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Substrate‐Dependent Modulation of UDP‐Glucuronosyltransferase 1A1 (UGT1A1) by Propofol in Recombinant Human UGT1A1 and Human Liver Microsomes
Author(s) -
Mano Yuji,
Usui Takashi,
Kamimura Hidetaka
Publication year - 2007
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2007.00112.x
Subject(s) - glucuronidation , microsome , recombinant dna , chemistry , substrate (aquarium) , propofol , microsoma , glucuronosyltransferase , enzyme , ic50 , biochemistry , pharmacology , in vitro , biology , ecology , gene
Our previous study has shown that propofol, a probe substrate for human UDP‐glucuronosyltransferase (UGT) 1A9, activated the glucuronidation of 4‐methylumbelliferone (4‐MU) by recombinant UGT1A1 in a concentration‐dependent manner. In the present study, we investigated the mechanism of activation, and whether the stimulatory effect occurs when another substrate is used with human liver microsomes. The glucuronidation of 4‐MU followed Michaelis‐Menten kinetics with a K m value of 101 µM in the absence of propofol. In the presence of 200 µM propofol, a concentration that causes heterotopic activation of 4‐MU glucuronidation (4‐MUG), the V max value increased to 1.5‐fold, while the K m value decreased to 0.53‐fold. In order to assess whether propofol activates UGT1A1 activity for a substrate other than 4‐MU, the effect of propofol on oestradiol 3β‐glucuronidation by recombinant UGT1A1 and in human liver microsomes was evaluated. In contrast to 4‐MUG activity, propofol inhibited UGT1A1‐catalysed oestradiol 3β‐glucuronidation in recombinant UGT1A1 as well as in human liver microsomes with IC 50 values of 59 and 228 µM, respectively. In addition, a known UGT1A1 modulator, 17α‐ethynyloestradiol, stimulated oestradiol 3β‐glucuronidation slightly at a concentration of 5 µM, while it inhibited 4‐MUG in recombinant UGT1A1 at all concentrations tested (5–100 µM). These findings indicate that the modulation of UGT1A1 by propofol is substrate‐dependent, and thus care should be taken when extrapolating the stimulatory effects of drugs for one glucuronidation substrate.