Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4)

Active efflux of both drugs and organic anion metabolites is mediated by the multidrug resistance proteins (MRPs). MRP1 (ABCC1), MRP2 (ABCC2), MRP3 (ABCC3), and MRP4 (ABCC4) have partially overlapping substrate specificities and all transport 17 beta-estradiol 17-(beta-D-glucuronide) (E(2)17 beta G). The cysteinyl leukotriene receptor 1 (CysLT(1)R) antagonist MK-571 inhibits all four MRP homologs, but little is known about the modulatory effects of newer leukotriene modifiers (LTMs). Here we examined the effects of seven CysLT(1)R- and CysLT(2)R-selective LTMs on E(2)17 beta G uptake into MRP1-4-enriched inside-out membrane vesicles. Their effects on uptake of an additional physiologic solute were also measured for MRP1 [leukotriene C-4 (LTC4)] and MRP4 [prostaglandin E-2 (PGE(2))]. The two CysLT(2)R-selective LTMs studied were generally more potent inhibitors than CysLT(1)R-selective LTMs, but neither class of antagonists showed any MRP selectivity. For E(2)17 beta G uptake, LTM IC(50)s ranged from 1.2 to 26.9 mu M and were most comparable for MRP1 and MRP4. The LTM rank order inhibitory potencies for E(2)17 beta G versus LTC4 uptake by MRP1, and E(2)17 beta G versus PGE(2) uptake by MRP4, were also similar. Three of four CysLT(1)R-selective LTMs also stimulated MRP2 (but not MRP3) transport and thus exerted a concentration-dependent biphasic effect on MRP2. The fourth CysLT(1)R antagonist, LY171883, only stimulated MRP2 (and MRP3) transport but none of the MRPs were stimulated by either CysLT(2)R-selective LTM. We conclude that, in contrast to their CysLTR selectivity, CysLTR antagonists show no MRP homolog selectivity, and data should be interpreted cautiously if obtained from LTMs in systems in which more than one MRP is present.