QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.009753v1 67/6/1999    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sesink, A. L. A. Articles by Russel, F. G. M. Search for Related Content PubMed PubMed Citation Articles by Sesink, A. L. A. Articles by Russel, F. G. M.

Breast Cancer Resistance Protein (Bcrp1/Abcg2) Limits Net Intestinal Uptake of Quercetin in Rats by Facilitating Apical Efflux of Glucuronides

Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (A.L.A.S., F.G.M.R.); RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Wageningen, The Netherlands (I.C.W.A., V.C.J.d.B., P.C.H.H.); and Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands (P.B., J.H.M.S.)

The intestinal absorption of the flavonoid quercetin in rats is limited by the secretion of glucuronidated metabolites back into the gut lumen. The objective of this study was to determine the role of the intestinal efflux transporters breast cancer resistance protein (Bcrp1)/Abcg2 and multidrug resistance-associated protein 2 (Mrp2)/Abcc2. To study the possible involvement of Mrp2, we compared intestinal uptake of quercetin-3-glucoside between control and Mrp2-deficient rats, using an in situ intestinal perfusion system. The contribution of Bcrp1 was determined using the specific inhibitor fumitremorgin C (FTC) in Mrp2-deficient rats. Furthermore, vectorial transport of quercetin was studied in Madin-Darby canine kidney (MDCK)II cells transfected with either human MRP2 or murine Bcrp1. In these MDCKII cells, we showed an efficient efflux-directed transport of quercetin by mouse Bcrp1, whereas in control and MRP2-transfected cells no vectorial transport of quercetin was observed. In Mrp2-deficient rats, intestinal uptake of quercetin from quercetin-3-glucoside, efflux of quercetin glucuronides to the gut lumen, and plasma concentration of quercetin were similar to that in control rats. When intestinal Bcrp1 was inhibited by FTC in Mrp2-deficient rats, total plasma concentrations of quercetin and its methylated metabolite isorhamnetin after 30 min of perfusion were more than twice that of controls (12.3 ± 1.5 versus 5.6 ± 1.3 µM; p < 0.01), whereas uptake of free quercetin from the intestinal lumen was not affected. Instead, inhibition of Bcrp1 lowered the efflux of quercetin glucuronides into the perfusion fluid by approximately 4-fold. In conclusion, Bcrp1 limits net intestinal absorption of quercetin by pumping quercetin glucuronides back into the lumen.

Address correspondence to: Dr. Frans G. M. Russel, Department of Pharmacology and Toxicology 233, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O Box 9101, 6500 HB, Nijmegen, The Netherlands. E-mail: f.russel{at}ncmls.ru.nl

This article has been cited by other articles:

				R. Mols, J. Brouwers, A. H. Schinkel, P. Annaert, and P. Augustijns INTESTINAL PERFUSION WITH MESENTERIC BLOOD SAMPLING IN WILD-TYPE AND KNOCKOUT MICE: Evaluation of a Novel Tool in Biopharmaceutical Drug Profiling Drug Metab. Dispos., June 1, 2009; 37(6): 1334 - 1337. [Abstract] [Full Text] [PDF]

				J. W Lampe Interindividual differences in response to plant-based diets: implications for cancer risk Am. J. Clinical Nutrition, May 1, 2009; 89(5): 1553S - 1557S. [Abstract] [Full Text] [PDF]

				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]

				I. S. Westley, R. G. Morris, A. M. Evans, and B. C. Sallustio Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR- Rat Liver Microsomes Drug Metab. Dispos., January 1, 2008; 36(1): 46 - 50. [Abstract] [Full Text] [PDF]

				G. Williamson, I. Aeberli, L. Miguet, Z. Zhang, M.-B. Sanchez, V. Crespy, D. Barron, P. Needs, P. A. Kroon, H. Glavinas, et al. Interaction of Positional Isomers of Quercetin Glucuronides with the Transporter ABCC2 (cMOAT, MRP2) Drug Metab. Dispos., August 1, 2007; 35(8): 1262 - 1268. [Abstract] [Full Text] [PDF]

				H. Saito, H. Hirano, H. Nakagawa, T. Fukami, K. Oosumi, K. Murakami, H. Kimura, T. Kouchi, M. Konomi, E. Tao, et al. A New Strategy of High-Speed Screening and Quantitative Structure-Activity Relationship Analysis to Evaluate Human ATP-Binding Cassette Transporter ABCG2-Drug Interactions J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1114 - 1124. [Abstract] [Full Text] [PDF]