Chemical and biological considerations in the treatment of metal intoxications by chelating agents.

Effective chelation treatment of metal intoxications requires that the pharmacokinetics of the administered chelator in fact leads to chelation of the toxic metal, preferably forming a less toxic species which is effectively excreted. This depends on physical and chemical characteristics of metals and chelators as e.g. ionic diameter, ring size and deformability, hardness/softness of electron donors and acceptors, administration route, bioavailability, metabolism, organ and intra/extra cellular compartmentalization, and excretion. In vivo chelation is unlikely to reach equilibrium determined by the standard stability constant, as rate effects and ligand exchange reactions as well as the pharmacokinetics of the chelator considerably influence complex formation. Hydrophilic chelators enhance renal metal excretion, but mainly their extracellular distribution limit their effect to mainly extracellular metal pools. Lipophilic chelators can decrease intracellular stores, but may redistribute toxic metals to e.g. the brain. In chronic metal induced disease, necessitating life-long chelation, toxicity and side effects of the chelator may limit the treatment. The metal selectivity of chelators is important, due to the risk of essential metals depletion. Dimercaptosuccinic acid and dimercaptopropionic sulfonate are presently gaining increased acceptance among clinicians, undoubtedly improving the management of human metal intoxications including lead, arsenic and mercury compounds. Still, development of new safer chelators suited for long-term oral administration for chelation of metal deposits, mainly iron, is an important challenge to the future research.

Gold sodium thiomalate toxicity in cadmium-sensitive and cadmium-resistant Chinese hamster ovary cells.

Gold sodium thiomalate was incubated with one cadmium-sensitive cell line and two cadmium-resistant variants. The resistant lines have been reported to synthesize metallothionein (MT) in response to both cadmium and zinc, whereas the sensitive line does not. All cell lines showed a dose-dependent inhibition of growth as a result of gold sodium thiomalate treatment. However, daily comparisons of cell numbers indicate that the cadmium-resistant lines actually increase in number at the highest gold concentrations, whereas numbers of cells in the nonresistant line decrease. MT biosynthesis was measured by monitoring the incorporation of [35S )cysteine into low molecular weight protein. None of the cells synthesized MT in response to gold. When incubated with both zinc and gold, MT was synthesized by both of the cadmium resistant lines; however, the amount of MT synthesized was reduced in the presence of gold which appears to inhibit the uptake of [35S]cysteine by all the cell lines. Although MT is synthesized in the presence of zinc and gold sodium thiomalate, the MT does not have a significant effect on the ability of these cells to withstand high concentrations of gold.