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 (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 micromol/kg HgCl2 (containing 203Hg2+) conjugated to 1.25 micromol/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+.
Mercer University School of Medicine, Division of Basic Medical Sciences, Macon, Georgia 31207, USA. bridges_cc@mercer.edu
Christy C
CC
Bridges
Lucy
L
Joshee
Rudolfs K
RK
Zalups
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001822:Body Burden; D002614:Chelating Agents / Q000494:pharmacology*; D003545:Cysteine / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008628:Mercury / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D004113:Succimer / Q000494:pharmacology*; D014494:Unithiol / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002614:Chelating Agents; D006710:Homocysteine; D014494:Unithiol; D004113:Succimer; D008628:Mercury; D003545:Cysteine