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*ETOPOSIDE

Vol. 31, Issue 5, 589-595, May 2003

Glucuronidation of Etoposide in Human Liver Microsomes Is Specifically Catalyzed by UDP-Glucuronosyltransferase 1A1

Yuichiro Watanabe, Miki Nakajima, Noriko Ohashi, Toshiyuki Kume, and Tsuyoshi Yokoi

Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (Y.W., M.N., T.Y.); and Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan (N.O., T.K.)

A metabolite formed by incubation of human liver microsomes, etoposide, and UDP-glucuronic acid was identified as etoposide glucuronide by liquid chromatography-tandem mass spectrometry analysis. According to the derivatization with trimethylsilylimidazole (Tri-Sil-Z), it was confirmed that the glucuronic acid is linked to an alcoholic hydroxyl group of etoposide and not to a phenolic group. Among nine recombinant human UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9. UGT1A10, UGT2B7, and UGT2B15), only UGT1A1 exhibited the catalytic activity of etoposide glucuronidation. The enzyme kinetics in pooled human liver microsomes and recombinant UGT1A1 microsomes showed a typical Michaelis-Menten plot. The kinetic parameters of etoposide glucuronidation were Km = 439.6 ± 70.7 µM and Vmax = 255.6 ± 19.2 pmol/min/mg of protein in human liver microsomes and Km = 503.2 ± 110.2 µM and Vmax = was 266.5 ± 28.6 pmol/min/mg of protein in recombinant UGT1A1. The etoposide glucuronidation in pooled human liver microsomes was inhibited by bilirubin (IC50 = 31.7 µM) and estradiol (IC50 = 34 µM) as typical substrates for UGT1A1. The inhibitory effects of 4-nitrophenol (IC50 = 121.0 µM) as a typical substrate for UGT1A6 and UGT1A9, imipramine (IC50 = 393.8 µM) as a typical substrate for UGT1A3 and UGT1A4, and morphine (IC50 = 109.3 µM) as a typical substrate for UGT2B7 were relatively weak. The interindividual difference in etoposide glucuronidation in 13 human liver microsomes was 78.5-fold (1.4-109.9 pmol/min/mg of protein). The etoposide glucuronidation in 10 to 13 human liver microsomes was significantly correlated with beta -estradiol-3-glucuronidation (r = 0.841, p < 0.01), bilirubin glucuronidation (r = 0.935, p < 0.01), and the immunoquantified UGT1A1 protein content (r = 0.800, p < 0.01). These results demonstrate that etoposide glucuronidation in human liver microsomes is specifically catalyzed by UGT1A1.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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