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Keywords:

  • UGT isozymes;
  • inhibition;
  • 4-methylumbelliferone

Abstract

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 Km value of 8.3 µM, while that in UGT1A1 and 1A8 was linear to at least 100 µM. β-estradiol had potent inhibitory effects on UGT1A9 as well as on UGT1A1 with IC50 values of 2.1 and 7.2 µM, respectively. Propofol inhibited UGT1A9 activity with an IC50 of 55 µM, while the IC50 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.