Interaction of 2,3-dimercapto-1-propane sulfonate with the human organic anion transporter hOAT1.
The kidney is the primary target organ in which inorganic mercury (Hg2+) accumulates and expresses its toxic effects. The chelating agent 2,3-dimercapto-1-propanesulfonic acid (DMPS) can rapidly reduce the renal burden of mercury and increase the urinary excretion of mercury. However, the cellular and molecular basis of its efficacy is still unknown. A number of previous studies implicated the "classical organic anion secretory pathway" in the secretion of DMPS and its chelation products. In this study we used the human ortholog of the organic anion transporter (hOAT1) expressed in the Xenopus oocyte expression system to study the interaction of DMPS and its mercury chelates with hOAT1. [3H]PAH was used to show the transport activity of hOAT1 (Km = 3.9 +/-1.3 microM). Uptake of [3H]para-aminohippuric acid (PAH) was inhibited by reduced DMPS (K(i) = 22.4 +/- 8.4 microM). We also investigated the interaction of oxidized DMPS with hOAT1 because it has been shown that at least 80% of DMPS in the blood is oxidized within 30 min. Oxidized DMPS also inhibited uptake of [3H]PAH (K(i) = 66 +/-13.6 microM). In contrast, we found no interaction of the DMPS-Hg chelate with hOAT1. To determine whether DMPS and oxidized DMPS are transported by hOAT1 we examined the effect of inwardly directed gradients these two compounds on efflux of [3H]PAH from HeLa cells transiently transfected with hOAT1. Gradients of both DMPS and oxidized DMPS significantly trans-stimulated efflux of [3H]PAH. These data suggest that hOAT1 can transport DMPS and oxidized DMPS, whereas the DMPS-Hg chelate has no significant affinity for the transporter.
Islinger
F
F
Department of Physiology, University of Arizona, Tucson, 85724, USA.
Gekle
M
M
Wright
S H
SH
D000418:Albumins / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008628:Mercury / Q000494:pharmacology; D027362:Organic Anion Transport Protein 1 / Q000187:drug effects*; D010084:Oxidation-Reduction; D014494:Unithiol / Q000494:pharmacology*; D010130:p-Aminohippuric Acid / Q000378:metabolism
D000418:Albumins; D002614:Chelating Agents; D027362:Organic Anion Transport Protein 1; D014494:Unithiol; D008628:Mercury; D010130:p-Aminohippuric Acid