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+) ac cumulates and expresses its toxic effects. The chelating agent 2,3-dimercap to-1-propanesulfonic acid (DMPS) can rapidly reduce the renal burden of mer cury and increase the urinary excretion of mercury. However, the cellular a nd molecular basis of its efficacy is still unknown. A number of previous s tudies implicated the "classical organic anion secretory pathway" in the se cretion 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. [H-3]PAH was used to show the transport activity of hO AT1 (K-m = 3.9 +/- 1.3 muM). Uptake of [H-3]para-aminohippuric acid (PAH) w as inhibited by reduced DMPS (K-i = 22.4 +/- 8.4 muM). 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 [H-3]PAH (K-i = 66 +/- 13.6 muM). In contrast, we found no interaction of the DMPS-Hg chelate with hOAT1. To determine wheth er DMPS and oxidized DMPS are transported by hOAT1 we examined the effect o f inwardly directed gradients these two compounds on efflux of [H-3]PAH fro m HeLa cells transiently transfected with hOAT1. Gradients of both DMPS and oxidized DMPS significantly trans-stimulated efflux of [H-3]PAH. These dat a suggest that hOAT1 can transport DMPS and oxidized DMPS, whereas the DMPS -Hg chelate has no significant affinity for the transporter.