Determination and metabolism of dithiol chelating agents: the zinc chelate of the dimethyl ester of meso-2,3-dimercaptosuccinic acid increase biliary excretion of cadmium and platinum.
meso-2,3-Dimercaptosuccinic acid is an orally active chelating agent useful for the treatment of lead intoxication. Since it is believed to be extracellular in its distribution, analogs have been synthesized in a search for one that will enter the cell and successfully complete for firmly bound intracellular toxic heavy metals such as cadmium and platinum. The biological properties of the zinc chelate of DiMeDMSA, ([Zn(DiMeDMSA)2]2- with tetramethylammonium or sodium as the counterion, have been investigated in the rat. In short-term (hourly) experiments, [Zn(DiMeDMSA)2]2- increased the biliary excretion of cadmium and platinum. In experiments of longer duration (days), severe renal toxicity was noted even in the absence of any exogenously administered cadmium chloride or cis-dichlorodiammineplatinum(II). The zinc content of the kidneys of rats receiving Na2[Zn(DiMeDMSA)2]2- was found to be about 10-fold greater than rats receiving saline or meso-dimethyldimercaptosuccinic acid. Although it appears that the source of the zinc is the injected [Zn(DiMeDMSA)2]2-, at this time it is unknown as to whether the toxicity is due to the Zn chelate molecule, per se, or Zn derived from the molecule after its degradative biotransformation.
University Department of Molecular and Cellular Biology, University of Arizona, Tucson 85721.
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Aposhian
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Levine
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Rivera
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Fernando
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D002104:Cadmium / Q000378:metabolism*; D002106:Cadmium Radioisotopes; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002945:Cisplatin / Q000633:toxicity; D004492:Edetic Acid / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010984:Platinum / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D004113:Succimer / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015032:Zinc / Q000494:pharmacology* / Q000633:toxicity
D002106:Cadmium Radioisotopes; D002614:Chelating Agents; D000644:Quaternary Ammonium Compounds; D002104:Cadmium; D010984:Platinum; D004492:Edetic Acid; D004113:Succimer; C027917:tetramethylammonium; D015032:Zinc; D002945:Cisplatin