Monoisoamyl meso-2,3-dimercaptosuccinate: interaction with metallothionein-bound cadmium in vitro and evidence of active transport into renal and hepatic cells in vivo.
Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and the unesterified 2,3-dimercaptosuccinic acid (DMSA) were evaluated for relative reactivities against metallothionein (MT)-bound cadmium (Cd) in vitro by elution of the reaction products through Sephadex G-75 gel. After 3 hr of incubation, Mi-ADMS removed about 70% of the Cd from Cd-MT, and a new peak emerged which corresponded to that obtained by elution of a 2:1 molar mixture of Mi-ADMS and Cd. Only about 15% of the Cd was removed from Cd-MT by DMSA. After 24 hr of incubation with Mi-ADMS, no evidence remained of the presence of Cd-MT; all of the Cd was recovered in a very high molecular weight fraction and in a fraction corresponding to Cd ion. In contrast, after 24 hr of incubation with DMSA, 25% of the Cd was still present as Cd-MT, while the remainder eluted in a fraction corresponding to a 2:1 molar complex of DMSA and Cd. When Mi-ADMS was administered to Cd-bearing mice which had received an inhibitor of organic anion transport, probenecid (PBC) or sulfinpyrazone (SPZ), prior to administration of the monoester, there was a marked attenuation of the Cd mobilizing actions of Mi-ADMS as reflected in whole body Cd levels. Analysis of organ Cd concentrations revealed that PBC blocked primarily the mobilization of renal Cd by Mi-ADMS, while the principal action of SPZ in antagonizing the action of Mi-ADMS was on hepatic Cd mobilization. It was concluded that Mi-ADMS has a higher affinity for Cd in Cd-MT than does DMSA, and that the access of Mi-ADMS to intracellular Cd is, at least in part, mediated by the organic anion transport system.
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Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina 29401.
Gale
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Smith
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Jones
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Singh
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D000818:Animals; D001693:Biological Transport, Active; D002104:Cadmium / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D011339:Probenecid / Q000494:pharmacology; D013386:Succinates / Q000378:metabolism* / Q000493:pharmacokinetics; D013442:Sulfinpyrazone / Q000494:pharmacology; D013859:Thiocarbamates / Q000378:metabolism* / Q000493:pharmacokinetics
D013386:Succinates; D013859:Thiocarbamates; C004203:cadmium-binding protein; D002104:Cadmium; D008668:Metallothionein; D011339:Probenecid; D013442:Sulfinpyrazone