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Drug Metabolism and Disposition Fast Forward
First published on June 18, 2007; DOI: 10.1124/dmd.107.015909

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Received for publication March 26, 2007.
Revised June 11, 2007.
Accepted for publication June 13, 2007.

Stereoselective glucuronidation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin by human UGT1A1, UGT1A9, and UGT2B15: effects of UGT-UGT interactions

Miki Nakajima 1, Hiroyuki Yamanaka 1, Ryoichi Fujiwara 1, Miki Katoh 1, Tsuyoshi Yokoi 1*

1 Kanazawa University

* Address correspondence to: E-mail: tyokoi{at}kenroku.kanazawa-u.ac.jp

Abstract

5-(4'-Hydroxyphenyl)-5-phenylhydantoin (4'-HPPH), a major metabolite of phenytoin in human, is exclusively metabolized to a glucuronide. 4'-HPPH has a chiral center. (S)-4'-HPPH is a predominant form produced from phenytoin in humans, and (R)-4'-HPPH is an extremely toxic form with respect to gingival hyperplasia. In the present study, we investigated the stereoselective 4'-HPPH O-glucuronide formation in human liver microsomes. Human liver microsomes predominantly formed (S)-4'-HPPH O-glucuronide rather than (R)-4'-HPPH O-glucuronide from racemic 4'-HPPH. Among human UDP-glucuronosyltransferase (UGT) enzymes, UGT1A1, UGT1A9, and UGT2B15 showed the 4'-HPPH O-glucuronide formation. Interestingly, UGT1A1 stereoselectively formed (R)-4'-HPPH O-glucuronide, whereas UGT1A9 and UGT2B15 stereoselectively formed (S)-4'-HPPH O-glucuronide from racemic 4'-HPPH. Using UGT1A double expression systems in HEK293 cells that we previously established, the effects of UGT-UGT interaction on 4'-HPPH O-glucuronide formation were investigated. It was demonstrated that coexpression of UGT1A4 increased the Vmax values of (S)- and (R)-4'-HPPH O-glucuronide formation catalyzed by UGT1A1, but decreased the Vmax values of (S)- and (R)-4'-HPPH O-glucuronide formation catalyzed by UGT1A9. Coexpression of UGT1A6 increased the S50 values and decreased the Vmax values of (S)- and (R)-4'-HPPH glucuronide formation catalyzed by UGT1A1 and UGT1A9. However, the interaction did not alter the stereoselectivity. In conclusion, we found that 4'-HPPH O-glucuronide formation in human liver microsomes is catalyzed by UGT1A1, UGT1A9, and UGT2B15 in a stereoselective manner, being modulated by interaction with other UGT1A isoforms.


Key words: glucuronidation, phase II drug metabolism, UDP glucuronyltransferases


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 Drug Metab. Dispos.Home page
R. Fujiwara, M. Nakajima, H. Yamanaka, and T. Yokoi
Key Amino Acid Residues Responsible for the Differences in Substrate Specificity of Human UDP-Glucuronosyltransferase (UGT)1A9 and UGT1A8
Drug Metab. Dispos., January 1, 2009; 37(1): 41 - 46.
[Abstract] [Full Text] [PDF]


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