Structure-activity studies of verapamil analogs that modulate transport ofleukotriene C-4 and reduced glutathione by multidrug resistance protein MRP1

The 190-kDa multidrug resistance protein MRP1 is an ATP-binding cassette pr otein that confers resistance to multiple antineoplastic agents and activel y transports conjugated organic anions, We have previously shown that MRP1- mediated GSH transport is stimulated by verapamil but transport of verapami l in the presence or absence of GSH is not observed. We have now examined 2 0 sulfur-containing verapamil analogs for their ability to inhibit MRP1-med iated leukotriene C-4 (LTC4) transport and stimulate GSH uptake into inside -out membrane vesicles. All of the derivatives were poor inhibitors of LTC4 uptake. However, the inhibitory potency of the more lipophilic dithiane co mpounds could be enhanced by coincubation with GSH whereas this was not the ease for the more hydrophilic dithiane tetraoxides. The dithiane derivativ es stimulated GSH transport whereas, with one exception, the dithiane tetra oxides did not. One pair of dithiane stereoisomers differed significantly i n their ability to stimulate GSH transport although their ability to inhibi t LTC4 uptake in the presence of GSH was comparable. Our findings indicate that the GSH transport activity of MRP1 can be dissociated from its conjuga ted organic anion transport activity. (C) 2000 Academic Press.