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

Abstract

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.

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

“…Alkyl derivatives of GSH stimulated binding of LY475776 up to S ‐propyl‐GSH, longer side chains prevented binding. This correlation has already been stated above . Similar observations have been made by Qian et al.…”

“…S ‐octyl‐GSH and S ‐decyl‐GSH were the most potent inhibitors, preventing LTC 4 transport nearly completely at 1 μM. S ‐decyl‐GSH was shown to be a competitive inhibitor, which also stimulated the MRP1 ATPase at concentrations between 100 and 300 μM . Similar observations have been made by the same working group with respect to MRP1‐mediated transport of aflatoxine B 1 , showing the same correlation between chain length and inhibitory potency .…”

“…Besides these described alkylated GSH analogs, S ‐( p ‐nitrobenzyl)‐GSH and S ‐( p ‐chlorphenacyl)‐GSH (Figure ) were found to be equally potent . Oxidized glutathione (GSSG; Figure ), which is also a substrate of MRP1, also competitively inhibited LTC 4 transport, but with much lesser potency …”

“…Cysteine leukotriene receptor 1 and 2 antagonists as inhibitors of MRP1 were examined by Csandl et al. The import of the MRP1 substrates [ 3 H]LTC 4 and [ 3 H]E 2 17 β G into inside‐out membrane vesicles derived from MRP1‐transfected HEK293/MRP1 cells was measured . The authors determined IC 50 values for [ 3 H]LTC 4 and [ 3 H]E 2 17 β G transport inhibition by MK571 (2.7 and 1.8 μM), ONO‐1078 (3.3 and 2.8 μM), BayCysLT 2 (3.4 and 1.9 μM), BAY‐u9773 (4.3 and 1.9 μM), HAMI 3379 (3.3 and 1.6 μM), LY171883 (tomelukast; 52.2 and 16.1 μM), and montelukast (10.2 and 7.2 μM; Figure ).…”

“…Loe et al. used in 1996 membrane vesicles derived from MRP1‐transfected HeLa T14 cells as well as doxorubicin‐selected H69AR cells to analyze the relation of LTC 4 to MRP1 . They found that inhibition of [ 3 H]LTC 4 transport mediated by MRP1 increased with elongation of chain length of the GSH analogs.…”