title: Effect of UDP-glucuronosyltransferase 2B15 polymorphism on bisphenol A glucuronidation.
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.
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama, Japan. nhanioka@cc.okayama-u.ac.jp
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Hanioka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Oka
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Nagaoka
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ikushiro
authors.forename: Shizuo
authors.initials: S
authors.lastname: Narimatsu
mesh_terms: D000395:Air Pollutants, Occupational / Q000633:toxicity*; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001559:Benzhydryl Compounds; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007313:Insecta; D008862:Microsomes, Liver / Q000201:enzymology; D010636:Phenols / Q000633:toxicity*; D010957:Plasmids / Q000235:genetics; D011110:Polymorphism, Genetic; D000098826:Bisphenol A Compounds
chemical_list: D000395:Air Pollutants, Occupational; D001559:Benzhydryl Compounds; D020719:Glucuronides; D014453:Glucuronosyltransferase; D010636:Phenols; C472000:UDP-glucuronosyltransferase 2B15, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds