Influence of 2,3-dimercaptopropane-1-sulfonate and dimercaptosuccinic acid on the mobilization of mercury from tissues of rats pretreated with mercuric chloride, phenylmercury acetate or mercury vapors.

The efficiency of the sodium salt of 2,3-dimercaptopropanesulfonic acid (DMPS) and meso-dimercaptosuccinic acid (DMSA) to mobilize mercury from tissues has been assessed in rats pretreated with different doses of HgCl2, phenylmercury acetate or exposed to different concentrations of mercury vapors. These pretreatments increase the mercury concentration in the kidney and to a lower extent in the liver. Only exposure to metallic mercury vapor leads to mercury accumulation in the brain. Both chelators mobilize mercury stored in the kidney and the amount of metal excreted in urine following a single administration of DMSA is a good indicator of the renal burden of mercury. The rate of removal is greater after DMPS administration than after DMSA but repeated administration of either agents eventually leads to the same total amount of mercury mobilized from the kidney. The loss of mercury from the liver can be slightly accelerated by repeated administration of the chelators. However, the chelators are inefficient in removing mercury from the brain.

Determination and metabolism of dithiol chelating agents. III. Formation of oxidized metabolites of 2,3-dimercaptopropane-1-sulfonic acid in rabbit.

Disulfide metabolites of 2,3-dimercaptopropane-1-sulfonic acid (DMPS), a heavy metal chelating agent, have been found in the urine of catheterized rabbits after a single dose of DMPS. After treating the urine with a reducing agent such as NaBH4, a 20-fold increase in DMPS was observed within 6 hr after administration. This suggested the presence of disulfide metabolites of DMPS. The disulfide metabolites were isolated from urine by extraction and were further purified by ion-interaction reverse phase HPLC. Upon reduction with NaBH4 or dithiothreitol, the isolated disulfides converted to DMPS. The isolated metabolites were not chelates of copper or zinc as determined by atomic absorption. Negative ion fast atom bombardment mass spectra indicated that the isolated metabolites were cyclic and acyclic polymeric disulfides of DMPS. The cyclic polymeric disulfides consisted of dimeric and trimeric forms of DMPS. One of the acyclic polymeric disulfides was identified as a DMPS dimer. Urinary excretion profiles of rabbits revealed that the majority of the altered DMPS consisted of cyclic and acyclic polymeric disulfides of DMPS. The cyclic disulfides increased with time while the acyclic disulfides decreased with time, suggesting that the acyclic forms are intermediates and oxidize to the cyclic forms. The rapid formation of stable 8-membered cyclic dimeric and 12-membered cyclic trimeric disulfides of DMPS strongly suggests that oxidation-reduction reactions are occurring. Both spontaneous and enzymatic oxidation mechanisms appear to be involved.

In vivo renal tubular secretion and metabolism of the disulfide of 2,3-dimercaptopropane-1-sulfonate.

The in vivo renal tubular secretion and metabolism of the disulfide of the heavy metal-complexing agent 2,3-dimercaptopropane-1-sulfonate (DMPS) was examined in the Sperber preparation. DMPS was readily oxidized to DMPS disulfide when incubated with chicken plasma, with whole blood or with urine in the presence of transition metals. Net reduction of the disulfide was not detected when the disulfide was incubated with chicken blood. When the disulfide was infused into the saphenous vein of chickens at a rate of 1 mumol of DMPS equivalents.min-1.kg of body weight-1, 62% of the DMPS disulfide that entered the renal portal circulation of the ipsilateral kidney was excreted in the urine unchanged during a single pass through the peritubular capillaries, 28% was excreted as DMPS, and 9% as an unidentified mixed disulfide. Net reduction of DMPS disulfide to DMPS occurred in vitro in rat kidney cytosol (pH 7.4) supplemented with 0.5 or 5.0 mM reduced glutathione. Reduction of DMPS disulfide to DMPS also occurred in EDTA-Tris HCl (pH 9) containing glutathione disulfide and glutathione reductase. Intracellular reduction of DMPS disulfide to DMPS in the kidney, involving a glutathione-disulfide exchange reaction, may be important for the in vivo activity of DMPS as a complexing agent for mercury.

Determination and metabolism of dithiol-chelating agents: electrolytic and chemical reduction of oxidized dithiols in urine.

The presence of oxidized species of the dithiol-chelating agents, meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS), in human urine was determined by chemical and electrolytic reduction methods. Urine from a human given either DMSA or DMPS was treated with electrolysis, dithiothreitol, or sodium tetrahydridoborate (NaBH4). The SH groups were derivatized with monobromobimane for the determination of unaltered dithiols. Total dithiol (unaltered and oxidized) was determined by reduction followed by derivatization with monobromobimane. The bimane derivatives were identified and quantified by HPLC and fluorescence. Although all three reduction methods gave similar results, electrolytic reduction of oxidized DMSA and chemical reduction with NaBH4 of oxidized DMPS are recommended based upon both day to day reproducibility and recovery of standards. After reduction a 4-fold increase in DMSA and a 20-fold increase in DMPS were found in urine by 12 h after an oral dose of DMSA or DMPS. These new methods for the determination of dithiols and their oxidized forms should lead to a better understanding of the metabolic properties of these increasingly important orally effective chelating agents.