title: Chalcogenopyrylium dyes as differential modulators of organic anion transport by multidrug resistance protein 1 (MRP1), MRP2, and MRP4.
abstract: Multidrug resistance proteins (MRPs) mediate the ATP-dependent efflux of structurally diverse compounds, including anticancer drugs and physiologic organic anions. Five classes of chalcogenopyrylium dyes (CGPs) were examined for their ability to modulate transport of [(3)H]estradiol glucuronide (E(2)17βG; 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 E(2)17βG uptake by >50% (IC50 values: 0.7-7.6 µM). Of 9 CGPs with IC50 values ≤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, V-4, V-6), whereas a fifth (I-5) inhibited efflux by just 23%. These five CGPs also inhibited [(3)H]E(2)17βG uptake by MRP4. In contrast, their effects on MRP2 varied, with two (V-4, V-6) inhibiting E(2)17βG transport (IC(50) values: 2.0 and 9.2 µM) and two (V-3, III-1) stimulating transport (>2-fold), whereas 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 to 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.
authors.affiliation: Department of Pathology & Molecular Medicine, Queen’s University Cancer Research Institute, Kingston, Ontario, Canada.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Myette
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Conseil
authors.forename: Sean P
authors.initials: SP
authors.lastname: Ebert
authors.forename: Bryan
authors.initials: B
authors.lastname: Wetzel
authors.forename: Michael R
authors.initials: MR
authors.lastname: Detty
authors.forename: Susan P C
authors.initials: SP
authors.lastname: Cole
mesh_terms: D002461:Cell Line, Transformed; D018011:Chalcogens / Q000737:chemistry / Q000494:pharmacology; D004396:Coloring Agents / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000502:physiology*
chemical_list: D018011:Chalcogens; D004396:Coloring Agents; D006575:Heterocyclic Compounds, 3-Ring; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C505939:pyrylium 1; C421109:multidrug resistance-associated protein 1