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 17b-estradiol 17-(b-D-glucuronide) (E 2 17bG). 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 17bG 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 (LTC 4 )] 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 17bG uptake, LTM IC 50 s ranged from 1.2 to 26.9 mM and were most comparable for MRP1 and MRP4. The LTM rank order inhibitory potencies for E 2 17bG versus LTC 4 uptake by MRP1, and E 2 17bG 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.
Multidrug resistance protein 1 (MRP1), MRP2, MRP3, and MRP4 are membrane transporters that mediate ATP‐dependent efflux of xenobiotics, their metabolites, and many physiological organic anions. MRP1‐4 have distinct substrate profiles; however, they can all transport the glucuronide conjugate of estradiol (E217bG). An established physiological role of MRP1 is to efflux the proinflammatory leukotriene C4 (LTC4). MK‐571 was originally designed as a leukotriene receptor 1 (CysLT1R) antagonist to treat asthma; it is also the most popular MRP1 inhibitor. However, MK‐571 is non‐specific and inhibits most MRP homologs as well as some solute carrier organic anion (SCLO) importers, limiting its usefulness as an experimental tool. Other leukotriene modifiers (LTMs) have been developed to treat inflammatory diseases but little is known of their ability to modulate MRP1 and its homologs. In this study, the effect of a series of LTMs specific for either CysLT1R or CysLT2R on E217bG uptake into MRP1, MRP2, MRP3, or MRP4‐enriched membrane vesicles was measured. The IC50 values for the 5 LTMs tested ranged from 0.91 to 25.27 uM; MRP1 and MRP4 IC50 values were the most alike. In contrast, some LTMs stimulated MRP2 and MRP3. Thus, LY171883 stimulated MRP2 and MRP3‐mediated E217bG uptake by about 2.3 and 4‐fold, respectively, while Montelukast modulated MRP2 in a biphasic manner. CysLT1R specific LTMs were generally a less potent class of MRP modulators. These data suggest that like MK‐571, most LTMs are non‐selective modulators of MRP1‐4 transport, and should therefore be used with caution because of their potential to confound data interpretation. Supported by Canadian Institutes of Health Research MOP‐133584
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