To conduct a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty nine twin pairs [110 monozygotic (MZ) and 29 dizygotic (DZ)] underwent a 30-min infusion of stable isotope-labelled nicotine and its major metabolite, cotinine, followed by an 8-h in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine and metabolites by gas chromatography–mass spectrometry or liquid chromatography–mass spectrometry and subsequent characterization of pharmacokinetic and metabolism phenotypes. DNA was genotyped to confirm zygosity and for variation in the gene for the primary enzyme involved in nicotine metabolism, CYP2A6 (alleles tested: *1, *1×2, *2, *4, *7, *9 and *12). Univariate biometric analyses quantified genetic and environmental influences on each pharmacokinetic measure in the presence and absence of covariates, including measured CYP2A6 genotype. The best-fitting model identified a substantial amount of variation in the weight-adjusted rate of total clearance of nicotine attributable to additive genetic influences [59.4%, 95% confidence interval (CI)=44.7–70.7]. The majority of variation in the clearance of nicotine via the cotinine pathway was similarly genetically influenced (60.8%, 95% CI=46.9–71.5). Heritability estimates were reduced to 54.2% and 51.8%, respectively, but remained substantial after taking into account the effect of variation in CYP2A6 genotype. These results suggest the involvement of additional genetic factors (e.g. uncharacterized or novel CYP2A6 alleles as well as other genes in the metabolic pathway) that remain to be identified.
aCenter for Health Sciences, SRI International, Menlo Park, California, USA
bDivision of Clinical Pharmacology, Departments of Medicine, Psychiatry and Biopharmaceutical Sciences, University of California, San Francisco, California, USA
cCAMH and Department of Pharmacology, University of Toronto, Toronto, Canada
dFormerly of Department of Neurology, University of California, San Francisco, now at Department of Genetics, University of North Carolina, Raleigh, North Carolina, USA
Sponsorship: This study was supported by National Institute on Drug Abuse grants DA11170 (G.E.S.), DA02277 (N.L.B.), and DA12393 (N.L.B.). Carried out in part at the General Clinical Research Center at San Francisco General Hospital Medical Center with support of the NIH Division of Research Resources, grant RR00083, and at the University of Toronto with support of grant CIHR MOP 53248 (R.F.T.) and a CRC to R.F.T.
Correspondence and requests for reprints to Gary E. Swan, Center for Health Sciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA
Tel: +1 650 8595322; fax: +1 650 8595099;
Received 14 October 2004 Accepted 22 November 2004