Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes

Basic Clin Pharmacol Toxicol. 2007 Sep;101(3):211-4. doi: 10.1111/j.1742-7843.2007.00112.x.


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.

MeSH terms

  • Estradiol / metabolism*
  • Ethinyl Estradiol / analogs & derivatives
  • Ethinyl Estradiol / pharmacology
  • Glucuronides / metabolism
  • Glucuronosyltransferase / metabolism*
  • Humans
  • Hymecromone / analogs & derivatives*
  • Hymecromone / metabolism
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Propofol / pharmacology*
  • Recombinant Proteins / metabolism


  • Glucuronides
  • Recombinant Proteins
  • Hymecromone
  • Ethinyl Estradiol
  • Estradiol
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Propofol