinine / Q000378:metabolism; D018592:Cross-Over Studies; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics*; D009538:Nicotine / Q000378:metabolism / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000378:metabolism / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D012907:Smoking / Q000378:metabolism; D055815:Young Adult
D009125:Muscle Relaxants, Central; D018722:Nicotinic Agonists; D009538:Nicotine; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D002753:Chlorzoxazone; D003367:Cotinine