title: Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes.
abstract: 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 microM in the absence of propofol. In the presence of 200 microM 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 3beta-glucuronidation by recombinant UGT1A1 and in human liver microsomes was evaluated. In contrast to 4-MUG activity, propofol inhibited UGT1A1-catalysed oestradiol 3beta-glucuronidation in recombinant UGT1A1 as well as in human liver microsomes with IC(50) values of 59 and 228 microM, respectively. In addition, a known UGT1A1 modulator, 17alpha-ethynyloestradiol, stimulated oestradiol 3beta-glucuronidation slightly at a concentration of 5 microM, while it inhibited 4-MUG in recombinant UGT1A1 at all concentrations tested (5-100 microM). 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.
authors: Drug Metabolism Research Laboratories, Astellas Pharma Inc., Tokyo, Japan. mano_180sx@yahoo.co.jp
authors: Yuji
authors: Y
authors: Mano
authors: Takashi
authors: T
authors: Usui
authors: Hidetaka
authors: H
authors: Kamimura
mesh_terms: D004958:Estradiol / Q000378:metabolism*; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015742:Propofol / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D004958:Estradiol; D004997:Ethinyl Estradiol; D020719:Glucuronides; D014453:Glucuronosyltransferase; D006923:Hymecromone; D015742:Propofol; D011994:Recombinant Proteins; D000099148:UGT1A1 Enzyme