Effect of UDP-glucuronosyltransferase 2B15 polymorphism on bisphenol A glucuronidation

Nobumitsu Hanioka, Hiroyuki Oka, Kenjiro Nagaoka, Shinichi Ikushiro, Shizuo Narimatsu

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Bisphenol A (BPA) is one of a number of potential endocrine-disrupting chemicals, which are metabolized mainly by UDP-glucuronosyltransferase 2B15 (UGT2B15) in humans. Six UGT2B15 allelic variants (UGT2B15*2, UGT2B15*3, UGT2B15*4, UGT2B15*5, UGT2B15*6, and UGT2B15*7; wild-type, UGT2B15*1) with amino acid substitutions have been found in Caucasian, African-American, Hispanic, and Oriental populations to date. In this study, the effects of amino acid substitutions in UGT2B15 on BPA glucuronidation were studied using recombinant UGT2B15 enzymes of wild-type (UGT2B15.1) and all identified variants (UGT2B15.2, UGT2B15.3, UGT2B15.4, UGT2B15.5, UGT2B15.6, and UGT2B15.7) expressed in insect (Sf9) cells. The K m, V max, and CL int values of UGT2B15.1 for BPA glucuronidation were 3.9 μM, 650 pmol/min/mg protein, and 170 μL/min/mg protein, respectively. Although there is no significant difference in the K m value between wild-type and any variant UGT2B15, the V max and CL int values of UGT2B15 variants having D85Y substitution were markedly reduced to 14 and 10% for UGT2B15.2, and 4.3 and 3.9% for UGT2B15.5 compared with those of UGT2B15.1, respectively. However, the K m, V max, and CL int values of UGT2B15.3, UGT2B15.4, UGT2B15.6, and UGT2B15.7 having L86S, T352I, and/or K523T substitution(s) for BPA glucuronidation were comparable to those of UGT2B15.1. These findings suggest that D85Y substitution in UGT2B15 decreases enzymatic function and that the polymorphic alleles of UGT2B15 are closely associated with variations in the metabolism and toxicity of BPA. The information gained in this study should help with in vivo extrapolation to assess the toxicity of endocrine-disrupting chemicals.

Original languageEnglish
Pages (from-to)1373-1381
Number of pages9
JournalArchives of Toxicology
Volume85
Issue number11
DOIs
Publication statusPublished - Nov 2011

Keywords

  • Bisphenol A
  • Genetic polymorphism
  • Glucuronidation
  • UDP-glucuronosyltransferase 2B15 (UGT2B15)

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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