title: Phenothiazine maleates stimulate MRP1 transport activity in human erythrocytes.
abstract: The expression of multidrug resistance-associated protein (MRP1) results in ATP-dependent reduction of drugs' concentration in cancer cells, i.e., multidrug resistance (MDR). Since the majority of projects are concentrated on the search of the new MDR modulators, there are very few reports on drug-induced stimulation of MDR transporters activity. In the present work, by means of functional fluorescence assay we have shown that MRP1-mediated efflux of 2',7'-bis-(3-carboxypropyl)-5-(and-6)-carboxyfluorescein (BCPCF) out of human erythrocytes is stimulated by phenothiazine maleates that have been already identified as P-glycoprotein inhibitors. Phenothiazine maleates-induced stimulation of ATP-dependent uptake of 2',7'-bis-(3-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) into inside-out membrane vesicles prepared from erythrocyte membranes has been also demonstrated. Moreover, it was shown that phenothiazine maleates exerted stimulating effect on ATPase activity measured in erythrocyte membranes. To our best knowledge, this report is the first one demonstrating that compounds able to inhibit transport activity of P-glycoprotein can stimulate MRP1 transporter. We conclude that phenothiazine maleates probably exert their stimulatory effect on MRP1 by direct interaction with the protein at the site different from the substrate binding site.
authors.affiliation: Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 10, 50-368 Wrocław, Poland. olawes@biofiz.am.wroc.pl
authors.forename: Olga
authors.initials: O
authors.lastname: Wesołowska
authors.forename: Daniela
authors.initials: D
authors.lastname: Mosiadz
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Masami
authors.initials: M
authors.lastname: Kawase
authors.forename: Krystyna
authors.initials: K
authors.lastname: Michalak
mesh_terms: D001553:Benzbromarone / Q000494:pharmacology; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D008298:Maleates / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000097:blood*; D010640:Phenothiazines / Q000494:pharmacology*; D014638:Vanadates / Q000494:pharmacology
chemical_list: D001553:Benzbromarone; D017301:Ca(2+) Mg(2+)-ATPase; D005452:Fluoresceins; D008298:Maleates; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010640:Phenothiazines; D014638:Vanadates; C473073:2',7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein; C043829:2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; C421109:multidrug resistance-associated protein 1