Related Experiment Videos
Multiple flavonoid-binding sites within multidrug resistance protein MRP1
D Trompier1, H Baubichon-Cortay, X-B Chang
1Institut de Biologie et Chimie des Protéines, UMR5086 CNRS/Université Claude Bernard-Lyon I, IFR128 BioSciences Lyon-Gerland, 7 Passage du Vercors, 69367 Lyon, France.
Cellular and Molecular Life Sciences : CMLS
|November 18, 2003
Summary
Dehydrosilybin, a flavonoid, binds to multidrug resistance protein MRP1, inhibiting its transport activity and reversing cellular multidrug resistance. Its derivatives show altered binding and activity, suggesting multiple binding sites on MRP1.
Area of Science:
- Biochemistry
- Molecular Pharmacology
- Drug Resistance
Background:
- Multidrug resistance protein 1 (MRP1) is a key transporter involved in cellular multidrug resistance.
- Flavonoids are natural compounds with potential therapeutic properties, including anticancer effects.
Purpose of the Study:
- To investigate the direct interaction of recombinant nucleotide-binding domains (NBDs) of MRP1 with flavonoids.
- To evaluate the effect of flavonoids on MRP1-mediated transport and cellular multidrug resistance.
Main Methods:
- Overexpression and purification of recombinant MRP1 NBDs.
- Binding assays with various flavonoids.
- Measurement of MRP1-mediated transport activity (LTC4 transport).
- Assessment of chemosensitization to vincristine.
Main Results:
- Dehydrosilybin showed the highest affinity for MRP1 NBDs, with binding to NBD1 inhibited by ATP.
- Dehydrosilybin stimulated MRP1 ATPase activity and inhibited LTC4 transport, reversing vincristine resistance.
- Hydrophobic modification of dehydrosilybin altered its binding and inhibitory properties, suggesting multiple binding sites.
Conclusions:
- Dehydrosilybin interacts with MRP1 NBDs and inhibits its function, offering potential for overcoming multidrug resistance.
- The binding and activity of dehydrosilybin derivatives indicate complex interactions with both cytosolic and transmembrane domains of MRP1.