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Drug Metabolism and Disposition Fast Forward
First published on November 8, 2007; DOI: 10.1124/dmd.107.018788

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Swati Nagar
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Received for publication September 10, 2007.
Revised October 31, 2007.
Accepted for publication November 6, 2007.

Resveratrol glucuronidation exhibits atypical enzyme kinetics in various protein sources

Otito F Iwuchukwu 1 Swati Nagar 1*

1 Temple University

* Address correspondence to: E-mail: swati.nagar{at}temple.edu

Abstract

The dietary polyphenol trans-resveratrol is glucuronidated at the 3 and 4’ positions to yield two major glucuronide conjugates – resveratrol-3-O-glucuronide (R3G) and resveratrol-4’-O-glucuronide (R4’G). The major enzymes catalyzing this conjugation reaction are members of the UGT1A family and include UGT1A1 and UGT1A9, with minor contributions by UGT1A10. The kinetics of resveratrol glucuronidation in these three UGT1A isoforms as well as in human liver and intestinal microsomes were characterized across a wide concentration range. Atypical kinetics was observed for resveratrol glucuronidation in all the protein sources studied. The Vmax estimate per total protein for both glucuronides was higher in human intestinal microsomes compared with human liver microsomes (12.2 ± 0.34 vs 7.4 ± 0.25 nmol/min/mg for R3G and 8.9 ± 0.14 vs 0.45 ± 0.01 nmol/min/mg for R4’G). The kinetic profile for formation of R3G in both human liver and intestinal microsomes fit a substrate inhibition model while that for R4’G exhibited a biphasic kinetic profile in human liver microsomes and substrate inhibition in human intestinal microsomes. In recombinant human UGT supersomes, for both glucuronides, UGT1A9 exhibited higher activity than UGT1A1 while the lowest activity was observed with UGT1A10. The kinetic profile for R3G exhibited substrate inhibition for all three isoforms while that for R4’G differed, exhibiting substrate inhibition for UGT1A1 and UGT1A10 and Hill kinetics for UGT1A9. These results suggest that in vitro kinetics of resveratrol glucuronidation at high concentrations cannot be ignored in predicting in vivo clearance upon high dose consumption of resveratrol.


Key words: antioxidants, metabolite kinetics, microsomes, phase II drug metabolism, UDP glucuronyltransferases


This article has been cited by other articles:


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O. F. Iwuchukwu, J. Ajetunmobi, D. Ung, and S. Nagar
Characterizing the Effects of Common UDP Glucuronosyltransferase (UGT) 1A6 and UGT1A1 Polymorphisms on cis- and trans-Resveratrol Glucuronidation
Drug Metab. Dispos., August 1, 2009; 37(8): 1726 - 1732.
[Abstract] [Full Text] [PDF]


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