title: Glucuronidation of mono(2-ethylhexyl) phthalate in humans: roles of hepatic and intestinal UDP-glucuronosyltransferases.
abstract: Mono(2-ethylhexyl) phthalate (MEHP) is an active metabolite of di(2-ethylhexyl) phthalate (DEHP), which is an endocrine-disrupting chemical. In the present study, MEHP glucuronidation in humans was studied using recombinant UDP-glucuronosyltransferases (UGTs) and microsomes of the liver and intestine. Among the recombinant UGTs examined, UGT1A3, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, and UGT2B7 glucuronidated MEHP. The kinetics of MEHP glucuronidation by UGT1A3, UGT1A7, UGT1A8, UGT1A10, UGT2B4, and UGT2B7 followed the Michaelis-Menten model, whereas that by UGT1A9 fit the negative allosteric model. CLintvalues were in the order of UGT1A9 > UGT2B7 > UGT1A7 > UGT1A8 ≥ UGT1A10 > UGT1A3 > UGT2B4. The kinetics of MEHP glucuronidation by liver microsomes followed the Michaelis-Menten model. Diclofenac (20 µM) and raloxifene (20 µM) decreased CLintvalues to 43 and 36 % that of native microsomes, respectively. The kinetics of MEHP glucuronidation by intestine microsomes fit the biphasic model. Diclofenac (150 and 450 µM) decreased CLintvalues to 32 and 13 % that of native microsomes for the high-affinity phase, and to 28 and 21 % for the low-affinity phase, respectively. Raloxifene (2.5 and 7.0 µM) decreased CLintvalues to 35 and 4.1 % that of native microsomes for the high-affinity phase, and to 48 and 53 % for the low-affinity phase, respectively. These results suggest that MEHP glucuronidation in humans is catalyzed by UGT1A3, UGT1A9, UGT2B4, and/or UGT2B7 in the liver, and by UGT1A7, UGT1A8, UGT1A9, UGT1A10, and/or UGT2B7 in the intestine, and also that these UGT isoforms play important and characteristic roles in the detoxification of DEHP.
authors.affiliation: Laboratory of Xenobiotic Metabolism, Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, 245-0066, Japan. nhanioka@hamayaku.ac.jp.
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Hanioka
authors.affiliation: Laboratory of Health Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama, 700-8530, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kinashi
authors.affiliation: Laboratory of Environmental Toxicology, Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, 245-0066, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka-Kagawa
authors.affiliation: Laboratory of Xenobiotic Metabolism, Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, 245-0066, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Laboratory of Hygienic Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Jinno
mesh_terms: D004008:Diclofenac / Q000494:pharmacology; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D052244:Endocrine Disruptors / Q000378:metabolism / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008962:Models, Theoretical; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D011994:Recombinant Proteins; D004008:Diclofenac; D020849:Raloxifene Hydrochloride; D004051:Diethylhexyl Phthalate; D014453:Glucuronosyltransferase; C016599:mono-(2-ethylhexyl)phthalate
keywords: Glucuronidation; Human intestine microsomes; Human liver microsomes; Mono(2-ethylhexyl) phthalate (MEHP); Recombinant human UGT; UDP-glucuronosyltransferase (UGT)