title: Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence.
abstract: 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, *1x2, *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.
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, California 94025, USA. gary.swan@sri.com
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.forename: Christina N
authors.initials: CN
authors.lastname: Lessov
authors.forename: Peyton
authors.initials: P
authors.lastname: Jacob
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.forename: Kirk
authors.initials: K
authors.lastname: Wilhelmsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D002853:Chromatography, Liquid; D003367:Cotinine / Q000378:metabolism / Q000493:pharmacokinetics; D065637:Cytochrome P-450 CYP2A6; D005192:Family Health; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D009538:Nicotine / Q000378:metabolism* / Q000493:pharmacokinetics; D010641:Phenotype; D018433:Twin Studies as Topic; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic
chemical_list: D009538:Nicotine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine