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.

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.

• Authors: Rene M Balliet, Gang Chen, Ryan W Dellinger, Philip Lazarus
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 38 Issue 3 Pg. 484-90 (Mar 2010) ISSN: 1521-009X [Electronic] United States
• PMID: 20007297 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Isoenzymes
• Minor Histocompatibility Antigens
• Nitrosamines
• Pyridines
• bilirubin glucuronoside glucuronosyltransferase
• bilirubin uridine-diphosphoglucuronosyl transferase 1A10
• Glucuronosyltransferase
• UGT2B17 protein, human
• 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol

Topics

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