Structure-activity studies of verapamil analogs that modulate transport of leukotriene C(4) and reduced glutathione by multidrug resistance protein MRP1.
The 190-kDa multidrug resistance protein MRP1 is an ATP-binding cassette protein that confers resistance to multiple antineoplastic agents and actively transports conjugated organic anions. We have previously shown that MRP1-mediated GSH transport is stimulated by verapamil but transport of verapamil in the presence or absence of GSH is not observed. We have now examined 20 sulfur-containing verapamil analogs for their ability to inhibit MRP1-mediated leukotriene C(4) (LTC(4)) transport and stimulate GSH uptake into inside-out membrane vesicles. All of the derivatives were poor inhibitors of LTC(4) uptake. However, the inhibitory potency of the more lipophilic dithiane compounds could be enhanced by coincubation with GSH whereas this was not the case for the more hydrophilic dithiane tetraoxides. The dithiane derivatives stimulated GSH transport whereas, with one exception, the dithiane tetraoxides did not. One pair of dithiane stereoisomers differed significantly in their ability to stimulate GSH transport although their ability to inhibit LTC(4) uptake in the presence of GSH was comparable. Our findings indicate that the GSH transport activity of MRP1 can be dissociated from its conjugated organic anion transport activity.
Loe
D W
DW
Cancer Research Laboratories, Queen's University, Kingston, Ontario, K7L 3N6, Canada.
Oleschuk
C J
CJ
Deeley
R G
RG
Cole
S P
SP
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000378:metabolism*; D006367:HeLa Cells; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; D005978:Glutathione; D006571:Heterocyclic Compounds; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013457:Sulfur Compounds; D014700:Verapamil