MRP2 and the handling of mercuric ions in rats exposed acutely to inorganic and organic species of mercury
2011
Bridges, Christy C. | Joshee, Lucy | Zalups, Rudolfs K.
Mercuric ions accumulate preferentially in renal tubular epithelial cells and bond with intracellular thiols. Certain metal-complexing agents have been shown to promote extraction of mercuric ions via the multidrug resistance-associated protein 2 (MRP2). Following exposure to a non-toxic dose of inorganic mercury (Hg²⁺), in the absence of complexing agents, tubular cells are capable of exporting a small fraction of intracellular Hg²⁺ through one or more undetermined mechanisms. We hypothesize that MRP2 plays a role in this export. To test this hypothesis, Wistar (control) and TR⁻ rats were injected intravenously with a non-nephrotoxic dose of HgCl₂ (0.5μmol/kg) or CH₃HgCl (5mg/kg), containing [²⁰³Hg], in the presence or absence of cysteine (Cys; 1.25μmol/kg or 12.5mg/kg, respectively). Animals were sacrificed 24h after exposure to mercury and the content of [²⁰³Hg] in blood, kidneys, liver, urine and feces was determined. In addition, uptake of Cys-S-conjugates of Hg²⁺ and methylmercury (CH₃Hg⁺) was measured in inside-out membrane vesicles prepared from either control Sf9 cells or Sf9 cells transfected with human MRP2. The amount of mercury in the total renal mass and liver was significantly greater in TR⁻ rats than in controls. In contrast, the amount of mercury in urine and feces was significantly lower in TR⁻ rats than in controls. Data from membrane vesicles indicate that Cys-S-conjugates of Hg²⁺ and CH₃Hg⁺ are transportable substrates of MRP2. Collectively, these data indicate that MRP2 plays a role in the physiological handling and elimination of mercuric ions from the kidney.
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