Mechanisms by which the dithiol chelating agent 2, 3-dimercaptopropane-1-sulfonate (DMPS) significantly alters the renal tubular transport, accumulation, and toxicity of inorganic mercury were studied in isolated perfused pars recta (S2) segments of proximal tubules of rabbits. Addition of 200 microM DMPS to the bath provided complete protection from the toxic effects of 20 microM inorganic mercury in the lumen. The protection was linked to decreased uptake and accumulation of mercury. Additional data indicated that, when DMPS and inorganic mercury were coperfused through the lumen, very little inorganic mercury was taken up from the lumen. We also obtained data indicating that DMPS is transported by the organic anion transport system and that this transport is linked to the therapeutic effects of DMPS. Interestingly, very little inorganic mercury was taken up and no cellular pathological changes were detected when inorganic mercury and DMPS were added to the bath. We also tested the hypothesis that DMPS can extract cellular mercury while being transported from the bath into the luminal compartment. Our findings showed that, when DMPS was applied to the basolateral membranes of S2 segments after they had been exposed to mercuric conjugates of glutathione of the laminal membrane, the tubular content of mercury was greatly reduced and the rates of disappearance of mercury from the lumen changed from positive values to markedly negative values. We conclude that inorganic mercury is extracted from proximal tubular cells by a transport process involving the movement of DMPS from the bathing compartment to the luminal compartment.
Abstract. The aim of this study was to define mechanisms involved in the luminal uptake of inorganic mercury in the kidney using isolated perfused straight (S2) segments of the proximal tubule. When mercuric conjugates of glutathione (GSH), cysteinylglycine, or cysteine (containing 203Hg2+) were perfused through the lumen, the rates of luminal disappearance flux (JD) of inorganic mercury were approximately 39, 53, and 102 fmol/min per mm, respectively. Thus, the rates of luminal uptake of mercury are greater when the mercury is in the form of a mercuric conjugate of cysteine than in the form of a mercuric conjugate of cysteinylglycine or GSH. Addition of acivicin to the perfusate, to inhibit activity of the γ-glutamyltransferase, caused significant reductions in the JD for mercury in tubules perfused with mercuric conjugates of GSH. Addition of cilastatin, an inhibitor of dehydropeptidase-1 (cysteinylglycinase) activity, caused significant reductions in the uptake of mercury in tubules perfused with mercuric conjugates of cysteinylglycine. These findings indicate that a significant amount of the luminal uptake of mercury, when mercuric conjugates of GSH are present in the lumen, is dependent on the activity of both γ-glutamyltransferase and cysteinylglycinase. Finally, the JD for mercury in tubules perfused with mercuric conjugates of cysteine was reduced by approximately 50% when 3.0 mM L-lysine or 5.0 mM cycloleucine was added to the perfusate. It is concluded that these findings indicate that at least some of the luminal uptake of mercuric conjugates of cysteine occurs at the site of one or more amino acid transporters via a mechanism involving molecular homology.
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