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

Bloom, A. Joseph; Martínez, Maribel; Bierut, Laura J.; Goate, Alison M.; Murphy, Sharon E.

doi:10.1097/fpc.0000000000000011

Cited by 14 publications

(18 citation statements)

References 46 publications

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“…The much lower predictive value of the genetic score in Japanese Americans may be due to the higher prevalence of CYP2A6 null variants in this group (27). We previously reported that CYP2A6 alleles contribute to variation in plasma nicotine glucuronide levels among European Americans (23), and in the subjects of this study, the CYP2A6 ratio for Japanese Americans was half the ratio for African Americans (32). In both Japanese Americans and Native Hawaiians low CYP2A6 activity is associated with decreased nicotine equivalents (29).…”

Section: Discussionsupporting

confidence: 46%

“…However, nicotine glucuronidation may account for up to 40% of the nicotine equivalents excreted by smokers (16, 17). UGT2B10 catalyzes both nicotine and cotinine glucuronidation (21–23), and our analysis has determined that a high fraction of individual variation of cotinine glucuronidation is explained by genetic differences, which can be parsimoniously characterized using a genetic score of 15 SNPs from 9 chromosomes with SNPs near UGT2B10 showing the strongest associations. The fraction of variance explained by this genetic score is estimated to be 33% overall ethnic groups considered.…”

Section: Discussionmentioning

confidence: 99%

“…The other pathways of nicotine metabolism, N -oxidation and N -glucuronidation each typically contribute < 10 % to total metabolism, although, in some individuals N -glucuronidation may account for > 40% of the excreted nicotine metabolites (16, 17). UGT2B10 and UGT1A4 both catalyze nicotine and cotinine N -glucuronidation, however UGT2B10 is a significantly more efficient catalyst and appears to be the enzyme responsible for nicotine and cotinine glucuronidation in smokers (18–23). 3-HCOT is O-glucuronidated, a reaction catalyzed, at least in part, by UGT2B17 (3, 18, 22, 24) an enzyme that does not catalyze N -glucuronidation (25).…”

Section: Introductionmentioning

confidence: 99%

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The Contribution of Common Genetic Variation to Nicotine and Cotinine Glucuronidation in Multiple Ethnic/Racial Populations

Patel

Stram

Wilkens

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background The lung cancer risk of smokers varies by race/ethnicity even after adjustment for smoking. Evaluating the role of genetics in nicotine metabolism is likely important in understanding these differences, as disparities in risk may be related to differences in nicotine dose and metabolism. Methods We conducted a genome-wide association study in search of common genetic variants that predict nicotine and cotinine glucuronidation in a sample of 2,239 smokers (437 European Americans, 364 African Americans, 453 Latinos, 674 Japanese Americans and 311 Native Hawaiians) in the Multiethnic Cohort Study. Urinary concentration of nicotine and its metabolites were determined. Results Among 11,892,802 variants analyzed, 1,241 were strongly associated with cotinine glucuronidation, 490 of which were also associated with nicotine glucuronidation (p<5×10−8). The vast majority were within chromosomal region 4q13, near UGT2B10. Fifteen independent and globally significant SNPs explained 33.2% of the variation in cotinine glucuronidation, ranging from 55% for African Americans to 19% for Japanese Americans. The strongest single SNP association was for rs115765562 (p=1.60×10−155). This SNP is highly correlated with a UGT2B10 splice site variant, rs116294140, which together with rs6175900 (Asp67Tyr) explain 24.3% of the variation. The top SNP for nicotine glucuronidation (rs116224959, p=2.56×10−43) was in high LD (r2=.99) with rs115765562. Conclusions Genetic variation in UGT2B10 contributions significantly to nicotine and cotinine glucuronidation but not to nicotine dose. Impact The contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk.

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Section: Discussionsupporting

confidence: 46%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Contribution of Common Genetic Variation to Nicotine and Cotinine Glucuronidation in Multiple Ethnic/Racial Populations

Patel

Stram

Wilkens

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…A missense mutation in UGT2B10 (rs61750900) reduces nicotine and cotinine glucuronidation metabolic ratios (most often expressed as glucuronidated metabolite/free substrate or glucuronidated metabolite/total nicotine equivalents) in European American smokers during ad libitum smoking [22, 23], or at a single time-point following oral administration of labeled nicotine-d2 [23]. Among African Americans, nicotine glucuronidation ratios are lower than in European Americans [24, 25].…”

Section: Introductionmentioning

confidence: 99%

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

Taghavi

Helen

Benowitz

et al. 2017

Pharmacogenetics and Genomics

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OBJECTIVES Nicotine metabolism rates differ greatly among individuals, even after controlling for variation in the major nicotine metabolizing enzyme, CYP2A6. In this study, the impact of genetic variation in alternative metabolic enzymes and transporters on nicotine and cotinine pharmacokinetics and smoking was investigated. METHODS We examined the impact of UGT2B10, UGT2B17, FMO3, NAT1, and OCT2 variation on pharmacokinetics and smoking (total nicotine equivalents and topography), before and after stratifying by CYP2A6 genotype in 60 African American smokers who received a simultaneous intravenous infusion of deuterium-labeled nicotine and cotinine. RESULTS Variants in UGT2B10 and UGT2B17 were associated with urinary glucuronidation ratios (glucuronide/free substrate). UGT2B10 rs116294140 was associated with significant alterations in cotinine and modest alterations in nicotine pharmacokinetics. These alterations, however, were not sufficient to change nicotine intake or topography. Neither UGT2B10 rs61750900, UGT2B17*2, FMO3 rs2266782, nor NAT1 rs13253389 altered nicotine or cotinine pharmacokinetics among all subjects (n=60); or among individuals with reduced CYP2A6 activity (n=23). The organic cation transporter OCT2 rs316019 significantly increased nicotine and cotinine Cmax (p=0.005, p=0.02, respectively) and decreased nicotine clearance (p=0.05). UGT2B10 rs116294140 had no significant impact on the plasma or urinary trans-3’-hydroxycotinine/cotinine ratio, commonly used as a biomarker of CYP2A6 activity. CONCLUSIONS We demonstrated that polymorphisms in genes other than CYP2A6 represent minor sources of variation in nicotine pharmacokinetics, insufficient to alter smoking in African Americans. The change in cotinine pharmacokinetics with UGT2B10 rs116294140 highlights the UGT2B10 gene as a source of variability in cotinine as a biomarker of tobacco exposure among African American smokers.

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“…Enzymes of nicotine metabolism are highly polymorphic and their genetic variants can cause differences in enzyme activity [7,[10][11][12][13][14][15][16]. This may translate into inter-individual differences in the concentration of nicotine in the body and to differences in the number of cigarettes consumed by smokers [17].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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

Cited by 14 publications

References 46 publications

The Contribution of Common Genetic Variation to Nicotine and Cotinine Glucuronidation in Multiple Ethnic/Racial Populations

The Contribution of Common Genetic Variation to Nicotine and Cotinine Glucuronidation in Multiple Ethnic/Racial Populations

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

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

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