Cadmium Mobilization by Monoaralkyl‐ and Monoalkyl Esters of meso‐2,3‐Dimercaptosuccinic Acid and by a Dithiocarbamate

Abstract

Syntheses and relative cadmium mobilizing properties are described for three new monoaralkyl esters (HOOCCH(SH)CH(SH)COOR, where R = phenylethyl ((CH2)2C6H5), MPhEDMS; R = 3-phenylpropyl ((CH2)3C6H5), MPhPDMS; and R = 2-phenoxyethyl ((CH2)2OC6H5). MPhOEDMS) of meso-2,3-dimercaptusuccinic acid. These were prepared by the reaction of the corresponding alcohol with meso-2,3-dimercaptosuccinic acid (DMSA) in aqueous HCl. When administered intraperitoneally to cadmium-loaded mice at 0.50 mmol/kg/day for four consecutive days, all induced significant reductions in the whole body cadmium levels. MPhEDMS, 60%; MPhPDMS, 66%; and MPhOEDMS, 58% in comparison with control levels. At the same dosage monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and a dithiocarbamate, sodium N-benzyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioate++ + (BLDTC) induced reductions of 65% and 57%, respectively. Hepatic and renal cadmium were also depleted significantly, while brain cadmium levels were unchanged. These compounds induced a significant reduction in the cadmium levels of the spleen, and one, MPhOEDMS, produced a 10% decrease in pancreatic cadmium. The manner in which the later injections removed smaller fractions of the total body cadmium is consistent with a bodily distribution of these compounds by which they are concentrated primarily in the kidneys and the liver, with much smaller amounts reaching other organs. It is proposed that these compounds enter renal and hepatic cells through an anion transport system.

Design of in vivo Cadmium-Mobilizing Agents: Synthesis and Properties of Monobenzyl meso-2,3-Dimercaptosuccinate

“…Compounds of this sort are designed primarily to mobilize a larger portion of intracellular cadmium via the biliary route. In a recent report from this laboratory on a structurally related compound, i.e., mono-2-phenoxyethyl meso-2,3-dimercaptosuccinate (MPhOEDMS), it was discovered that fecal excretion is the predominant route of cadmium mobilization which eliminates approximately 8-fold excess cadmium than through the urine (29). The study also revealed that the majority of cadmium excretion occurred within 5 h of the initial administration of the aforementioned compound.…”

Zinc and multi-mineral supplementation should mitigate the pathogenic impact of cadmium exposure

“…In any case, it would probably be appropriate to conduct clinical studies to assess whether prolonged oral protocols of DMSA (or perhaps other orally administrable agents capable of chelating Cd [102]) might have a worthwhile impact on Cd body burden in patients with excessive Cd levels. Certain ester derivatives of DMSA (such as the monoisoamyl ester) have greater cell permeability, and can promote excretion of metallothionein-bound Cd in mice [103,104]; unfortunately, these agents have never been approved for clinical use, and may have more toxic potential than well-tolerated DMSA [105].…”

On the effect of chelating agents and antioxidants on cadmium-induced organ toxicity. An overview

“…MPhOEDMS) of meso-2,3-dimercaptusuccinic acid have been effective in reducing the hepatic and renal Cd concentration in Cd-intoxicated rats, but no information regarding the effect of the chelating agents on the trace elements homeostasis has been presented. Furthermore, the esters of DMSA have been administrated i.p., which could be a disadvantage of these agents over others chelators for the treatment of Cd-intoxication (Table 6) [64].…”