Inhibition of MRP1-mediated efflux in human erythrocytes by mono-anionic bile salts.

BACKGROUND Multidrug resistance-associated protein 1 (MRP1 or ABCC1) -mediated transport is an important mechanism in multidrug resistance during cancer treatment. One strategy for the reversal of MRP1-mediated multidrug resistance is inhibition of this efflux pump. Therefore, efficient inhibitors are searched for and the structure-activity relationships of inhibitors are studied. In the present work, the ability of a series of mono-anionic bile salts to inhibit MRP1-like substrate transport was examined. MATERIALS AND METHODS The effect of bile salts on the efflux of the MRP1 substrate 2,7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein (BCPCF) from human erythrocytes was fluorimetrically monitored. RESULTS All bile salts inhibited the BCPCF efflux. The most efficient inhibitor, lithocholic acid, decreased the BCPCF efflux by 50% (IC50) at 4 microM during 60 min of incubation at 37 degrees C. The most efficient bile salt inhibitors showed high haemolysis start/IC50 concentration ratios and did not induce membrane bending or phosphatidylserine (PS) exposure at IC50. CONCLUSION The overall hydrophobicity, as well as the orientation of the hydroxyl groups and conjugation with glycine or taurine per se, affect the inhibitory potency of bile salts. The most efficient inhibitors apparently interact with MRP1 in a specific way.