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

Pharmacogenet Genomics. 2008 Mar;18(3):181-91. doi: 10.1097/FPC.0b013e3282f4dbdd.

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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Base Sequence
  • Cell Line
  • DNA Primers / genetics
  • DNA, Complementary / genetics
  • Glucuronosyltransferase / antagonists & inhibitors*
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism
  • Haplotypes
  • Humans
  • Liver / enzymology
  • Mutation, Missense*
  • Neoplasms / etiology
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nitrosamines / metabolism*
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Smoking / adverse effects
  • Smoking / genetics
  • Smoking / metabolism
  • Tobacco / chemistry

Substances

  • DNA Primers
  • DNA, Complementary
  • Nitrosamines
  • Recombinant Proteins
  • Glucuronosyltransferase