Variation in Levels of the Lung Carcinogen NNAL and Its Glucuronides in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer

Park, Sungshim L.; Carmella, Steven G.; Ming, Xun; Vielguth, Elizabeth; Stram, Daniel O.; Marchand, Loı̈c Le; Hecht, Stephen S.

doi:10.1158/1055-9965.epi-14-1054

Cited by 41 publications

(50 citation statements)

References 47 publications

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“…This methodology incorporates several sample processing steps and corresponding LC-MS runs using up to 180 μL of urine specimen and a nano-LC-MS instrument (35). This method is sensitive, reaching levels as low as 0.10 nM for the quantification of urinary free NNAL (35, 46). Limitations of this procedure include the fact that NNAL- N -Gluc and NNAL- O -Gluc are not directly measured, and that the ( R )- and ( S )-NNAL- O -Gluc diasteriomers are not measured individually.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…2–4, 12, 18–25 In contrast to the relatively high tumorigenicity exhibited by both ( R )- and ( S )-NNAL, glucuronidated NNAL (NNAL-Gluc) is non-tumorigenic after subcutaneous injection into A/J mice. 26 It has been shown that NNAL glucuronides are formed extensively in human liver microsomes (HLM).…”

Section: Introductionmentioning

confidence: 99%

“…20, 27 The NNAL enantiomers and their glucuronides can also be detected in the urine of past and current smokers. 3, 22–25, 28–32 It has been found that while ( S )-NNAL is stereoselectively retained in rat lung and has a higher tumorigenicity than ( R )-NNAL, ( R )-NNAL exhibits a higher rate of glucuronidation in rats 33–36 and the A/J mouse. 26, 36 However, studies indicate that ( S )-NNAL may be stereo-selectively retained in smokeless tobacco users 37 but exhibits a higher rate of glucuronidation in the patas monkey.…”

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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“…Results from several human studies demonstrate that such a ratio varies among individuals (Carmella et al, 1995;Park et al, 2015). It is possible that individuals with a low basal urinary ratio of NNAL-gluc to free NNAL may more likely benefit from DHM in reducing their lung cancer risk via enhancing/restoring their detoxification capacity.…”

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confidence: 99%

Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification

Narayanapillai

Carmella

Leitzman

et al. 2016

Drug Metabolism and Disposition

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Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM's differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O-glucuronidated NNAL (NNAL-O-gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O-glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL-O-gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents.

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Variation in Levels of the Lung Carcinogen NNAL and Its Glucuronides in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer

Cited by 41 publications

References 47 publications

Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers

Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers

Stereospecific Metabolism of the Tobacco-Specific Nitrosamine, NNAL

Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification

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