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Experimental Therapeutics |
Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [Z-S. C., K. L., S. W., R. B. R., H. Z., G. D. K.], and Department of Medicinal Biochemistry, Graduate School of Medical Sciences, Kyushu University School of Medicine, Fukuoka 812-8582, Japan [M. K.]
Human MRP4 (ABCC4, MOAT-B) is a lipophilic anion transporter that is able to confer resistance to nucleotide analogues and methotrexate (MTX). We previously investigated the implications of the ability of MRP4 to confer resistance to nucleotide analogues and determined that the pump is competent in the MgATP-energized transport of cyclic nucleotides and estradiol 17ß-D-glucuronide. Here we examine the potential role of MRP4 in conferring resistance to MTX and related processes by determining the selectivity of the transporter for MTX, MTX polyglutamates, and physiological folates. In so doing, it is shown that MRP4 is active in the transport of MTX as well as the physiological folates folic acid (FA) and N5-formyltetrahydrofolic acid (leucovorin). MTX, FA, and leucovorin are subject to high capacity [Vmax(MTX), 0.24 ± 0.05 nmol/mg/min; Vmax (FA), 0.68 ± 0.14 nmol/mg/min; Vmax(leucovorin), 1.95 ± 0.18 nmol/mg/min], low affinity [Km(MTX), 0.22 ± 0.01 mM; Km(FA), 0.17 ± 0.02 mM; Km (leucovorin), 0.64 ± 0.23 mM] transport by MRP4. In addition, as would be expected were MRP4 a component of the MTX efflux system, its capacity to transport this agent is abrogated by the addition of a single glutamyl residue. It is also shown that glutamylation similarly affects the ability of MRP2 to transport MTX. On the basis of these transport properties, it is concluded that the efflux system for MTX includes MRP2 and MRP4, in addition to MRP1 and MRP3, and that MRP4 represents a common efflux system for both MTX and certain nucleotide analogues.
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G. Reid, P. Wielinga, N. Zelcer, M. de Haas, L. van Deemter, J. Wijnholds, J. Balzarini, and P. Borst Characterization of the Transport of Nucleoside Analog Drugs by the Human Multidrug Resistance Proteins MRP4 and MRP5 Mol. Pharmacol., May 1, 2003; 63(5): 1094 - 1103. [Abstract] [Full Text] [PDF]
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Y. G. Assaraf, L. Rothem, J. H. Hooijberg, M. Stark, I. Ifergan, I. Kathmann, B. A. C. Dijkmans, G. J. Peters, and G. Jansen Loss of Multidrug Resistance Protein 1 Expression and Folate Efflux Activity Results in a Highly Concentrative Folate Transport in Human Leukemia Cells J. Biol. Chem., February 21, 2003; 278(9): 6680 - 6686. [Abstract] [Full Text] [PDF]
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Z.-S. Chen, E. Hopper-Borge, M. G. Belinsky, I. Shchaveleva, E. Kotova, and G. D. Kruh Characterization of the Transport Properties of Human Multidrug Resistance Protein 7 (MRP7, ABCC10) Mol. Pharmacol., February 1, 2003; 63(2): 351 - 358. [Abstract] [Full Text] [PDF]
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M. G. Belinsky, Z.-S. Chen, I. Shchaveleva, H. Zeng, and G. D. Kruh Characterization of the Drug Resistance and Transport Properties of Multidrug Resistance Protein 6 (MRP6, ABCC6) Cancer Res., November 1, 2002; 62(21): 6172 - 6177. [Abstract] [Full Text] [PDF]
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