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Clinical Pharmacology and Toxicology of Dichloroacetate
Peter W. Stacpoole, George N. Henderson, Zimeng Yan and Margaret O. James
Environmental Health Perspectives
Vol. 106, Supplement 4: Integrated Approaches for Studying Hazardous Substances (Aug., 1998), pp. 989-994
Published by: The National Institute of Environmental Health Sciences
Stable URL: http://www.jstor.org/stable/3434142
Page Count: 6
You can always find the topics here!Topics: Dosage, Toxicology, Energy metabolism, Kinetics, Metabolism, Humans, Lactic acidosis, Glyoxylates, Lactates, Oxalates
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Dichloroacetate (DCA) is a xenobiotic of interest to both environmental toxicologists and clinicians. The chemical is a product of water chlorination and of the metabolism of various drugs and industrial chemicals. Its accumulation in groundwater and at certain Superfund sites is considered a potential health hazard. However, concern about DCA toxicity is predicated mainly on data obtained in inbred rodent strains administered DCA at doses thousands of times higher than those to which humans are usually exposed. In these animals, chronic administration of DCA induces hepatotoxicity and neoplasia. Ironically, the DCA doses used in animal toxicology experiments are very similar to those used clinically for the chronic or acute treatment of several acquired or hereditary metabolic or cardiovascular diseases. As a medicinal, DCA is generally well tolerated and stimulates the activity of the mitochondrial pyruvate dehydrogenase enzyme complex, resulting in increased oxidation of glucose and lactate and an amelioration of lactic acidosis. By this mechanism, the drug may also enhance cellular energy metabolism. DCA is dehalogenated in vivo to monochloroacetate and glyoxylate, from which it can be further catabolized to glycolate, glycine, oxalate, and carbon dioxide. It remains to be determined whether important differences in its metabolism and toxicology exist in humans between environmentally and clinically relevant doses.
Environmental Health Perspectives © 1998 The National Institute of Environmental Health Sciences