Stereoselective glucuronidation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin by human UDP-glucuronosyltransferase (UGT) 1A1, UGT1A9, and UGT2B15: effects of UGT-UGT interactions.
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Nakajima M, Yamanaka H, Fujiwara R, Katoh M, Yokoi T
Stereoselective glucuronidation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin by human UDP-glucuronosyltransferase (UGT) 1A1, UGT1A9, and UGT2B15: effects of UGT-UGT interactions.
Drug Metab Dispos. 2007 Sep;35(9):1679-86. doi: 10.1124/dmd.107.015909. Epub 2007 Jun 18.
- PubMed ID
- 17576806 [ View in PubMed]
- 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 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 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. By using UGT1A double-expression systems in HEK293 cells that we previously established, the effects of UGT-UGT interactions on 4'-HPPH O-glucuronide formation were investigated. It was demonstrated that coexpression of UGT1A4 increased the V(max) values of (S)- and (R)-4'-HPPH O-glucuronide formation catalyzed by UGT1A1 but decreased the V(max) values of (S)- and (R)-4'-HPPH O-glucuronide formation catalyzed by UGT1A9. Coexpression of UGT1A6 increased the S(50) values and decreased the V(max) 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Deferasirox UDP-glucuronosyltransferase 1-9 Protein Humans UnknownInhibitorDetails