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Organic anion transporter 3 (OAT3) and renal transport of the metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS).

ABSTRACT: Recent investigations involving intact rabbit renal proximal tubules indicated that organic anion transporter 3 (OAT3) may be involved in the transport of 2,3-dimercapto-1-propanesulfonic acid (DMPS). Therefore, we evaluated the interaction of OAT3 with DMPS to determine the effect of OAT3 on basolateral DMPS uptake. We used stably transfected HEK293 cells expressing human and rabbit orthologs of the exchanger OAT1 and OAT3. Using 6-carboxyfluorescein (6-CF) as a substrate, the IC50 determinations for reduced DMPS (DMPSH) revealed a stronger interaction with OAT1 than with OAT3 (rbOAT1, 123.3 +/- 13.7; hOAT1, 85.1 +/- 8.8; rbOAT3, 171.7 +/- 22.3; and hOAT3, 172.2 +/- 36.4 micromol/L). However, inhibition of 6-CF uptake by the oxidized form of DMPS (DMPSS), the main form of DMPS in the blood, showed a greater affinity for OAT3 (rbOAT1, 237.4 +/- 23; hOAT1, 104.6 +/- 13.1; rbOAT3, 52.4 +/- 7.6; and hOAT3, 31.6 +/- 6.6 micromol/L). To determine whether DMPSH and DMPSS are substrates for OAT3, we performed efflux studies with [14C]glutarate and inwardly directed gradients of glutarate. The inhibitors trans-stimulated the efflux of [14C]glutarate, suggesting that OAT3 may be able to transport both forms of DMPS. On the basis of the substantial interaction of OAT3 with DMPSS, we conclude that OAT3 represents the dominant basolateral player in renal detoxification processes resulting from use of DMPS.

SUBMITTER: Rodiger M

PROVIDER: S-EPMC4417359 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Organic anion transporter 3 (OAT3) and renal transport of the metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS).

Rödiger Matthias M Zhang Xiaohong X Ugele Bernhard B Gersdorff Nikolaus N Wright Stephen H SH Burckhardt Gerhard G Bahn Andrew A

Canadian journal of physiology and pharmacology 20100201 2

Recent investigations involving intact rabbit renal proximal tubules indicated that organic anion transporter 3 (OAT3) may be involved in the transport of 2,3-dimercapto-1-propanesulfonic acid (DMPS). Therefore, we evaluated the interaction of OAT3 with DMPS to determine the effect of OAT3 on basolateral DMPS uptake. We used stably transfected HEK293 cells expressing human and rabbit orthologs of the exchanger OAT1 and OAT3. Using 6-carboxyfluorescein (6-CF) as a substrate, the IC50 determinatio ...[more]

PMID: 20237588

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Project description:Carboxyfluoroquinolones, such as ciprofloxacin, are used for the treatment of numerous infectious diseases. Renal secretion is a major determinant of their systemic and urinary concentration, but the specific transporters involved are virtually unknown. In vivo studies implicate the organic anion transporter (OAT) family as a pivotal component of carboxyfluoroquinolone renal secretion. Therefore, this study identified the specific renal basolateral OAT(s) involved, thereby highlighting potential sources of carboxyfluoroquinolone-drug interactions and variable efficacy. Two heterologous expression systems, Xenopus laevis oocytes and cell monolayers, were used to determine the roles of murine and human renal basolateral mOat1/hOAT1 and mOat3/hOAT3. Ciprofloxacin was transported by mOat3 in both systems (K(m) value, 70 +/- 6 microM) and demonstrated no interaction with mOat1 or hOAT1. Furthermore, ciprofloxacin, norfloxacin, ofloxacin, and gatifloxacin exhibited concentration-dependent inhibition of transport on mOat3 in cells with inhibition constants of 198 +/- 39, 558 +/- 75, 745 +/- 165, and 941 +/- 232 microM, respectively. Ciprofloxacin and gatifloxacin also inhibited hOAT3. Thereafter, in vivo elimination of ciprofloxacin was assessed in wild-type and Oat3 null mice [Oat3-/-]. Oat3-/- mice exhibited significantly elevated plasma levels of ciprofloxacin at clinically relevant concentrations (P < 0.05, male mice; P < 0.01, female mice). Oat3-/- mice also demonstrated a reduced volume of distribution (27%, P < 0.01, male mice; 14%, P < 0.01, female mice) and increased area under the concentration-time curve (25%, P < 0.05, male mice; 33%, P < 0.01, female mice). Female Oat3-/- mice had a 35% (P < 0.01) reduction in total clearance of ciprofloxacin relative to wild type. In addition, putative ciprofloxacin metabolites were significantly elevated in Oat3-/- mice. The present findings indicate that polymorphisms of and drug interactions on hOAT3 may influence carboxyfluoroquinolone efficacy, especially in urinary tract infections.

Dataset Information

Organic anion transporter 3 (OAT3) and renal transport of the metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS).

Publications

Organic anion transporter 3 (OAT3) and renal transport of the metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS).

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