MRP3, an organic anion transporter able to transport anti-cancer drugs

The human multidrug-resistance protein (MRP) gene family contains at least six members: MRP1, encoding the multidrug-resistance protein; MRP2 or cMOAT , encoding the canalicular multispecific organic anion transporter; and fou r homologs, called MRP3, MRP4, MRP5, and MRP6. In this report, we character ize MRP3, the closest homolog of MRP1. Cell lines were retrovirally transdu ced with MRP3 cDNA, and new monoclonal antibodies specific for MRP3 were ge nerated. We show that MRP3 is an organic anion and multidrug transporter, l ike the GS-X pumps MRP1 and MRP2. In Madin-Darby canine kidney IZ cells, MR P3 routes to the basolateral membrane and mediates transport of the organic anion S-(2,4-dinitrophenyl-) glutathione toward the basolateral side of th e monolayer. In ovarian carcinoma cells (2008), expression of MRP3 results in low-level resistance to the epipodophyllotoxins etoposide and teniposide . In short-term drug exposure experiments, MRP3 also confers high-level res istance to methotrexate. Neither 2008 cells nor Madin-Darby canine kidney I I cells overexpressing MRP3 showed an increase in glutathione export or a d ecrease in the level of intracellular glutathione, in contrast to cells ove rexpressing MRP1 or MRP2. We discuss the possible function of MRP3 in (hepa tic) physiology and its potential contribution to drug resistance of cancer cells.