The dichloroacetate dilemma: Environmental hazard versus therapeutic Goldmine-both or neither?

Abstract

Background: Dichloroacetate (DCA) is known to environmental scientists as a by-product of water chlorination and as a metabolite of industrial solvents, including Superfund chemicals. In contrast, DCA is studied by clinical investigators for its therapeutic potential in several life-threatening conditions, including genetic mitochondrial diseases, pulmonary arterial hypertension, and cancer. Thus, DCA holds an almost unique position at the interface between environmental science and allopathic medicine. Objective: I critically reviewed laboratory and clinical pharmacological research on DCA to address questions about the current and future status of DCA in relation to human health. Discussion: Recent information on the clinical toxicogenetics of DCA is interpreted particularly in light of its use as an investigational drug. Adverse effects from chronic DCA exposure have been identified in several target organs in animals. However, in humans, toxicity has so far been limited to reversible effects on the nervous system and liver. DCA is primarily biotransformed to glyoxylate by the bifunctional enzyme glutathione transferase zeta1 and maleylacetoacetate isomerase (GSTz1/MAAI), which also catalyzes the penultimate step in the phenylalanine and tyrosine catabolic pathway. DCA is a suicide inhibitor of GSTz1/MAAI, which can result in delayed plasma clearance of DCA and the accumulation of potentially toxic tyrosine intermediates. Age and GSTz1/MAAI haplotype can markedly affect the toxicokinetics of DCA in humans and rodents. Conclusions: I have defined new potential avenues of research that focus on discrete human populations that may be at increased health risk or that may receive increased health benefit from chronic exposure to DCA at both environmentally and clinically relevant concentrations.