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

Marcel Kool, Marcel Van Der Linden, Marcel De Haas, George L. Scheffer, J. Marleen L. De Vree, Alexander J. Smith, Gerrit Jansen, Godefridus J. Peters, Nico Ponne, Rik J. Scheper, Ronald P.J. Oude Elferink, Frank Baas, Piet Borst

Research output: Contribution to journalArticlepeer-review

601 Citations (Scopus)

Abstract

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 four homologs, called MRP3, MRP4, MRP5, and MRP6. In this report, we characterize MRP3, the closest homolog of MRP1. Cell lines were retrovirally transduced with MRP3 cDNA, and new monoclonal antibodies specific for MRP3 were generated. We show that MRP3 is an organic anion and multidrug transporter, like the GS-X pumps MRP1 and MRP2. In Madin-Darby canine kidney II cells, MRP3 routes to the basolateral membrane and mediates transport of the organic anion S-(2,4-dinitrophenyl-) glutathione toward the basolateral side of the 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 resistance to methotrexate. Neither 2008 cells nor Madin-Darby canine kidney II cells overexpressing MRP3 showed an increase in glutathione export or a decrease in the level of intracellular glutathione, in contrast to cells overexpressing MRP1 or MRP2. We discuss the possible function of MRP3 in (hepatic) physiology and its potential contribution to drug resistance of cancer cells.

Original languageEnglish
Pages (from-to)6914-6919
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number12
DOIs
Publication statusPublished - 8 Jun 1999
Externally publishedYes

Keywords

  • Etoposide
  • Methotrexate
  • Multidrug resistance

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