PHARMACOGENETICS OF NICOTINE METABOLISM. IMPLICATIONS IN NICOTINE ADDICTION

Yadira  Xitlalli Perez Paramo

Nicotine is the addictive substance in tobacco, leading to the rewarding effects experienced by smokers. Metabolism of nicotine is a major factor in nicotine dependence. Nicotine is metabolized primarily through hydroxylation by cytochrome P450 2A6 (CYP2A6), but is also acted upon by UDP-glucuronosyltransferases (UGTs) to make glucuronides, and flavin monooxigenases (FMOs) to produce N-oxides. While previous studies have suggested that hepatic FMO3 is the principal enzyme involved in nicotine-N’-oxidation, a comprehensive analysis of all FMOs had not previously been performed. We demonstrated that the wild-type FMO isoforms 3>1>2 have catalytic activity against nicotine. Seven non-synonymous polymorphisms in FMO3 were evaluated and all of them exhibited decreased catalytic efficiencies when compared to the wild-type FMO3 isoform. A genetic variant in FMO1 (I303V) was found to have one third of its wild-type catalytic activity. FMO2 deleterious variant (Q472Stop) codes for an early stop codon and results in a truncated and inactive protein. In addition to nicotine, cotinine also undergoes N-oxidization, but to date no enzyme had been reported to mediate this reaction. In this study we identified CYP2A6, CYP2B6, and CYP2C19 as the enzymes involved in cotinine-N-oxide formation. We found significant associations with levels of cotinine-N-oxide formation and the *2 and *17 genetic variants in CYP2C19. We observed a 33% increase in cotinine-N-oxide formation in the CYP2C19-ultra-rapid metabolizer group when compared to the CYP2C19-poor metabolizer group. Additionally, we analyzed the levels of nicotine metabolites among 636 Chinese smokers, a population known for its high frequency of individuals carrying CYP2A6 defective alleles. When analyzing samples by CYP2A6 metabolizing groups, we observed a significant correlation between CYP2A6 genotype and urinary levels of nicotine, nicotine-N-glucuronide, nicotine-N’-oxide, and trans-3’-hydroxycotinine. CYP2B6 had significant correlations with trans-3’-hydroxycotinine, nicotine-N’-oxide, and 4-hydroxy-4-(3-pyridyl)-butanoic acid levels; and FMO3 exhibited significant effects on nicotine-N’-oxide levels. UGT2B10 genotype had a significant effect on cotinine, nicotine-glucuronide, and cotinine-glucuronide levels. Finally, the UGT2B17 genotype had a significant effect on of trans-3’-hydroxycotinine and trans-3’-hydroxycotinine-O-glucuronide levels. Together these data highlight the importance of genetic variants in the enzymes driving the metabolism of nicotine, as well as nicotine biomarkers and their use in personalized pharmacotherapy and smoking cessation.

PHARMACOGENETICS OF NICOTINE METABOLISM. IMPLICATIONS IN NICOTINE ADDICTION

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