Multiple flavonoid-binding sites within multidrug resistance protein MRP1

D. Trompier, H. Baubichon-Cortay, X. B. Chang, M. Maitrejean, D. Barron, J. R. Riordan, A. Di Pietro

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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-[α-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-[α- 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.

Original languageEnglish (US)
Pages (from-to)2164-2177
Number of pages14
JournalCellular and Molecular Life Sciences
Volume60
Issue number10
DOIs
StatePublished - Oct 2003

Keywords

  • ABC transporter
  • Chemosensitization
  • Drug-binding site
  • Flavonoid
  • Multidrug resistance (MDR)
  • Multidrug resistance protein 1 (MRP1)
  • Nucleotide-binding domain (NBD)

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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