Journal
PHARMACOGENETICS AND GENOMICS
Volume 18, Issue 3, Pages 181-191Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FPC.0b013e3282f4dbdd
Keywords
haplotype; liver; 4-(methyinitrosaimino)-1-(3-pyridyl)-1-butane; polymorphism; tobacco-specific nitrosamines; UDP-glucuronosyltransferase; UGT2B10
Funding
- NCI NIH HHS [P01-CA68384, P01 CA068384] Funding Source: Medline
- NIDCR NIH HHS [R01 DE013158, R01-DE13158] Funding Source: Medline
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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.
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