DMD Large equally mixed donor pool

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


     

Drug Metabolism and Disposition Fast Forward
First published on May 3, 2007; DOI: 10.1124/dmd.106.014241

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.106.014241v1
35/8/1262    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 Williamson, G.
Right arrow Articles by Grigorov, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Williamson, G.
Right arrow Articles by Grigorov, M.


Received for publication December 8, 2006.
Revised May 2, 2007.
Accepted for publication May 2, 2007.

INTERACTION OF POSITIONAL ISOMERS OF QUERCETIN GLUCURONIDES WITH THE TRANSPORTER ABCC2 (CMOAT, MRP2)

Gary Williamson 1*, Isabelle Aeberli 1, Laurence Miguet 1, Ziding Zhang 1, Maria-Belen Sanchez 1, Vanessa Crespy 1, Denis Barron 1, Paul Needs 2, Paul A. Kroon 2, H Glavinas 3, Peter Krajcsi 4, Martin Grigorov 1

1 Nestle Research Center 2 Institute of Food Research 3 Solvo Biotechnology 4 Solvo Biotechnolgy

* Address correspondence to: E-mail: gary.williamson{at}rdls.nestle.com

Abstract

The exporter ABCC2 (cMOAT, MRP2) is a membrane bound protein on the apical side of enterocytes and hepatic biliary vessels that transports leukotriene C4, glutathione, some conjugated bile salts, drugs, xenobiotics and phytonutrients. The latter class includes quercetin, a bioactive flavonoid found in foods such as onions, apples, tea and wine. There is no available 3D structure of ABCC2. We have predicted the 3D structure by in silico modeling, showing that MK571 binds most tightly to the putative binding site and then tested the computational prediction experimentally by measuring interaction with all quercetin mono-glucuronides occurring in vivo (quercetin substituted with glucuronic acid at the 3, 3', 4' and 7 hydroxyl groups). The 4'-O-{beta}-D-glucuronide is predicted in silico to interact most strongly, and the 3-O-{beta}-D-glucuronide most weakly, and this is supported experimentally using binding and competition assays on ABCC2 over-expressing baculovirus-infected Sf9 cells. To test the transport in situ, we examined the effect of two ABCC2 inhibitors, MK571 and cyclosporin A, on the transport into the media of quercetin glucuronides produced intracellularly by Caco2 cells. The inhibitors reduced the amount of all quercetin glucuronides in the media. The results show that the molecular model of ABCC2 agrees well with experimentally determined ABCC2-ligand interactions, and importantly that the interaction of ABCC2 with quercetin glucuronides is dependent on the position and nature of substitution.


Key words: ABC transporters, antioxidants, bioavailability, glucuronidation, hepatic transport, intestinal bioavailability, intestinal transport


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
W. Brand, P. A. I. van der Wel, M. J. Rein, D. Barron, G. Williamson, P. J. van Bladeren, and I. M. C. M. Rietjens
Metabolism and Transport of the Citrus Flavonoid Hesperetin in Caco-2 Cell Monolayers
Drug Metab. Dispos., September 1, 2008; 36(9): 1794 - 1802.
[Abstract] [Full Text] [PDF]


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

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics.