Flavonoids as inhibitors of MRP1-like efflux activity in human erythrocytes. A structure-activity relationship study

The potency of flavonoids (isoflavones, flavones, and flavanones) to inhibit efflux of 2',7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein (BCPCF) from human erythrocytes was investigated. Structure-activity relationship analysis showed that the strongest inhibitors were found among flavanones bearing a hydrophobic prenyl, geranyl, or lavandulyl group at position 8 (and hydroxyl groups at 5 and 7) in ring A. A prenyl group at position 5' or stilbene at positions 4'-5' in ring B further seemed to increase inhibitor potency. The most efficient flavanones, euchrestaflavanone A and sophoraflavanone H, were approximately 20 times more efficient than genistein, and induced 50% inhibition of BCPCF efflux (IC50) at 3 microM (60 min, 37 degrees C). This is comparable to IC50 of benzbromarone (4 microM) and lower than IC50 of indomethacin (10 microM), both known MRP1 (ABCC1) inhibitors. It is suggested that BCPCF efflux is mainly due to MRP1 activity. Our results indicate that flavonoid molecular structure provides a promising base for development of potent MRP1 inhibitors.