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Nicotine dependence is associated with functional variation in FMO3, an enzyme that metabolizes nicotine in the brain.

ABSTRACT: A common haplotype of the flavin-containing monooxygenase gene FMO3 is associated with aberrant mRNA splicing, a twofold reduction in in vivo nicotine N-oxidation and reduced nicotine dependence. Tobacco remains the largest cause of preventable mortality worldwide. CYP2A6, the primary hepatic nicotine metabolism gene, is robustly associated with cigarette consumption but other enzymes contribute to nicotine metabolism. We determined the effects of common variants in FMO3 on plasma levels of nicotine-N-oxide in 170 European Americans administered deuterated nicotine. The polymorphism rs2266780 (E308G) was associated with N-oxidation of both orally administered and ad libitum smoked nicotine (P?3.3 × 10-5 controlling for CYP2A6 genotype). In vitro, the FMO3 G308 variant was not associated with reduced activity, but rs2266780 was strongly associated with aberrant FMO3 mRNA splicing in both liver and brain (P?6.5 × 10-9). Surprisingly, in treatment-seeking European American smokers (n=1558) this allele was associated with reduced nicotine dependence, specifically with a longer time to first cigarette (P=9.0 × 10-4), but not with reduced cigarette consumption. As N-oxidation accounts for only a small percentage of hepatic nicotine metabolism we hypothesized that FMO3 genotype affects nicotine metabolism in the brain (unlike CYP2A6, FMO3 is expressed in human brain) or that nicotine-N-oxide itself has pharmacological activity. We demonstrate for the first time nicotine N-oxidation in human brain, mediated by FMO3 and FMO1, and show that nicotine-N-oxide modulates human ?4?2 nicotinic receptor activity in vitro. These results indicate possible mechanisms for associations between FMO3 genotype and smoking behaviors, and suggest nicotine N-oxidation as a novel target to enhance smoking cessation.

SUBMITTER: Teitelbaum AM

PROVIDER: S-EPMC5599305 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Nicotine dependence is associated with functional variation in FMO3, an enzyme that metabolizes nicotine in the brain.

Teitelbaum A M AM Murphy S E SE Akk G G Baker T B TB Germann A A von Weymarn L B LB Bierut L J LJ Goate A A Kharasch E D ED Bloom A J AJ

The pharmacogenomics journal 20170314 1

A common haplotype of the flavin-containing monooxygenase gene FMO3 is associated with aberrant mRNA splicing, a twofold reduction in in vivo nicotine N-oxidation and reduced nicotine dependence. Tobacco remains the largest cause of preventable mortality worldwide. CYP2A6, the primary hepatic nicotine metabolism gene, is robustly associated with cigarette consumption but other enzymes contribute to nicotine metabolism. We determined the effects of common variants in FMO3 on plasma levels of nico ...[more]

PMID: 28290528

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Project description:Technological advances have led to the discovery of genetic variants that contribute to many illnesses including nicotine dependence. A multi-stage model of the development of nicotine dependence underlies these genetic studies, and it includes a progression through several stages of smoking behavior from never smoking to nicotine dependence. The final step in this model of dependence is the progression from established smoking behavior to the development of nicotine dependence. Contrasting individuals who smoke only a few cigarettes per day, or "chippers", to heavy smoking, nicotine dependent subjects, focuses a genetic study on the transition from smoking to nicotine dependence. This approach has identified distinct genetic variants that contribute to nicotine dependence on chromosome 15 in the region of the alpha5-alpha3-beta4 family of nicotinic receptor genes. This region of association includes an amino acid change in the alpha5 nicotinic receptor protein, which is most likely a biological variant altering the risk of developing dependence. There is also evidence that other variants alter alpha5 nicotinic receptor gene expression and potentially the risk of smoking. The discovery of these genetic variants and their contribution to the development of nicotine dependence highlight some of the many challenges in genetic studies. The first is that the prevalence of risk alleles can vary across populations so that a genetic risk factor can have a larger or small effect in a population depending on its frequency. The second challenge is that the risk that each genetic variant contributes in the development of a disorder is small and so it is many genes along with environmental risk factors that contribute to the development of a disorder. Interestingly, recent genetic studies of lung cancer and chronic obstructive pulmonary disease demonstrate that this same region has an important genetic influence on these disorders. Finally, there are differences in the risk of developing nicotine dependence based on gender and socioeconomic status. As our understanding of the genetic contributions of nicotine dependence increases, we may improve and personalize our treatments for smoking cessation and enhance our knowledge of other smoking related diseases in those who are at high risk for the many adverse consequences of smoking.

Project description:INTRODUCTION:This study investigated the effects of nicotine/tobacco on neural activation during performance of a monetary incentive delay task. AIMS AND METHODS:Prior to each scan, nonsmokers received nicotine or placebo nasal spray, and smokers were smoking satiated or 24-hour withdrawn. During the scan, participants made timed responses to reward-related cues and received feedback. Parameter estimates from cue- and feedback-related activation in medial prefrontal regions and the nucleus accumbens were extracted and underwent within- and between-group analyses. Smokers' nicotine dependence severity was included as a continuous predictor variable for neural activation. RESULTS:Among smokers (n = 21), withdrawal decreased cue-related activation in the supplementary motor area and ventromedial prefrontal cortex, and the difference in activation (satiety > withdrawal) in these regions negatively correlated with nicotine dependence severity (Fagerström Test for Nicotine Dependence). Among nonsmokers (n = 22), nicotine increased the difference in nucleus accumbens activation between rewarded and nonrewarded feedback phases. Tobacco withdrawal and acute nicotine also had widespread effects on activation throughout the brain during the feedback phase. CONCLUSIONS:Acute nicotine in nonsmokers may have increased the salience of feedback information, but produced few effects on reward-related activation overall, perhaps reflecting nicotine's modest, indirect effects on reward processing. Conversely, tobacco withdrawal decreased activation compared with satiety, and this difference between conditions correlated with nicotine dependence severity. This suggests that as smokers become more dependent on nicotine, tobacco withdrawal has a more pronounced effect on reward processing. IMPLICATIONS:Relative to the acute effects of nicotine in nonsmokers, withdrawal from daily tobacco use had more significant effects on reward-related brain activation. This study suggests that the effects of tobacco withdrawal on reward-related brain function interact with subjects' level of nicotine dependence severity. These are potentially important sources of variability that could contribute to smoking cessation outcomes.

Dataset Information

Nicotine dependence is associated with functional variation in FMO3, an enzyme that metabolizes nicotine in the brain.

Publications

Nicotine dependence is associated with functional variation in FMO3, an enzyme that metabolizes nicotine in the brain.

Similar Datasets

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