Determination and metabolism of dithiol chelating agents. VII. Biliary excretion of dithiols and their interactions with cadmium and metallothionein.
N-(2,3-Dimercaptopropyl) phthalamidic acid (DMPA), meso-dimercaptosuccinic acid (DMSA), and 2,3-dimercapto-1-propanesulfonic acid (DMPS) are dithiol chelating agents with antidotal activity for lead, mercury, arsenic, and other heavy metals. The biliary excretion of these compounds was studied in male Sprague-Dawley rats. After iv administration of DMPA, 72% of the injected dose was recovered in the bile. Half of the recovered DMPA was in the unaltered form (parent compound) and the other half was in the altered form (parent compound recovered after chemical reduction by DTT). An altered, presumably disulfide, form of DMPS was found in the bile. Neither unaltered nor altered DMSA was detected in the bile. DMPA (0.10 mmol/kg), given to rats 3 days after exposure to Cd, elicited within 30 min a 20-fold increase in biliary Cd excretion. The increase of biliary Cd by DMPA was dose-related and not due to an increase of bile flow rate. DMSA and DMPS did not significantly affect the biliary excretion of Cd. Incubation of DMPA or DMSA with Cd-saturated metallothionein (MT) resulted in the removal of Cd from MT. DMPA was more active than DMSA in this respect. The evidence strongly supports the mechanism that the increase of biliary cadmium following DMPA administration is the result of DMPA entering cells and mobilizing and removing the cadmium from MT. The removal of cadmium from metallothionein by dithiol chelating agents provides another dimension to their mechanisms of action and may provide an important new tool for the study of cadmium as well as metallothionein.
Zheng
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Department of Pharmacology and Toxicology, University of Arizona, Tucson 85721.
Maiorino
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RM
Brendel
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Aposhian
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HV
D000818:Animals; D001646:Bile / Q000378:metabolism*; D002104:Cadmium / Q000378:metabolism*; D002106:Cadmium Radioisotopes; D002614:Chelating Agents / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D010795:Phthalic Acids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D004113:Succimer / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014462:Ultrafiltration; D014494:Unithiol / Q000378:metabolism
D002106:Cadmium Radioisotopes; D002614:Chelating Agents; D010795:Phthalic Acids; D013438:Sulfhydryl Compounds; D002104:Cadmium; C029298:N-(2,3-dimercaptopropyl)phthalamidic acid; D014494:Unithiol; D008668:Metallothionein; D004113:Succimer