Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers. Article

Chen, Gang, Luo, Shaman, Kozlovich, Shannon et al. (2016). Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers. . 25(7), 1175-1184. 10.1158/1055-9965.epi-15-1245

cited authors

  • Chen, Gang; Luo, Shaman; Kozlovich, Shannon; Lazarus, Philip

fiu authors

abstract

  • Background

    The most abundant and potent carcinogenic tobacco-specific nitrosamine 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. The goal of the present study was to directly examine the role of UGT genotypes on urinary levels of NNAL glucuronides in smokers.

    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 functional knockout 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

publication date

  • July 1, 2016

keywords

  • Carcinogens
  • Genotype
  • Glucuronates
  • Glucuronides
  • Glucuronosyltransferase
  • Humans
  • Isomerism
  • Minor Histocompatibility Antigens
  • Neoplasms, Glandular and Epithelial
  • Nitrosamines
  • Polymorphism, Genetic
  • Pyridines
  • Smoking
  • Tobacco Products

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • 1175

end page

  • 1184

volume

  • 25

issue

  • 7