期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 288, 期 2, 页码 F327-F333出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00133.2004
关键词
multidrug resistance protein; kidney; cGMP; positive cooperativity
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 muM) 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 muM 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.
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