[Human renal urate transpoter URAT1 mediates the transport of salicylate].
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.
Ohtsu
Naoko
N
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
Anzai
Naohiko
N
Fukutomi
Toshiyuki
T
Kimura
Toru
T
Sakurai
Hiroyuki
H
Endou
Hitoshi
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D027361:Organic Anion Transporters / Q000502:physiology*; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D011898:Ranidae; D012459:Salicylates / Q000378:metabolism* / Q000494:pharmacology; D014527:Uric Acid / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D012459:Salicylates; D014527:Uric Acid