Determinants of the rate of nicotine metabolism and effects on smoking behavior.
BACKGROUND
Studies on cytochrome P450 (CYP) 2A6 suggest that genotype affects the rate of nicotine metabolism and, consequently, cigarette consumption. However, known alleles of CYP2A6 associated with fast or slow metabolism are relatively uncommon, and there remains considerable variation in metabolic activity among those with presumed wild-type CYP2A6 alleles, suggesting that other genetic or environmental factors also influence the rate of nicotine metabolism.


METHODS
We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism.


RESULTS
The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and *12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P = .02), plasma nicotine concentration (P < .0001), and age (P = .02) but was not associated with dependence score (P > .20). The ratio also predicted the number of cigarettes smoked at will per day, although the association was weak (F(1, 492) = 4.05, P = .04).


CONCLUSIONS
In this cohort the rate of nicotine metabolism is related to age, sex, CYP2A6 genotype, and CYP2B6 genotype and may affect the level of tobacco consumption.
Johnstone
Elaine
E
Department of Clinical Pharmacology, Cancer Research UK Medical Statistics Group, Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom. elaine.johnstone@clinpharm.ox.ac.uk
Benowitz
Neal
N
Cargill
Anna
A
Jacob
Robyn
R
Hinks
Lesley
L
Day
Ian
I
Murphy
Mike
M
Walton
Robert
R
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D018849:Controlled Clinical Trials as Topic; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005731:Ganglionic Stimulants / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009538:Nicotine / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D012044:Regression Analysis; D012907:Smoking / Q000235:genetics / Q000378:metabolism*; D016540:Smoking Cessation / Q000379:methods; D006113:United Kingdom
D005731:Ganglionic Stimulants; D018722:Nicotinic Agonists; D009538:Nicotine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating