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Am J Physiol Renal Physiol (September 28, 2004). doi:10.1152/ajprenal.00133.2004
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Submitted on April 14, 2004
Accepted on September 23, 2004

Human Organic Anion Transporter MRP4 (ABCC4) is an Efflux Pump for the Purine End Metabolite Urate with Multiple Allosteric Substrate Binding Sites

Remon A.M.H. van Aubel1, Pascal H.E. Smeets1, J. J.M.W. van den Heuvel1, and Frans G.M. Russel1*

1 Department of Pharmacology-Toxicology 233, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

* To whom correspondence should be addressed. E-mail: F.Russel{at}ncmls.kun.nl.

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, apical cell-to-urine efflux mechanism has yet been unidentified. Here, we show that the renal apical organic anion efflux transporter human MRP4, but not apical MRP2, mediates ATP-dependent urate transport via a positive cooperative mechanism (Km of 1.5 ± 0.3 mM, Vmax of 47 ± 7 pmol/mg/min, 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 (Km and Vmax value of 180 ± 20 µM and 58 ± 4 pmol/mg/min, Hill coefficient of 1.4 ± 0.1) to single binding site kinetics (Km and Vmax value of 2.2 ± 0.9 mM and 280 ± 50 pmol/mg/min). 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.




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