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

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 variant, microsomes from HEK293 cells over expressing the UGT2B10 variant exhibited minimal glucuronide formation activity against NNAL or other tobacco-specific nitrosamines tested in vitro. CONCLUSIONS: The UGT2B10 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.

Original languageEnglish (US)
Pages (from-to)181-191
Number of pages11
JournalPharmacogenetics and Genomics
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2008

Fingerprint

Nitrosamines
Haplotypes
Tobacco
Liver Microsomes
Genes
HEK293 Cells
Microsomes
Human Activities
Single Nucleotide Polymorphism
Glucuronosyltransferase
Glucuronides
Aspartic Acid
Codon
Tyrosine
Complementary DNA
Smoking
Genotype
High Pressure Liquid Chromatography
Amino Acids
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

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title = "Identification of a prevalent functional missense polymorphism in the UGT2B10 gene and its association with UGT2B10 inactivation against tobacco-specific nitrosamines",
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 variant, microsomes from HEK293 cells over expressing the UGT2B10 variant exhibited minimal glucuronide formation activity against NNAL or other tobacco-specific nitrosamines tested in vitro. CONCLUSIONS: The UGT2B10 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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Identification of a prevalent functional missense polymorphism in the UGT2B10 gene and its association with UGT2B10 inactivation against tobacco-specific nitrosamines. / Chen, Gang; Dellinger, Ryan W.; Gallagher, Carla J.; Sun, Dongxiao; Lazarus, Philip.

In: Pharmacogenetics and Genomics, Vol. 18, No. 3, 01.03.2008, p. 181-191.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of a prevalent functional missense polymorphism in the UGT2B10 gene and its association with UGT2B10 inactivation against tobacco-specific nitrosamines

AU - Chen, Gang

AU - Dellinger, Ryan W.

AU - Gallagher, Carla J.

AU - Sun, Dongxiao

AU - Lazarus, Philip

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N2 - 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 variant, microsomes from HEK293 cells over expressing the UGT2B10 variant exhibited minimal glucuronide formation activity against NNAL or other tobacco-specific nitrosamines tested in vitro. CONCLUSIONS: The UGT2B10 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.

AB - 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 variant, microsomes from HEK293 cells over expressing the UGT2B10 variant exhibited minimal glucuronide formation activity against NNAL or other tobacco-specific nitrosamines tested in vitro. CONCLUSIONS: The UGT2B10 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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