DMD Large equally mixed donor pool

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

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

0090-9556/08/3602-322-330$20.00
DMD 36:322-330, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.107.018788v1
36/2/322    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Iwuchukwu, O. F.
Right arrow Articles by Nagar, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Iwuchukwu, O. F.
Right arrow Articles by Nagar, S.

Resveratrol (trans-Resveratrol, 3,5,4'-Trihydroxy-trans-stilbene) Glucuronidation Exhibits Atypical Enzyme Kinetics in Various Protein Sources

Otito Frances Iwuchukwu, and Swati Nagar

Department of Pharmaceutical Sciences, Temple University, Philadelphia, Pennsylvania

The dietary polyphenol trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene) 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 UDP-glucuronosyl transferase (UGT) 1A 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 were 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 versus 7.4 ± 0.25 nmol/min/mg for R3G and 8.9 ± 0.14 versus 0.45 ± 0.01 nmol/min/mg for R4'G). The kinetic profile for formation of R3G in both human liver and intestinal microsomes fits a substrate inhibition model, whereas 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, whereas the lowest activity was observed with UGT1A10. The kinetic profile for R3G exhibited substrate inhibition for all three isoforms, whereas 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.

Address correspondence to: Dr. Swati Nagar, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140. E-mail: swati.nagar{at}temple.edu




This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
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]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics.