Molecular mechanisms of in vivo metal chelation: implications for clinical treatment of metal intoxications.
Successful in vivo chelation treatment of metal intoxication requires that a significant fraction of the administered chelator in fact chelate the toxic metal. This depends on metal, chelator, and organism-related factors (e.g., ionic diameter, ring size and deformability, hardness/softness of electron donors and acceptors, route of administration, bioavailability, metabolism, organ and intra/extracellular compartmentalization, and excretion). In vivo chelation is not necessarily an equilibrium reaction, determined by the standard stability constant, because rate effects and ligand exchange reactions considerably influence complex formation. Hydrophilic chelators most effectively promote renal metal excretion, but they complex intracellular metal deposits inefficiently. Lipophilic chelators can decrease intracellular stores but may redistribute toxic metals to, for example, the brain. In chronic metal-induced disease, where life-long chelation may be necessary, possible toxicity or side effects of the administered chelator may be limiting. The metal selectivity of chelators is important because of the risk of depletion of the patient's stores of essential metals. Dimercaptosuccinic acid and dimercaptopropionic sulfonate have gained more general acceptance among clinicians, undoubtedly improving the management of many 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 research challenge for the future.
Andersen
Ole
O
Department of Life Sciences and Chemistry, Roskilde University, Postbox 260, 4000 Roskilde, Denmark. Andersen@ruc.dk
Aaseth
Jan
J
D001682:Biological Availability; D002118:Calcium / Q000737:chemistry; D002614:Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D007700:Kinetics; D008024:Ligands; D019216:Metals, Heavy / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D008962:Models, Theoretical; D013816:Thermodynamics
D002614:Chelating Agents; D008024:Ligands; D019216:Metals, Heavy; D007501:Iron; D002118:Calcium