ToxSci Advance Access originally published online on May 28, 2008
Toxicological Sciences 2008 105(1):211-220; doi:10.1093/toxsci/kfn107
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MRP2 and the DMPS- and DMSA-Mediated Elimination of Mercury in TR– and Control Rats Exposed to Thiol S-Conjugates of Inorganic Mercury
Mercer University School of Medicine, Division of Basic Medical Sciences, Macon, Georgia 31207
1 To whom correspondence should be addressed at Mercer University School of Medicine, Division of Basic Medical Sciences, 1550 College Street, Macon, GA 31207. Fax: (478) 301-5487. E-mail: bridges_cc{at}mercer.edu.
Received April 21, 2008; accepted May 21, 2008
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Abstract |
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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+.
Key Words: mercury; transport; chelators; multidrug resistance protein.