MRPs mediate the ATP-dependent efflux of a structurally diverse array of compounds. Certain MRPs, including MRP1, MRP2 and MRP4, are involved in multidrug resistance in tumour cells, while in non-malignant cells these MRPs can influence the distribution and/or elimination of many clinically important drugs. In addition, these MRPs mediate the efflux of physiological metabolites, many of which are conjugated organic anions. Modulation of the drug transporting activity of MRP1 (and to a lesser extent MRP2 and MRP4) has been a long sought after therapeutic objective. In this study, the modulatory abilities of five structurally distinct classes (I-V) of chalcogenopyrylium dyes (CGPs) were examined utilizing an in vitro assay which measures inhibition of radiolabeled estradiol glucuronide ([3H]E217βG) (a prototypical MRP substrate) uptake into inside-out membrane vesicles prepared from MRP-transfected human embryonic kidney (HEK) cells. Additionally, some CGPs were tested in a calcein efflux assay using intact MRP1-transfected HEK cells. Sixteen of 34 CGPs initially tested at a single concentration (≤30 μM) inhibited MRP1-mediated uptake by >50%, with IC50’s ranging from 0.7-7.6 μM. Of the 9 CGPs with IC50’s ≤2 μM, five belonged to Class I, two to Class II, and two to Class IV. When tested in the calcein efflux assay, only 4 of 16 CGPs inhibited MRP1-mediated cellular efflux by >50% (I-3, -4, -6, IV-1) while a fifth (II-5) inhibited efflux by 23%. These five CGPs were then tested as modulators of [3H]E217βG uptake by MRP2 and MRP4. Their effects on MRP2 transport activity were differential with two (I-4, I-6) inhibiting transport (IC50’s 2.0, 7.1 μM), two (I-3, IV-1) stimulating transport (>2-fold), while II-5 had no effect. On the other hand, all five CGPs inhibited [3H]E217βG uptake by MRP4, but less effectively than by MRP1. Finally, five analogs of CGP IV-1 were tested for their effects on MRP1, MRP2 and MRP4 [3H]E217βG uptake, but none were more efficacious than CGP IV-1. The CGPs tested here represent novel MRP1, MRP2 and MRP4 modulators with variable effects on transport activities. These CGPs may represent a new avenue for the development of clinically applicable modulators of MRP proteins involved in multidrug resistance. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2011-11-28 17:50:49.432