Effect of Leukotriene Modifiers on Transport Activity of Multidrug Resistance Proteins (MRPs)

Abstract

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