[Human renal urate transpoter URAT1 mediates the transport of salicylate].Nihon Jinzo Gakkai Shi. 2010; 52(4):499-504.NJ
Salicylic acid derivatives are the most prescribed analgesic-antipyretic and anti-inflammatory agents. It is well known that salicylate has a paradoxical effect on renal urate excretion. At low doses (5 - 10 mg/dL serum), renal urate excretion is decreased, whereas at high doses (> 15 mg/dL serum), renal urate excretion is increased. Since the molecular identification of the renal apical urate/anion exchanger URAT1, it has been suggested that this protein is responsible for the paradoxical effect because of cis-inhibition of salicylate (1 mM) on urate uptake by URAT1-expressing oocytes. The purpose of this study was to examine whether or not URAT1 is responsible for the paradoxical effect of salicylate. In URAT1-stably expressing HEK293 (HEK293-URAT1) cells, salicylate inhibited [14C] urate uptake dose-dependently (IC50, 23.9 microM). URAT1 mediated the time-dependent uptake of [3H] salicylate in these cells. [3H] Salicylate uptake via URAT1 was inhibited by non-labelled urate and salicylate, and the uricosuric agent, benzbromarone. In the URAT1-expressing oocytes, we observed the time- and concentration-dependent transport of salicylate (Km : 25.3 microM). Moreover, non-labelled salicylate injected into the URATI-expressing oocytes stimulated [14C] urate uptake. These results suggest that the "paradoxical effect" of salicylate can be explained by two modes of salicylate interaction with URAT1 : (1) acting as an exchange substrate to facilitate urate reabsorption, and (2) acting as an inhibitor for urate reabsorption.