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Drug Metabolism and Disposition Fast Forward
First published on April 4, 2006; DOI: 10.1124/dmd.106.009621

0090-9556/06/3407-1102-1108$20.00
DMD 34:1102-1108, 2006

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HUMAN UDP-GLUCURONOSYLTRANSFERASE, UGT1A8, GLUCURONIDATES DIHYDROTESTOSTERONE TO A MONOGLUCURONIDE AND FURTHER TO A STRUCTURALLY NOVEL DIGLUCURONIDE

Takahiro Murai, Naozumi Samata, Haruo Iwabuchi, and Toshihiko Ikeda

Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan

We identified human UDP-glucuronosyltransferase (UGT) isoforms responsible for producing dihydrotestosterone (DHT) diglucuronide, a novel glucuronide in which the second glucuronosyl moiety is attached at the C2' position of the first glucuronosyl moiety, leading to diglucuronosyl conjugation of a single hydroxyl group of DHT at the C17 position. Incubation of the DHT monoglucuronide with 12 cDNA-expressed recombinant human UGT isoforms and uridine 5'-diphosphoglucuronic acid resulted in a low but measurable DHT diglucuronidation activity primarily with UGT1A8, a gastrointestinal UGT, and to a lesser extent with UGT1A1 and UGT1A9. In contrast, the activity of DHT monoglucuronidation was high and was found in UGT2B17, UGT2B15, UGT1A8, and UGT1A4 in descending order. Among the 12 UGT isoforms tested, only UGT1A8 was capable of producing DHT diglucuronide from DHT. The kinetics of DHT diglucuronidation by microsomes from human liver and intestine fitted the Michaelis-Menten model, and the Vmax/Km value for the intestinal microsomes was approximately 4 times greater than that for the liver microsomes.

Address correspondence to: Takahiro Murai, Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. E-mail: tmurai{at}sankyo.co.jp




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T. Murai, N. Yamamura, T. Nitanai, N. Samata, M. Takei, H. Iwabuchi, K. Tanaka, K. Mikamoto, and T. Ikeda
Isolation and Identification of Diglucuronides of Some Endogenous Steroids in Dogs
Drug Metab. Dispos., February 1, 2008; 36(2): 368 - 374.
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