Glucuronidation of mono(2-ethylhexyl) phthalate in humans: roles of hepatic and intestinal UDP-glucuronosyltransferases

• Published in: Archives of toxicology Vol. 91; no. 2; pp. 689 - 698
• Main Authors: Hanioka, Nobumitsu, Kinashi, Yu, Tanaka-Kagawa, Toshiko, Isobe, Takashi, Jinno, Hideto
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2017; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Diclofenac - pharmacology; Diethylhexyl Phthalate - analogs & derivatives; Diethylhexyl Phthalate - metabolism; Diethylhexyl Phthalate - pharmacokinetics; Endocrine Disruptors - metabolism; Endocrine Disruptors - pharmacokinetics; Environmental Health; Enzymes; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Humans; Intestines - drug effects; Intestines - metabolism; Liver; Metabolites; Microsomes - drug effects; Microsomes - metabolism; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Models, Theoretical; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Raloxifene Hydrochloride - pharmacology; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Small intestine; Toxicity; Toxicokinetics and Metabolism; UDP-glucuronosyltransferase (UGT); Human liver microsomes; Mono(2-ethylhexyl) phthalate (MEHP); Glucuronidation; Recombinant human UGT; Human intestine microsomes
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-016-1708-9

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. CL int values 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 CL int values 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 CL int values 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 CL int values 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.