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

Abstract

Background 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-oxygenation 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. Methods 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. Results FMO3 haplotype, based on all common coding variants in Europeans, significantly predicts nicotine metabolism and accounts for approximately 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 (eQTL). 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 (CPD) in nicotine dependent European Americans (n=1,025, p=0.04), and significantly interact (p=0.016) with CYP2A6 genotype to predict CPD. Conclusion These findings suggest that common polymorphisms in FMO3 influence nicotine clearance, and that these genetic variants in turn influence cigarette consumption.

The contribution of common UGT2B10 and CYP2A6 alleles to variation in nicotine glucuronidation among European Americans

“…Variation in nicotine metabolism and nicotine metabolism genes has been associated with differences in cigarette consumption [15, 19, 22, 27, 45], smoking cessation [26] and liability for smoking-related disease [7, 46]. Although the majority of nicotine metabolism in most smokers is catalyzed by one enzyme, CYP2A6, there is evidence that other nicotine metabolism pathways may significantly impact smoking behavior[15, 27].…”

“…Although the majority of nicotine metabolism in most smokers is catalyzed by one enzyme, CYP2A6, there is evidence that other nicotine metabolism pathways may significantly impact smoking behavior[15, 27]. Nicotine glucuronidation has been shown to vary widely among subjects as well as among ethnic groups [13, 29, 47].…”

“…Therefore, heritable differences in nicotine half-life are likely to explain some of the observed differences in cigarettes per day (CPD) and related behaviors between fast and slow nicotine metabolizers and individuals who differ in CYP2A6 genotype [14, 19-26]. The other pathways of nicotine metabolism may also contribute to smoking behaviors and we have recently found evidence that genetic variation in FMO3 , the gene encoding the primary catalyst of nicotine- N -oxidation, is associated with differences in cigarette consumption[27]. Genetic variation in glucuronidation has been suggested to influence individual variability in total nicotine metabolism [28] and ethnic differences in glucuronidation and in UGT2B10 genotype [29] are reported to be associated with differences in cigarette consumption[15]; but with the exception of a non-synonymous variant, rs61750900 (D67Y) [12, 15], common variants in UGT2B10 have not been comprehensively tested.…”

Effect of UGT2B10, UGT2B17, FMO3, and OCT2 genetic variation on nicotine and cotinine pharmacokinetics and smoking in African Americans

“…The same is true for flavin-containing monoxygenase (FMO)-3 enzyme which catalyzes nicotine N’-oxidation, a pathway responsible for 4–7% of total nicotine urinary recovery [8], which increases in individuals with deleted CYP2A6 [21]. This suggests a potentially greater reliance on alternative nicotine metabolizing pathways mediated by UGT2B10 or FMO3 when CYP2A6 activity is reduced.…”

Variation in P450 oxidoreductase (POR) A503V and flavin-containing monooxygenase (FMO)-3 E158K is associated with minor alterations in nicotine metabolism, but does not alter cigarette consumption

“…Flavin-containing monoxygenase (FMO)-3 catalyzes hepatic nicotine N’-oxidation, a pathway responsible for ~4-7% of nicotine urinary recovery, but up to 30% in individuals with deleted CYP2A6 [5], suggestive of a greater reliance on FMO3-mediated nicotine metabolism when CYP2A6 activity is reduced. Variation in FMO3 , which may impact nicotine metabolism, is associated with altered ratios of COT/(COT + nicotine) and cigarette consumption in Caucasians [5].…”