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First published on April 4, 2006; DOI: 10.1124/dmd.106.009621

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Received for publication February 6, 2006.
Revised March 28, 2006.
Accepted for publication March 29, 2006.

Human UDP-glucuronosyltransferase, UGT1A8, Glucuronidates Dihydrotestosterone to a Monoglucuronide and Further to a Structurally Novel Diglucuronide

Takahiro Murai 1*, Naozumi Samata 1, Haruo Iwabuchi 1, Toshihiko Ikeda 1

1 Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.

* Address correspondence to: E-mail: tmurai{at}sankyo.co.jp

Abstract

We identified human UDP-glucuronosyltransferase (UGT) isoforms responsible for producing dihydrotestosterone (DHT) diglucuronide, a novel glucuronide where 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.


Key words: enzyme kinetics, glucuronidation, liver microsomes, mass spectrometry, metabolite identification, microsomes, steroids, structure elucidation, UDP glucuronyltransferases


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