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Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites

Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

Submitted 14 April 2004 ; accepted in final form 23 September 2004

The end product of human purine metabolism is urate, which is produced primarily in the liver and excreted by the kidney through a well-defined basolateral blood-to-cell uptake step. However, the apical cell-to-urine efflux mechanism is as yet unidentified. Here, we show that the renal apical organic anion efflux transporter human multidrug resistance protein 4 (MRP4), but not apical MRP2, mediates ATP-dependent urate transport via a positive cooperative mechanism (K_m of 1.5 ± 0.3 mM, V_max of 47 ± 7 pmol·mg^–1·min^–1, and Hill coefficient of 1.7 ± 0.2). In HEK293 cells overexpressing MRP4, intracellular urate levels were lower than in control cells. Urate inhibited methotrexate transport (IC₅₀ of 235 ± 8 µM) by MRP4, did not affect cAMP transport, whereas cGMP transport was stimulated. Urate shifted cGMP transport by MRP4 from positive cooperativity (K_m and V_max value of 180 ± 20 µM and 58 ± 4 pmol·mg^–1·min^–1, respectively, Hill coefficient of 1.4 ± 0.1) to single binding site kinetics (K_m and V_max value of 2.2 ± 0.9 mM and 280 ± 50 pmol·mg^–1·min^–1, respectively). Finally, MRP4 could transport urate simultaneously with cAMP or cGMP. We conclude that human MRP4 is a unidirectional efflux pump for urate with multiple allosteric substrate binding sites. We propose MRP4 as a candidate transporter for urinary urate excretion and suggest that MRP4 may also mediate hepatic export of urate into the circulation, because of its basolateral expression in the liver.

multidrug resistance protein; kidney; cGMP; positive cooperativity

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