Identification of a prevalent functional missense polymorphism in the UGT2B10 gene and its association with UGT2B10 inactivation against tobacco-specific nitrosamines. Other Scholarly Work

Chen, Gang, Dellinger, Ryan W, Gallagher, Carla J et al. (2008). Identification of a prevalent functional missense polymorphism in the UGT2B10 gene and its association with UGT2B10 inactivation against tobacco-specific nitrosamines. . 18(3), 181-191. 10.1097/fpc.0b013e3282f4dbdd

cited authors

  • Chen, Gang; Dellinger, Ryan W; Gallagher, Carla J; Sun, Dongxiao; Lazarus, Philip

fiu authors

abstract

  • Objective

    To study the potential association between UDP-glucuronosyltransferase (UGT)2B10 genotypes and [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol] NNAL-N-glucuronidation activity in human liver microsomes (HLM) and to identify potential functional polymorphisms.

    Methods

    A total of 77 subjects were genotyped for three UGT2B10 tagging single nucleotide polymorphisms NNAL-N-glucuronidation activity in HLM was determined by high-pressure liquid chromatography and analyzed by UGT2B10 haplotypes.

    Results

    Four common UGT2B10 haplotypes (termed A through D) were identified. Haplotype C was found to be significantly (P<0.001) associated with lower NNAL-N-glucuronidation in HLM. A 1.8-fold and 12-fold reduction in NNAL-N-glucuronidation levels and a 1.7-fold and 11-fold reduction in the ratio of NNAL-N-Gluc: NNAL-O-Gluc, were observed in HLM from subjects with one and two copies of UGT2B10 haplotype C, respectively. A novel polymorphism resulting in an aspartic acid to tyrosine amino acid change at codon 67 of the UGT2B10 complementary DNA was identified exclusively in subjects with a haplotype C. Unlike the high activity observed in microsomes from HEK293 cells over expressing the wild-type UGT2B10(67Asp) variant, microsomes from HEK293 cells over expressing the UGT2B10(67Tyr) variant exhibited minimal glucuronide formation activity against NNAL or other tobacco-specific nitrosamines tested in vitro.

    Conclusions

    The UGT2B10(67Tyr) variant corresponding to the UGT2B10 haplotype C is a functional single nucleotide polymorphism that may be responsible for inter individual variation in NNAL-N-glucuronidation activity and may increase susceptibility to smoking-related cancers.

publication date

  • March 1, 2008

keywords

  • Amino Acid Substitution
  • Base Sequence
  • Cell Line
  • DNA Primers
  • DNA, Complementary
  • Glucuronosyltransferase
  • Haplotypes
  • Humans
  • Liver
  • Mutation, Missense
  • Neoplasms
  • Nitrosamines
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide
  • Recombinant Proteins
  • Smoking
  • Tobacco

Digital Object Identifier (DOI)

Medium

  • Print

start page

  • 181

end page

  • 191

volume

  • 18

issue

  • 3