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Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2

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Author: Zanden, J.J. van · Wortelboer, H.M. · Bijlsma, S. · Punt, A. · Usta, M. · Bladeren, P.J.V. · Rietjens, I.M.C.M. · Cnubben, N.H.P.
Institution: TNO Kwaliteit van Leven
Source:Biochemical Pharmacology, 4, 69, 699-708
Identifier: 238347
doi: doi:10.1016/j.bcp.2004.11.002
Keywords: Nutrition Pharmacology · Analytical research · Calcein · Flavonoids · MRP1 · MRP2 · QSAR · 3 hydroxyflavone · 3' hydroxyflavone · 3',4' dihydroxyflavone · 3,3' dihydroxyflavone · 3,3',4' trihydroxyflavone · 4' hydroxyflavone · 5,7,3',4' tetramethoxyflavone · acacetin · apigenin · baicalein · catechin · chrysin · fisetin · flavone · flavonoid · galangin · kaempferide · kaempferol · luteolin · morin · multidrug resistance protein 1 · multidrug resistance protein 2 · myricetin · naringenin · protein inhibitor · quercetin · robinetin · taxifolin · unclassified drug · unindexed drug · valspodar · verlukast · animal cell · article · cell kinetics · cell transport · controlled study · drug effect · drug inhibition · drug potency · drug selectivity · genetic transfection · IC 50 · nonhuman · priority journal · protein analysis · quantitative structure activity relation · Animals · Cell Line · Dogs · Flavonoids · Fluoresceins · Membrane Transport Modulators · Membrane Transport Proteins · Multidrug Resistance-Associated Proteins · Quantitative Structure-Activity Relationship


In the present study, the effects of a large series of flavonoids on multidrug resistance proteins (MRPs) were studied in MRP1 and MRP2 transfected MDCKII cells. The results were used to define the structural requirements of flavonoids necessary for potent inhibition of MRP1- and MRP2-mediated calcein transport in a cellular model. Several of the methoxylated flavonoids are among the best MRP1 inhibitors (IC50 values, ranging between 2.7 and 14.3 μM) followed by robinetin, myricetin and quercetin (IC50 values ranging between 13.6 and 21.8 μM). Regarding inhibition of MRP2 activity especially robinetin and myricetin appeared to be good inhibitors (IC 50 values of 15.0 and 22.2 μM, respectively). Kinetic characterization revealed that the two transporters differ marginally in the apparent Km for the substrate calcein. For one flavonoid, robinetin, the kinetics of inhibition were studied in more detail and revealed competitive inhibition with respect to calcein, with apparent inhibition constants of 5.0 μM for MRP1 and 8.5 μM for MRP2. For inhibition of MRP1, a quantitative structure activity relationship (QSAR) was obtained that indicates three structural characteristics to be of major importance for MRP1 inhibition by flavonoids: the total number of methoxylated moieties, the total number of hydroxyl groups and the dihedral angle between the B- and C-ring. Regarding MRP2 mediated calcein efflux inhibition, only the presence of a flavonol B-ring pyrogallol group seems to be an important structural characteristic. Overall, this study provides insight in the structural characteristics involved in MRP inhibition and explores the differences between inhibitors of these two transporters, MRP1 and MRP2. Ultimately, MRP2 displays higher selectivity for flavonoid type inhibition than MRP1. © 2004 Elsevier Inc. All rights reserved.