Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence.

摘要: To conduct a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty nine twin pairs [110 monozygotic (MZ) 29 dizygotic (DZ)] underwent 30-min infusion stable isotope-labelled its major metabolite, cotinine, followed by an 8-h in-hospital stay. Blood urine samples were taken at regular intervals for analysis nicotine, cotinine metabolites gas chromatography-mass spectrometry or liquid subsequent characterization pharmacokinetic phenotypes. DNA was genotyped to confirm zygosity variation the gene primary enzyme involved metabolism, CYP2A6 (alleles tested: *1, *1x2, *2, *4, *7, *9 *12). Univariate biometric analyses quantified genetic environmental influences on each measure presence absence covariates, including measured genotype. The best-fitting model identified substantial amount weight-adjusted rate total clearance attributable additive [59.4%, 95% confidence interval (CI)=44.7-70.7]. majority via pathway similarly genetically influenced (60.8%, CI=46.9-71.5). Heritability estimates reduced 54.2% 51.8%, respectively, but remained after taking into account effect These results suggest involvement additional factors (e.g. uncharacterized novel alleles as well other genes metabolic pathway) that remain be identified.