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 Km 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 Vmax value increased to 1.5-fold, while the Km 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 IC50 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.