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Effects of β ‐estradiol and propofol on the 4‐methylumbelliferone glucuronidation in recombinant human UGT isozymes 1A1, 1A8 and 1A9
Author(s) -
Mano Yuji,
Usui Takashi,
Kamimura Hidetaka
Publication year - 2004
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.418
Subject(s) - glucuronidation , isozyme , recombinant dna , chemistry , microsome , biochemistry , glycosyltransferase , glucuronosyltransferase , enzyme , gene
The effects of β ‐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 µ M , while that in UGT1A1 and 1A8 was linear to at least 100 µ M . β ‐estradiol had potent inhibitory effects on UGT1A9 as well as on UGT1A1 with IC 50 values of 2.1 and 7.2 µ M , respectively. Propofol inhibited UGT1A9 activity with an IC 50 of 55 µ M , while the IC 50 value was much higher for UGT1A8. In contrast, β ‐estradiol and propofol activated 4‐MU glucuronidation in UGT1A1 and 1A8, respectively. This study therefore indicates that the use of β ‐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. Copyright © 2004 John Wiley & Sons, Ltd.