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The Human Multidrug Resistance Protein MRP5 Transports Folates and Can Mediate Cellular Resistance against Antifolates

¹ Division of Molecular Biology and Center of Biomedical Genetics, The Netherlands Cancer Institute; ² Pediatrics Oncology/Hematology, ³ Med Oncology, and ⁴ Rheumatology, VU University Medical Center; and ⁵ The Netherlands Ophthalmic Research Institute, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands

Requests for reprints: Piet Borst, Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 31-20-5122880; Fax: 31-20-6691383; E-mail: P.Borst{at}nki.nl.

Members of the multidrug resistance protein family, notably MRP1-4/ABCC1-4, and the breast cancer resistance protein BCRP/ABCG2 have been recognized as cellular exporters for the folate antagonist methotrexate (MTX). Here we show that MRP5/ABCC5 is also an antifolate and folate exporter based on the following evidence: (a) Using membrane vesicles from HEK293 cells, we show that MRP5 transports both MTX (K_M = 1.3 mmol/L and V_MAX = 780 pmol per mg protein per minute) and folic acid (K_M = 1.0 mmol/L and V_MAX = 875 pmol per mg protein per minute). MRP5 also transports MTX-glu₂ (K_M = 0.7 mmol/L and V_MAX = 450 pmol per mg protein per minute) but not MTX-glu₃. (b) Both accumulation of total [³H]MTX and of MTX polyglutamates were significantly reduced in MRP5 overexpressing cells. (c) Cell growth inhibition studies with MRP5 transfected HEK293 cells showed that MRP5 conferred high-level resistance (>160-fold) against the antifolates MTX, GW1843, and ZD1694 (raltitrexed) in short-term (4 hours) incubations with high drug concentrations; this resistance was proportional to the MRP5 level. (d) MRP5-mediated resistance (8.5- and 2.1-fold) was also found in standard long-term incubations (72 hours) at low concentrations of ZD1694 and GW1843. These results show the potential of MRP5 to mediate transport of (anti)folates and contribute to resistance against antifolate drugs.

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