Resveratrol Oligomers are Potent MRP1 Transport Inhibitors

Abstract

Background: Knowledge of the structure-activity relationships of multidrug resistance protein 1 (MRP1, ABCC1) inhibitors may aid in developing potent inhibitors that can be used to circumvent MRP1-mediated multidrug resistance. Materials and Methods: Six stilbenes were examined for their ability to inhibit MRP1-mediated transport of 2′,7′-bis- (carboxypropyl)-5(6)-carboxyfluorescein (BCPCF) from human erythrocytes and into inside-out erythrocyte membrane vesicles (IOVs). The concentrations of stilbenes decreasing BCPCF transport by 50% during 60 min of incubation at 37ÆC (IC₅₀) were determined from dose-response curves. Results: Stilbenes inhibited BCPCF transport in cells in the rank order (+)-α-viniferin (IC₅₀=0.8 μM) >sophorastilbene A (IC₅₀=3.1 μM) >(-)-ε-viniferin (IC₅₀=8.9 μM) >piceatannol (IC₅₀=57 μM). Resveratrol and rhaponticin were ineffective. (+)-α-Viniferin (IC₅₀=0.8 μM), sophorastilbene A (IC₅₀=3.7 μM) and (-)-ε-viniferin (IC₅₀=3.5 μM) were also efficient BCPCF transport inhibitors in IOVs. Conclusion: Stilbenes may efficiently inhibit MRP1-mediated organic anion transport. This inhibitory potency of stilbenes increases with oligomerisation. The membrane is not a strong barrier for the inhibitory activity of the trimeric stilbenes.