title: Effects of beta-estradiol and propofol on the 4-methylumbelliferone glucuronidation in recombinant human UGT isozymes 1A1, 1A8 and 1A9.
abstract: The effects of beta-estradiol and propofol on human UGT1A1, 1A8 and 1A9 activities were investigated using 4-methylumbelliferone (4-MU) as a substrate for glucuronidation. The formation of 4-MU glucuronide (4-MUG) from 4-MU, in recombinant human UGT 1A1, 1A8 and 1A9 was determined using HPLC with fluorescence detection. The glucuronidation activity of 4-MU was the highest in UGT1A9 with an apparent K(m) value of 8.3 microM, while that in UGT1A1 and 1A8 was linear to at least 100 microM. beta-estradiol had potent inhibitory effects on UGT1A9 as well as on UGT1A1 with IC(50) values of 2.1 and 7.2 microM, respectively. Propofol inhibited UGT1A9 activity with an IC(50) of 55 microM, while the IC(50) value was much higher for UGT1A8. In contrast, beta-estradiol and propofol activated 4-MU glucuronidation in UGT1A1 and 1A8, respectively. This study therefore indicates that the use of beta-estradiol as a specific inhibitor for UGT1A1 should be used with care in the identification of UGT isozymes responsible for glucuronidation in human liver microsomes.
authors.affiliation: Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co Ltd., 1-8, Azusawa 1-Chome, Itabashi-ku, Tokyo, Japan. mano@yamanouchi.co.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mano
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kamimura
mesh_terms: D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000378:metabolism*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007527:Isoenzymes; D015742:Propofol / Q000494:pharmacology*; D000099148:UGT1A1 Enzyme
chemical_list: D004958:Estradiol; D014453:Glucuronosyltransferase; D006923:Hymecromone; D006993:Hypnotics and Sedatives; D007527:Isoenzymes; D015742:Propofol; D000099148:UGT1A1 Enzyme; C454320:UDP-glucuronosyltransferase, UGT1A8