UDP-glucuronosyltransferase 1A10: activity against the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and a potential role for a novel UGT1A10 promoter deletion polymorphism in cancer susceptibility. Other Scholarly Work

Balliet, Rene M, Chen, Gang, Dellinger, Ryan W et al. (2010). UDP-glucuronosyltransferase 1A10: activity against the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and a potential role for a novel UGT1A10 promoter deletion polymorphism in cancer susceptibility. . 38(3), 484-490. 10.1124/dmd.109.030569

cited authors

  • Balliet, Rene M; Chen, Gang; Dellinger, Ryan W; Lazarus, Philip

fiu authors

abstract

  • The extrahepatic UDP-glucuronosyltransferase 1A10 (UGT1A10) is a phase II metabolizing enzyme that is active against a number of potent carcinogens. In the present study, UGT1A10 was examined for activity against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the major procarcinogenic metabolite of the potent tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and the promoter region of UGT1A10 was examined for variants that could lead to altered UGT1A10 expression. UGT1A10-overexpressing cell homogenates exhibited high O-glucuronidation activity against NNAL (K(M) = 5.95 mM). A 2000-base pair (bp) product corresponding to the UGT1A10 proximal promoter region was polymerase chain reaction (PCR)-amplified using genomic DNA from 97 white subjects, and 42 of these were sequenced. In addition to a previously reported C/G single-nucleotide polymorphism at -1271 bp (rs2741032), a novel 1664-bp deletion located between nucleotides -190 to -1856 relative to the UGT1A10 translation start site was identified. Using real-time multiplex PCR, this deletion exhibited a prevalence of 0.022 in whites (n = 156) and 0.056 in blacks (n = 133). To determine whether either polymorphism altered gene expression, in vitro assays were performed using luciferase constructs containing up to 2000 bp of the proximal UGT1A10 promoter. Constructs containing the 1664-bp deletion exhibited a significant (p = 0.009) 3-fold increase in luciferase activity compared with constructs containing the wild-type UGT1A10 promoter. No effect on luciferase activity was observed for the UGT1A10(-1271G) promoter variant. These data are consistent with previous studies that indicate the presence of a transcriptional repressor element within the newly identified deletion and that this deletion polymorphism may contribute to altered UGT1A10 expression and altered carcinogen detoxification between individuals.

publication date

  • March 1, 2010

keywords

  • Caco-2 Cells
  • Carcinogens
  • Carcinoma, Hepatocellular
  • Gene Expression Regulation, Neoplastic
  • Gene Frequency
  • Genes, Reporter
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genomic Structural Variation
  • Glucuronosyltransferase
  • Humans
  • Isoenzymes
  • Liver Neoplasms
  • Metabolic Detoxication, Phase II
  • Minor Histocompatibility Antigens
  • Nitrosamines
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Pyridines
  • Sequence Deletion

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • 484

end page

  • 490

volume

  • 38

issue

  • 3