<i>UGT1A</i> and <i>UGT2B</i> Genetic Variation Alters Nicotine and Nitrosamine Glucuronidation in European and African American Smokers

Wassenaar, Catherine A.; Conti, David V.; Das, Soma; Chen, Peixian; Cook, Edwin H.; Ratain, Mark J.; Benowitz, Neal L.; Tyndale, Rachel F.

doi:10.1158/1055-9965.epi-14-0804

Cited by 28 publications

(30 citation statements)

References 57 publications

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“…A strong association was observed between the levels of urinary NNAL- N -Gluc and urinary nicotine-Gluc but not the O -glucuronidated metabolite of 3′-OH-cotinine in smokers in the present study, a pattern consistent with the N -glucuronidating capacity of UGT2B10 previously described in in vitro studies (20, 37, 39). …”

Section: Discussionsupporting

confidence: 91%

Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers

Chen

Luo

Kozlovich

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background The most abundant and potent carcinogenic tobacco-specific nitrosamines in tobacco and tobacco smoke is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In vivo, NNK is rapidly metabolized to both the (R)- and (S)-enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which possesses similar carcinogenic properties as NNK. The major detoxification pathway for both NNAL enantiomers is glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes including UGT2B10 and UGT2B17. Methods NNAL-N-Gluc, (R)-NNAL-O-Gluc, (S)-NNAL-O-Gluc and free NNAL were simultaneously and directly quantified in the urine of smokers by LC-MS analysis. Genotypes were determined by Taqman-assay using genomic DNA. Results The average percentage of total urinary NNAL that existed as NNAL-N-Gluc, (R)-NNAL-O-Gluc, (S)-NNAL-O-Gluc, and free-NNAL in 180 active smokers was 23.2%, 21.7%, 26.9% and 28.2%, respectively. The functional knock-out polymorphism in the UGT2B10 gene at codon 67 (Asp>Tyr) was significantly (P<0.0001) associated with a 93% decrease in creatinine-adjusted NNAL-N-Gluc. The polymorphic whole-gene deletion of the UGT2B17 gene was associated with significant (P=0.0048) decreases in the levels of creatinine-adjusted (R)-NNAL-O-Gluc, with a 32% decrease in the levels of urinary (R)-NNAL-O-Gluc/(S)-NNAL-O-Gluc among subjects with the UGT2B17 (*2/*2) genotype as compared to subjects with the UGT2B17 (*1/*1) genotype. Conclusions These results suggest that functional polymorphisms in UGT2B10 and UGT2B17 are associated with a reduced detoxification capacity against NNAL and may therefore affect individual cancer risk upon exposure to tobacco. Impact This is the first report to clearly demonstrate strong genotype-phenotype associations between both the UGT2B10 codon 67 Asp

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Section: Discussionsupporting

confidence: 91%

Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers

Chen

Luo

Kozlovich

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…19, 29 In addition, UGT2B17 glucuronidates 3HC, and racial differences in the activity of this enzyme have also been reported. 30 However, variation in 3HC glucuronidation was not found to be associated with NMR or nicotine intake 31 and we have no reason to believe that there is any association between genetically determined slow glucuronidation and low CYP2A6 activity. Thus, we believe it is valid to use [cotinine + 3HC] as a measure to examine the relationship between NMR and nicotine intake within race.…”

Section: Discussionmentioning

confidence: 80%

Racial differences in the relationship between rate of nicotine metabolism and nicotine intake from cigarette smoking

Ross

Gubner

Tyndale

et al. 2016

Pharmacology Biochemistry and Behavior

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Rate of nicotine metabolism has been identified as an important factor influencing nicotine intake and can be estimated using the nicotine metabolite ratio (NMR), a validated biomarker of CYP2A6 enzyme activity. Individuals who metabolize nicotine faster (higher NMR) may alter their smoking behavior to titrate their nicotine intake in order to maintain similar levels of nicotine in the body compared to slower nicotine metabolizers. There are known racial differences in the rate of nicotine metabolism with African Americans on average having a slower rate of nicotine metabolism compared to Whites. The goal of this study was to determine if there are racial differences in the relationship between rate of nicotine metabolism and measures of nicotine intake assessed using multiple biomarkers of nicotine and tobacco smoke exposure. Using secondary analyses of the screening data collected in a recently completed clinical trial, treatment-seeking African American and White daily smokers (10 or more cigarettes per day) were grouped into NMR quartiles so that the races could be compared at the same NMR, even though the distribution of NMR within race differed. The results indicated that rate of nicotine metabolism is a more important factor influencing nicotine intake in White smokers. Specifically, Whites were more likely to titrate their nicotine intake based on the rate at which they metabolize nicotine. However, this relationship was not found in African Americans. Overall there was a greater step down, linear type relationship between NMR groups and cotinine or cotinine/cigarette in African Americans, which is consistent with the idea that differences in blood cotinine levels between the African American NMR groups were primarily due to differences in CYP2A6 enzyme activity without titration of nicotine intake among faster nicotine metabolizers.

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“…27, 38, 42–44 Three enzymes, UGT1A9, 20, 45 UGT2B7 20, 45, 46 and UGT2B17, 40, 45, 47, 48 were previously found to mediate hepatic NNAL- O -Gluc formation in humans, with UGT2B17 exhibiting the lowest K M in vitro . While both UGTs 1A4 20, 27, 39, 45, 49 and 2B10 44, 45, 49 mediate NNAL- N -Gluc formation in humans, 27, 38, 39, 43, 50, 51 UGT2B10 was shown to account for ~95% of total hepatic NNAL- N -Gluc activity ex vivo. 49 …”

Section: Introductionmentioning

confidence: 99%

“…39, 40 This variation was suggested to be, in part, mediated by genetic polymorphisms in UGT2B17 and UGT2B10. Previous studies have shown that the prevalent UGT2B17 whole-gene deletion polymorphism [31-33% allelic prevalence in Caucasians] 48, 52–54 and the UGT2B10 codon 67 Asp>Tyr SNP [9.1% allelic prevalence in Caucasians] 45, 55 are associated with large variability in hepatic NNAL- O -Gluc and NNAL- N -Gluc formation activities, respectively. 40, 44, 45, 48, 49 In addition, the UGT2B17 gene deletion polymorphism was significantly associated with lung cancer risk in women.…”

Section: Introductionmentioning

confidence: 99%

Stereospecific Metabolism of the Tobacco-Specific Nitrosamine, NNAL

Kozlovich

Chen

Lazarus

2015

Chem. Res. Toxicol.

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Among the most potent carcinogens in tobacco are the tobacco-specific nitrosamines (TSNAs), with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) the most abundant as well as the most potent. NNK is extensively metabolized to the equally carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Of the two NNAL enantiomers, (S)-NNAL appears to be preferentially glucuronidated and excreted in humans, but also exhibits higher stereoselective tissue retention in mice and humans and has been shown to be more carcinogenic in mice than its (R)- counterpart. Due to the differential carcinogenic potential of the two NNAL enantiomers, it is increasingly important to know which UGT enzyme targets the specific NNAL enantiomers for glucuronidation. To examine this, a chiral separation method was developed to isolate entiomerically pure (S)- and (R)-NNAL. Comparison of NNAL glucuronide (Gluc) peaks formed in reactions of UGT2B7-, UGT2B17-, UGT1A9-, and UGT2B10-over-expressing cell microsomes with pure NNAL enantiomers showed large differences in kinetics for (S)- versus (R)-NNAL, indicating varying levels of enantiomeric preference for each enzyme. UGT2B17 preferentially formed (R)-NNAL-O-Gluc and UGT2B7 preferentially formed (S)-NNAL-O-Gluc. When human liver microsomes (HLM) were independently incubated with each NNAL enantiomer, the ratio of (R)-NNAL-O-Gluc to (S)-NNAL-O-Gluc formation in HLM from subjects exhibiting the homozygous deletion UGT2B17 (*2/*2) genotype was significantly lower (p=0.012) than HLM from wild-type (*1/*1) subjects. There was a significant trend (p=0.015) towards decreased (R)-NNAL-O-Gluc:(S)-NNAL-O-Gluc ratio with increasing numbers of the UGT2B17*2 deletion allele. These data demonstrate that variations in the expression or activity of specific UGTs may affect individual susceptibility to cancers induced by specific NNAL enantiomers.

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UGT1A and UGT2B Genetic Variation Alters Nicotine and Nitrosamine Glucuronidation in European and African American Smokers

Cited by 28 publications

References 57 publications

Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers

Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers

Racial differences in the relationship between rate of nicotine metabolism and nicotine intake from cigarette smoking

Stereospecific Metabolism of the Tobacco-Specific Nitrosamine, NNAL

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