Effects of beta-estradiol and propofol on the 4-methylumbelliferone glucuronidation in recombinant human UGT isozymes 1A1, 1A8 and 1A9

Biopharmaceutics & Drug Disposition
Yuji ManoHidetaka Kamimura

Abstract

The effects of beta-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 K(m) value of 8.3 microM, while that in UGT1A1 and 1A8 was linear to at least 100 microM. beta-estradiol had potent inhibitory effects on UGT1A9 as well as on UGT1A1 with IC(50) values of 2.1 and 7.2 microM, respectively. Propofol inhibited UGT1A9 activity with an IC(50) of 55 microM, while the IC(50) value was much higher for UGT1A8. In contrast, beta-estradiol and propofol activated 4-MU glucuronidation in UGT1A1 and 1A8, respectively. This study therefore indicates that the use of beta-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.

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Citations

Jan 25, 2007·European Journal of Clinical Pharmacology·Yuji ManoHidetaka Kamimura
Jul 11, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kristine C OlsonPhilip Lazarus
Mar 24, 2015·Expert Opinion on Drug Metabolism & Toxicology·Zoe Riches, Abby C Collier
May 31, 2006·Biopharmaceutics & Drug Disposition·Yuji ManoHidetaka Kamimura
Jul 31, 2013·Journal of Veterinary Pharmacology and Therapeutics·C D van BeusekomJ A Schrickx
Apr 15, 2015·Journal of the National Cancer Institute·Travis J YatesVinata B Lokeshwar
Nov 9, 2016·Frontiers in Pharmacology·Ryoichi FujiwaraMiki Nakajima
Sep 12, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Sara AlgeelaniDavid J Greenblatt
Sep 9, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kimberly LaphamAmit S Kalgutkar
May 29, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hirotada ShirataniTsuyoshi Yokoi
Jun 27, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hiroyuki YamanakaTsuyoshi Yokoi
Jan 23, 2013·Chemical Communications : Chem Comm·Takuya TeraiTetsuo Nagano
Oct 8, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hiroyuki YamanakaTsuyoshi Yokoi

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