Clinical Pharmacology and Toxicology of Dichloroacetate

Abstract

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. -Environ Health Perspect 106(Suppl 4):989-994 (1998). http://ehpnetl.niehs.nih.gov/docs/1998/Suppl-4/989-994stacpoole/abstract.html

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

“…In exposed in vivo models, mainly rodents, DCA is reported to cause developmental- (Smith et al 1992), spermato- (Linder et al 1997), immuno-, and hepatotoxicity (Cai et al 2007;Hassoun and Dey 2008). However, concern about DCA adversity underlies on the data generated in rodents after their exposure to this chemical at doses (up to~4,000 mg/kg) thousands of times higher than those to which humans are usually exposed (Stacpoole et al 1998). In the same context, a dose range of 10-100 mg/kg of DCA is suggested as therapeutics for human use via intravenous and oral routes (Stacpoole 2011).…”

Use of Oral Dichloroacetate for Palliation of Leg Pain Arising from Metastatic Poorly Differentiated Carcinoma: A Case Report

“…We believe DCA should be formally studied as a palliative treatment in advanced-stage malignancies due to its favorable side effect profile 8 and potential for quality-of-life improvements as demonstrated by this case. Even though it has now been established that DCA has activity against cancer in humans, 9 ongoing DCA phase I/II trials have not been designed to evaluate quality-of-life parameters.…”

Metabolic Modulators to Treat Cardiac Arrhythmias Induced by Ischemia and Reperfusion

“…However, because the actions of DCA in humans often persist for several days after its clearance from plasma, it is possible that other reactive intermediates of DCA accumulate intracellularly at active sites and bind covalently to target proteins, or that DCA (or a metabolite) induces enzymes responsible for its pharmacodynamic effects. DCA is excreted with little of the dose unchanged (Stacpoole et al, 1998).…”