The Effect of Leukotriene Modifiers (LTMs) on Organic Anion Transport by Multidrug Resistance Proteins (MRPs)

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Csandl, Mark
Multidrug resistance proteins , Leukotriene receptor antagonists
The multidrug resistance proteins (MRPs) are plasma membrane efflux transporters that transport a diverse array of compounds. MRP1, MRP2, MRP3 and MRP4 are considered the most pharmacologically relevant drug-transporting MRPs and have broad substrate specificities that include many xenobiotics (e.g. pharmacological agents, environmental toxins), endobiotics, and their metabolites. Although MRP1-4 have distinct substrate profiles, they can all transport glucuronide conjugated estradiol (E217βG). MK-571 was originally designed as a type 1 cysteinyl leukotriene receptor (CysLT1R) antagonist to treat asthma; it is also the most popular MRP1 inhibitor. However, MK-571 is non-selective and inhibits all MRP homologues as well as at least one solute carrier transporter, limiting its usefulness as an experimental tool. Additional leukotriene modifiers (LTMs) selective for either CysLT1R or the type 2 cysteinyl leukotriene receptor (CysLT2R) have been developed but little is known of their ability to modulate MRP1 and its homologues. In this study, seven LTMs selective for either CysLT1R or CysLT2R were examined for their ability to modulate E217βG uptake into MRP1, MRP2, MRP3, or MRP4-enriched membrane vesicles. Their effect on the uptake of a second physiological organic anion was also measured for MRP1 (leukotriene C¬4; LTC¬4) and MRP4 (prostaglandin E2; PGE2). For E217βG, the IC50 values of the 7 LTMs tested ranged from 1.2 to 26.9 μM and the IC50 values for MRP1 and MRP4 were the most similar. In contrast, some LTMs stimulated MRP2 and MRP3 activity. Thus, LY171883 stimulated MRP2 and MRP3-mediated E217βG uptake by 2 to 4-fold while montelukast and pranlukast modulated MRP2 activity in a biphasic manner. CysLT1R-selective LTMs were generally less potent as modulators of MRP2 and MRP3 activity although CysLTR selectivity did not correlate with LTM potency for MRP1 and MRP4. The rank order of LTM inhibitory potencies for E217βG versus LTC4 uptake by MRP1 and E217βG versus PGE2 uptake by MRP4 were similar. These data suggest that, like MK-571, LTMs are generally non-selective modulators of MRP transport activity despite their CysLTR selectivity, and should therefore be used with caution in MRP-related research because of their potential to confound data interpretation.
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