10819
title and abstract
Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by MRP1, MRP2 and MRP4.
Multidrug resistance proteins (MRPs) mediate the ATP-dependent efflux of structurally diverse compounds, including anticancer drugs and physiological organic anions. Five classes of chalcogenopyrylium dyes (CGPs) were examined for their ability to modulate transport of [(3)H]estradiol glucuronide (E217βG) (a prototypical MRP substrate) into MRP-enriched inside-out membrane vesicles. Additionally, some CGPs were tested in intact transfected cells using a calcein efflux assay. Sixteen of 34 CGPs inhibited MRP1-mediated E217βG uptake by >50% (IC50's 0.7-7.6 μM). Of 9 CGPs with IC50's ≤2 μM, two belonged to Class I, two to Class III and five to Class V. When tested in the intact cells, only 4 of 16 CGPs (at 10 μM) inhibited MRP1-mediated calcein efflux by >50% (III-1, V-3, -4, -6) while a fifth (I-5) inhibited efflux by just 23%. These five CGPs also inhibited [(3)H]E217βG uptake by MRP4. In contrast, their effects on MRP2 varied with two (V-4, V-6) inhibiting E217βG transport (IC50's 2.0, 9.2 μM), two (V-3, III-1) stimulating transport (>2-fold), while CGP I-5 had no effect. Strikingly, although V-3 and V-4 had opposite effects on MRP2 activity, they are structurally identical except for their chalcogen atom (Se versus Te). This study is the first to identify Class V CGPs with their distinctive methine or trimethine linkage between two disubstituted pyrylium moieties as a particularly potent class of MRP modulators and also show that within this core structure, differences in the electronegativity associated with a chalcogen atom can be the sole determinant of whether a compound will stimulate or inhibit MRP2.