MRP2 and the DMPS- and DMSA-Mediated Elimination of Mercury in TR− and Control Rats Exposed to Thiol S-Conjugates of Inorganic Mercury

摘要

Cysteine (Cys) and homocysteine (Hcy)-S-conjugates of inorganic mercury (Hg²⁺) are transportable species of Hg²⁺ 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 Hg²⁺ 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 Hg²⁺ following administration of Hg²⁺ as an S-conjugate of Cys or Hcy. To test this hypothesis, control and TR⁻ (Mrp2-deficient) rats were injected with 0.5 μmol/kg HgCl2 (containing ²⁰³Hg²⁺) conjugated to 1.25 μmol/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 Hg²⁺ exposure. The renal and hepatic burden of Hg²⁺ was greater in saline-injected TR⁻ rats than in corresponding controls. Accordingly, the content of Hg²⁺ in the urine and feces was less in TR⁻ rats than in controls. Following treatment with DMPS or DMSA, the renal content of Hg²⁺ in both groups of rats was reduced significantly and the urinary excretion of Hg²⁺ was increased. In liver, the effect of each chelator appeared to be dependent upon the form in which Hg²⁺ was administered. In vitro experiments provide direct evidence indicating that DMPS and DMSA-S-conjugates of Hg²⁺ 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 Hg²⁺.