Dataset Information

Genetic variants in CYP2A6 and UGT1A9 genes associated with urinary nicotine metabolites in young Mexican smokers.

ABSTRACT: Nicotine is the major pharmacologically active substance in tobacco. Several studies have examined genotypes related to nicotine metabolism, but few studies have been performed in the Mexican population. The objective was to identify associations between gene variants in metabolizing enzymes and the urinary levels of nicotine metabolites among Mexican smokers. The levels of nicotine and its metabolites were determined in the urine of 88 young smokers from Mexico, and 167 variants in 24 genes associated with nicotine metabolism were genotyped by next-generation sequencing (NGS). Trans-3'-hydroxy-cotinine (3HC) and 4-hydroxy-4-(3-pyridyl)-butanoic acid were the most abundant metabolites (35 and 17%, respectively). CYP2A6*12 was associated with 3HC (p?=?0.014). The rs145014075 was associated with creatinine-adjusted levels of nicotine (p?=?0.035), while the rs12471326 (UGT1A9) was associated to cotinine-N-glucuronide (p?=?0.030). CYP2A6 and UGT1A9 variants are associated to nicotine metabolism. 4HPBA metabolite was an abundant urinary metabolite in young Mexican smokers.

SUBMITTER: Borrego-Soto G

PROVIDER: S-EPMC7375952 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Genetic variants in CYP2A6 and UGT1A9 genes associated with urinary nicotine metabolites in young Mexican smokers.

Borrego-Soto Gissela G Perez-Paramo Yadira X YX Chen Gang G Santuario-Facio Sandra K SK Santos-Guzman Jesus J Posadas-Valay Rodolfo R Alvarado-Monroy Fatima M FM Balderas-Renteria Isaias I Medina-Gonzalez Ramses R Ortiz-Lopez Rocio R Lazarus Philip P Rojas-Martinez Augusto A

The pharmacogenomics journal 20200121 4

Nicotine is the major pharmacologically active substance in tobacco. Several studies have examined genotypes related to nicotine metabolism, but few studies have been performed in the Mexican population. The objective was to identify associations between gene variants in metabolizing enzymes and the urinary levels of nicotine metabolites among Mexican smokers. The levels of nicotine and its metabolites were determined in the urine of 88 young smokers from Mexico, and 167 variants in 24 genes ass ...[more]

PMID: 31959879

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Project description:IntroductionVariation in CYP2A6, the primary enzyme responsible for nicotine metabolism, is associated with nicotine dependence, cigarette consumption, and abstinence outcomes in smokers. The impact of CYP2A6 activity on nicotine reinforcement and tobacco cue-reactivity, mechanisms that may contribute to these previous associations, has not been fully evaluated.Aims and methodsCYP2A6 activity was indexed using 3 genetic approaches in 104 daily smokers completing forced-choice and cue-induced craving tasks assessing nicotine reinforcement and tobacco cue-reactivity, respectively. First, smokers were stratified by the presence or absence of reduced/loss-of-function CYP2A6 gene variants (normal vs. reduced metabolizers). As nicotine metabolite ratio (NMR) is a reliable biomarker of CYP2A6 activity, our second and third approaches used additional genetic variants identified in genome-wide association studies of NMR to create a weighted genetic risk score (wGRS) to stratify smokers (fast vs. slow metabolizers) and calculate a wGRS-derived NMR.ResultsControlling for race and sex, normal metabolizers (vs. reduced) selected a greater proportion of puffs from nicotine-containing cigarettes (vs. denicotinized) on the forced-choice task (p = .031). In confirmatory analyses, wGRS-based stratification (fast vs. slow metabolizers) produced similar findings. Additionally, wGRS-derived NMR, which correlated with actual NMR assessed in a subset of participants (n = 55), was positively associated with the proportion of puffs from nicotine-containing cigarettes controlling for race and sex (p = .015). None of the CYP2A6 indices were associated with tobacco cue-reactivity in minimally deprived smokers.ConclusionsFindings suggest increased nicotine reinforcement is exhibited by smokers with high CYP2A6 activity, which may contribute to heavier smoking and poorer cessation outcomes previously reported in faster metabolizers.ImplicationsCYP2A6 activity is a key determinant of smoking behavior and outcomes. Therefore, these findings support the targeting of CYP2A6 activity, either therapeutically or as a clinically relevant biomarker in a precision medicine approach, for tobacco use disorder treatment.

Dataset Information

Genetic variants in CYP2A6 and UGT1A9 genes associated with urinary nicotine metabolites in young Mexican smokers.

Publications

Genetic variants in CYP2A6 and UGT1A9 genes associated with urinary nicotine metabolites in young Mexican smokers.

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