Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 251, Issue 1, Pages 50-58Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2010.11.015
Keywords
Mercury; Multidrug resistance-associated protein; Kidney; Transport
Categories
Funding
- National Institutes of Health/National Institute of Environmental Health Sciences [ES015157, ES05980, ES11288, ES015511]
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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 (Hg(2+)), in the absence of complexing agents, tubular cells are capable of exporting a small fraction of intracellular Hg(2+) 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 HgCl(2) (0.5 mu mol/kg) or CH(3)HgCl (5 mg/kg), containing [(203)Hg], in the presence or absence of cysteine (Cys: 1.25 mu mol/kg or 12.5 mg/kg. respectively). Animals were sacrificed 24 h after exposure to mercury and the content of [(203)Hg] in blood, kidneys, liver, urine and feces was determined. In addition, uptake of Cys-S-conjugates of Hg(2+) and methylmercury (CH(3)Hg(+)) 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 Hg(2+) and CH(3)Hg(+) 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. (C) 2010 Elsevier Inc. All rights reserved.
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