Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs

Two prominent members of the ATP-binding cassette superfamily of transmembr ane proteins, multidrug resistance 1 (MDR1) P-glycoprotein and multidrug re sistance protein 1 (MRP1), can mediate the cellular extrusion of xenobiotic s and (anticancer) drugs from normal and tumor cells. The MRP subfamily con sists of at least six members, and here we report the functional characteri zation of human MRP5, We found resistance against the thiopurine anticancer drugs, C-mercaptopurine (6-MP) and thioguanine, and the anti-HIV drug 9-(2 -phosphonylmethoxyethyl)adenine (PMEA) in MRP5-transfected cells. This resi stance is due to an increased extrusion of PMEA and 6-thioinosine monophosp hate from the cells that overproduce MRP5, In polarized Madin-Darby canine kidney II (MDCKII) cells transfected with an MRP5 cDNA construct, MRP5 is r outed to the basolateral membrane and these cells transport S-(2,4-dinitrop henyl)glutathione and glutathione preferentially toward the basal compartme nt Inhibitors of organic anion transport inhibit transport mediated by MRP5 , We speculate that MRP5 might play a role in some cases of unexplained res istance to thiopurines in acute lymphoblastic leukemia and/or to antiretrov iral nucleoside analogs in HIV-infected patients.