title: Modulation of the function of human MDR1 P-glycoprotein by the antimalarial drug mefloquine.
abstract: MDR1 P-glycoprotein in membranes of human tumor cells of the CEM/VBL100 line was selectively labelled using photoreactive analogs of verapamil, N-(p-azido-3-[125I]salicyl)amino-verapamil ([125I]ASA-V) and prazosin, 2-[4-(4-azido-3-[125I]iodobenzoyl)piperazin-1-yl]4 -amino-6,7-dimethoxyyquinazoline ([125I]ASA-P). Mefloquine, a quinolinemethanol antimalarial drug, was shown to inhibit the labelling of P-glycoprotein with an efficiency similar to that for verapamil, a known chemosensitizer. By contrast, chloroquine competed poorly for the binding site on P-glycoprotein. Mefloquine also inhibited the functional activity of P-glycoprotein. It decreased the rates of extrusion of [3H]vinblastine and the fluorescent dyes, fluo-3 acetomethoxy ester and rhodamine 123, from drug-resistant cells and decreased the level of resistance of these cells to vinblastine. The ability of mefloquine to inhibit P-glycoprotein function may be involved in the neurotoxic side-effects occasionally associated with the use of mefloquine as an antimalarial drug.
authors.affiliation: School of Biochemistry, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: C D
authors.initials: CD
authors.lastname: Riffkin
authors.forename: R
authors.initials: R
authors.lastname: Chung
authors.forename: D M
authors.initials: DM
authors.lastname: Wall
authors.forename: J R
authors.initials: JR
authors.lastname: Zalcberg
authors.forename: A F
authors.initials: AF
authors.lastname: Cowman
authors.forename: M
authors.initials: M
authors.lastname: Foley
authors.forename: L
authors.initials: L
authors.lastname: Tilley
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000345:Affinity Labels; D000962:Antimalarials / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D001693:Biological Transport, Active / Q000187:drug effects; D002738:Chloroquine / Q000378:metabolism; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D015767:Mefloquine / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism / Q000633:toxicity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000962:Antimalarials; D005456:Fluorescent Dyes; D014747:Vinblastine; D002738:Chloroquine; D014700:Verapamil; D015767:Mefloquine; D011224:Prazosin