title: Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs.
abstract: Two prominent members of the ATP-binding cassette superfamily of transmembrane proteins, multidrug resistance 1 (MDR1) P-glycoprotein and multidrug resistance protein 1 (MRP1), can mediate the cellular extrusion of xenobiotics and (anticancer) drugs from normal and tumor cells. The MRP subfamily consists of at least six members, and here we report the functional characterization of human MRP5. We found resistance against the thiopurine anticancer drugs, 6-mercaptopurine (6-MP) and thioguanine, and the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in MRP5-transfected cells. This resistance is due to an increased extrusion of PMEA and 6-thioinosine monophosphate from the cells that overproduce MRP5. In polarized Madin-Darby canine kidney II (MDCKII) cells transfected with an MRP5 cDNA construct, MRP5 is routed to the basolateral membrane and these cells transport S-(2,4-dinitrophenyl)glutathione and glutathione preferentially toward the basal compartment. Inhibitors of organic anion transport inhibit transport mediated by MRP5. We speculate that MRP5 might play a role in some cases of unexplained resistance to thiopurines in acute lymphoblastic leukemia and/or to antiretroviral nucleoside analogs in HIV-infected patients.
authors.affiliation: Division of Molecular Biology and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Wijnholds
authors.forename: C A
authors.initials: CA
authors.lastname: Mol
authors.forename: L
authors.initials: L
authors.lastname: van Deemter
authors.forename: M
authors.initials: M
authors.lastname: de Haas
authors.forename: G L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: F
authors.initials: F
authors.lastname: Baas
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: S
authors.initials: S
authors.lastname: Hatse
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: P
authors.initials: P
authors.lastname: Borst
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D004285:Dogs; D018432:Drug Resistance, Multiple; D006801:Humans; D017136:Ion Transport; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D009711:Nucleotides