In vivoscreening of potential antidotes for chronic cadmium intoxication

Abstract

Nineteen chelating agents have been screened under identical conditions of metal loading in an attempt to establish their relative ability to mobilize cadmium from the liver and kidney in mice with chronic cadmium intoxication. The compounds investigated were divided into five groups: polyaminocarboxylic acids, monothiols, dithiols, macrocycles, and a miscellaneous category. Only 2,3-dimercaptopropanol (BAL) and sodium diethyldithiocarbamate (NaDDTC) were able to produce a statistically significant (at the 95% level) reduction in the cadmium content of the kidney. The closely related dithiols sodium 2,3-dimercaptopropane-1-sulfonate and 2,3-dimercaptosuccinic acid produced statistically significant increases in the liver cadmium contents, as did N-(2-mercaptopropionyl)-glycine. The reduction in kidney cadmium levels produced by both BAL and NaDDTC was just under 40%.

Effect of chelating agent structure on the mobilization of cadmium from intracellular deposits

“…Among dithiocarbamates, the compounds containing only nonpolar groups in addition to the dithiocarbamate group (CS 2 Na) have an intrinsic level of toxicity that is significantly greater than that of the compounds that are either amphipathic or those that contain polar groups. The results as a whole support the reports from previous screening studies (Cantilena and Klaassen, 1982;Shinobu et al, 1983) in which few of the many types of chelating agents examined showed any significant ability to mobilize cadmium from animals when the interval between cadmium administration and chelate treatment was longer than 24 h. The data presented here show not only that one must have the proper type of chelating group, but also that the presence of appropriate additional groups in the molecule is essential for an appreciable level of efficacy. Compounds fail when they contain groups that result in their being too polar (e.g., 2,3-dimercaptobutan-1,4-diol) or too nonpolar.…”

“…The commonly used water-soluble chelating agents such as EDTA, DPTA, and similar compounds have, at most, a very slight effect on the cadmium present in such deposits, though they are effective in antagonizing acute toxic effects of injected cadmium salts (Rau et al, 1987;Cantilena and Klaassen, 1982;Eybl et al, 1965), because these chelating agents cannot gain access to cadmium bound to intracellular sites (Waalkes et al, 1983). In fact, it is generally stated that most of the commonly used watersoluble chelating agents are completely unable to remove cadmium from the intracellular deposits that result from chronic cadmium intoxication (Cantilena and Klaassen, 1981;Shinobu et al, 1983;Eybl et al, 1988).…”

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

“…Sodium 2,3-dimercaptopropane-1 -sulfonate (DMPS), which is known to undergo active transport by these systems (Klotzbach & Diamond 1988), has repeatedly been shown to be ineffective for the mobilization of cadmium from its aged deposits (Bakka & Aaseth 1979;Von Berg & Smith 1980;Planas-Bohne & Lehmann 1983;Shinobu et al 1983). Sodium 2,3-dimercaptopropane-1 -sulfonate (DMPS), which is known to undergo active transport by these systems (Klotzbach & Diamond 1988), has repeatedly been shown to be ineffective for the mobilization of cadmium from its aged deposits (Bakka & Aaseth 1979;Von Berg & Smith 1980;Planas-Bohne & Lehmann 1983;Shinobu et al 1983).…”

“…One of the basic reasons for the seriousness of chronic cadmium toxicity is the rapid movement of ingested cadmium from extracellular sites, where it is amenable to reaction with chelating agents such as EDTA, to intracellular sites, where the cellular membrane prevents most of the commonly used chelating agents from gaining access to the firmly bound metal (Waalkes et al 1993). These include vicinal dithiols, such as 2,3-dimercapto-1-propanol (BAL) (Shaikh & Lucis 1972;Cherian 1980;Von Berg & Smith 1980), but not meso-2,3-dimercaptosuccinic acid (DMSA) (Bakka & Aaseth 1979;Gale et al 1983a;Planas-Bohne & Lehmann 1983;Shinobu et al 1983) nor sodium 2,3-dimercaptopropanesulfonate (DMPS) (Bakka & Aaseth 1979). These factommake the removal of cadmium from intracellular sites a problem with special features.…”

Distribution of Cadmium in Body Organs and Hepatic Metallothionein Content Following Chelation Therapy

“…However, some chelating agents administered repeatedly were able to mobilize Cd even when treatment was delayed following Cd exposure. This may be due to the easier access of the chelators to the intracellular bound Cd, owing to their lipophilic nature (Gale et al 1983;Shinobu et a/. 1983) and their ability to mobilize Cd even from Cd-MT (Cherian 1980;Cherian & Rodgers 1982).…”