MRP2 and the DMPS- and DMSA-mediated elimination of mercury in TR- and control rats exposed to thiol S-conjugates of inorganic mercury

Cysteine (Cys) and homocysteine (Hcy)-S-conjugates of inorganic mercury (Hg(2+)) are transportable species of Hg(2+) that are taken up readily by proximal tubular cells. The metal chelators, 2,3-dimercaptopropane-1-sulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA), have been used successfully to extract Hg(2+) from these cells, presumably via the multidrug resistance protein (Mrp2). In the current study, we tested the hypothesis that Mrp2 is involved in the DMPS- and DMSA-mediated extraction of Hg(2+) following administration of Hg(2+) as an S-conjugate of Cys or Hcy. To test this hypothesis, control and TR(-) (Mrp2-deficient) rats were injected with 0.5 mu mol/kg HgCl(2) (containing (203)Hg(2+)) conjugated to 1.25 mu mol/kg Cys or Hcy. After 24 and 28 h, rats were treated with saline or 100 mg/kg DMPS or DMSA. Tissues were harvested 48 h after Hg(2+) exposure. The renal and hepatic burden of Hg(2+) was greater in saline-injected TR(-) rats than in corresponding controls. Accordingly, the content of Hg(2+) in the urine and feces was less in TR(-) rats than in controls. Following treatment with DMPS or DMSA, the renal content of Hg(2+) in both groups of rats was reduced significantly and the urinary excretion of Hg(2+) was increased. In liver, the effect of each chelator appeared to be dependent upon the form in which Hg(2+) was administered. In vitro experiments provide direct evidence indicating that DMPS and DMSA-S-conjugates of Hg(2+) are substrates for Mrp2. Overall, these data support our hypothesis that Mrp2 is involved in the DMPS and DMSA-mediated extraction of the body burden of Hg(2+).