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Cell Mol Life Sci. 2003 Oct;60(10):2164-77.

Multiple flavonoid-binding sites within multidrug resistance protein MRP1.

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1
Institut de Biologie et Chimie des Protéines, UMR5086 CNRS/Université Claude Bernard-Lyon I, IFR128 BioSciences Lyon-Gerland, 7 Passage du Vercors, 69367 Lyon, France.

Abstract

Recombinant nucleotide-binding domains (NBDs) from human multidrug resistance protein MRP1 were overexpressed in bacteria and purified to measure their direct interaction with high-affinity flavonoids, and to evaluate a potential correlation with inhibition of MRP1-mediated transport activity and reversion of cellular multidrug resistance. Among different classes of flavonoids, dehydrosilybin exhibited the highest affinity for both NBDs, the binding to N-terminal NBD1 being prevented by ATP. Dehydrosilybin increased vanadate-induced 8-N3-[alpha-32P]ADP trapping, indicating stimulation of ATPase activity. In contrast, dehydrosilybin strongly inhibited leukotriene C4 (LTC4) transport by membrane vesicles from MRP1-transfected cells, independently of reduced glutathione, and chemosensitized cell growth to vincristine. Hydrophobic C-isoprenylation of dehydrosilybin increased the binding affinity for NBD1, but outsite the ATP site, lowered the increase in vanadate-induced 8-N3-[alpha-32P]ADP trapping, weakened inhibition of LTC4 transport which became glutathione dependent, and induced some cross-resistance. The overall results indicate multiple binding sites for dehydrosilybin and its derivatives, on both cytosolic and transmembrane domains of MRP1.

PMID:
14618263
DOI:
10.1007/s00018-003-3177-6
[Indexed for MEDLINE]

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