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Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption.

ABSTRACT: Flavin-containing monooxygenases (FMO) catalyze the metabolism of nucleophilic heteroatom-containing drugs and xenobiotics, including nicotine. Rare mutations in FMO3 are responsible for defective N-oxidation of dietary trimethylamine leading to trimethylaminuria, and common genetic variation in FMO3 has been linked to interindividual variability in metabolic function that may be substrate specific.A genetic model of CYP2A6 function is used as a covariate to reveal functional polymorphism in FMO3 that indirectly influences the ratio of deuterated nicotine metabolized to cotinine following oral administration. The association is tested between FMO3 haplotype and cigarette consumption in a set of nicotine-dependent smokers.FMO3 haplotype, based on all common coding variants in Europeans, significantly predicts nicotine metabolism and accounts for ?2% of variance in the apparent percent of nicotine metabolized to cotinine. The metabolic ratio is not associated with FMO2 haplotype or an FMO1 expression quantitative trait locus. Cross-validation demonstrates calculated FMO3 haplotype parameters to be robust and significantly improve the predictive nicotine metabolism model over CYP2A6 genotype alone. Functional classes of FMO3 haplotypes, as determined by their influence on nicotine metabolism to cotinine, are also significantly associated with cigarettes per day in nicotine-dependent European Americans (n=1025, P=0.04), and significantly interact (P=0.016) with CYP2A6 genotype to predict cigarettes per day.These findings suggest that common polymorphisms in FMO3 influence nicotine clearance and that these genetic variants in turn influence cigarette consumption.

SUBMITTER: Bloom AJ

PROVIDER: S-EPMC4583063 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Project description:Background and aimsSmokers can regulate their nicotine intake by altering the number of cigarettes smoked per day (CPD) and their smoking intensity. The current study aimed to compare the utility of self-reported CPD, total nicotine equivalents (TNE) and urinary cotinine to estimate nicotine intake during pregnancy.DesignLongitudinal smoking behavior and biomarker data were collected at early pregnancy, late pregnancy and at postpartum as part of a smoking cessation trial to examine voucher-based incentives for decreasing smoking.SettingObstetric practices in Burlington, Vermont, United States.ParticipantsA subset of participants (n = 47) from the parent trial, recruited between December 2006 and June 2012, who provided a urine sample at each assessment during early pregnancy, late pregnancy and postpartum.MeasurementsSmoking was assessed using self-reported CPD, TNE, TNE/CPD and urinary cotinine.FindingsPregnant smokers reported smoking 10.4 CPD at early pregnancy, 7.2 CPD at late pregnancy (a 31% reduction at late pregnancy, P = 0.001) and 8.6 CPD at postpartum (a 19% increase from late pregnancy, P = 0.08). TNE exposure was 41% (P = 0.07) and 48% (P = 0.03) lower at early and late pregnancy, respectively, compared to postpartum. TNE/CPD was on average 167% higher at late pregnancy compared to early pregnancy (P = 0.01) and remained high at postpartum, where it was 111% higher compared to early pregnancy (P = 0.007). Uriniary cotinine underestimated nicotine intake by 55% during early pregnancy and by 65% during late pregnancy compared to postpartum (Pinteraction < 0.001); the underestimation was greater in slower (Pinteraction < 0.001) versus faster (Pinteraction = 0.04) nicotine metabolizers.ConclusionsNeither cigarettes smoked per day (CPD) nor cotinine provides an accurate estimate of nicotine exposure during pregnancy. CPD underestimates nicotine intake substantially due to under-reporting and/or higher intensity of smoking, while cotinine underestimates nicotine intake markedly due to accelerated nicotine (and cotinine) metabolism during pregnancy.

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Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption.

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