¹Department of Clinical Pharmacology, Cancer Research UK Medical Statistics Group, Centre for Statistics in Medicine, and Childhood Cancer Research Group, University of Oxford, Oxford; Departments of Medicine, Psychiatry, and Biopharmaceutical Sciences, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, San Francisco; Human Genetics Division, School of Medicine, Southampton General Hospital, University of Southampton, Southampton; and Medical Research Council Laboratories, Fajara.

Correspondence: Elaine Johnstone, PhD, Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, United Kingdom. E-mail: elaine.johnstone@clinpharm.ox.ac.uk

^*Financial support for this study was received from Cancer Research UK and US Public Health Service grant DA02277 from the National Institute on Drug Abuse, as well as the Wessex Medical Trust (Hope).

Received 6 October 2005; Accepted 12 June 2006.

Abstract

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).

Conclusion: 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.