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J. Biol. Chem., Vol. 283, Issue 24, 16332-16341, June 13, 2008

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Identification of a New Urate and High Affinity Nicotinate Transporter, hOAT10 (SLC22A13)^*

Andrew Bahn¹, Yohannes Hagos, Stefan Reuter, Daniela Balen^¶, Hrvoje Brzica^¶, Wolfgang Krick, Birgitta C. Burckhardt, Ivan Saboli^¶, and Gerhard Burckhardt

From the Zentrum Physiologie und Pathophysiologie, Abteilung Vegetative Physiologie und Pathophysiologie, Humboldtallee 23, 37073 Göttingen, Germany, the ^¶Unit of Molecular Toxicology, Institute for Medical Research & Occupational Health, Ksaverska cesta 2, HR-10001 Zagreb, Croatia, and the Universitätsklinikum Münster, Medizinische Klinik und Poliklinik D, Exp. Nephrologie, Domagkstrasse 3a, 48147 Münster, Germany

The orphan transporter hORCTL3 (human organic cation transporter like 3; SLC22A13) is highly expressed in kidneys and to a weaker extent in brain, heart, and intestine. hORCTL3-expressing Xenopus laevis oocytes showed uptake of [³H]nicotinate, [³H]p-aminohippurate, and [¹⁴C]urate. Hence, hORCTL3 is an organic anion transporter, and we renamed it hOAT10. [³H]Nicotinate transport by hOAT10 into X. laevis oocytes and into Caco-2 cells was saturable with Michaelis constants (K_m) of 22 and 44 µM, respectively, suggesting that hOAT10 may be the molecular equivalent of the postulated high affinity nicotinate transporter in kidneys and intestine. The pH dependence of hOAT10 suggests p-aminohippurate^–/OH^–, urate^–/OH^–, and nicotinate^–/OH^– exchange as possible transport modes. Urate inhibited [³H]nicotinate transport by hOAT10 with an IC₅₀ value of 759 µM, assuming that hOAT10 represents a low affinity urate transporter. hOAT10-mediated [¹⁴C]urate uptake was elevated by an exchange with L -lactate, pyrazinoate, and nicotinate. Surprisingly, we have detected urate^–/glutathione exchange by hOAT10, consistent with an involvement of hOAT10 in the renal glutathione cycle. Uricosurics, diuretics, and cyclosporine A showed substantial interactions with hOAT10, of which cyclosporine A enhanced [¹⁴C]urate uptake, providing the first molecular evidence for cyclosporine A-induced hyperuricemia.

Received for publication, January 29, 2008 , and in revised form, March 14, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-551-395894; Fax: 49-551-395883; E-mail: abahn{at}physiol.med.uni-goettingen.de.

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