| Dichloroacetate (DCA) is considered a hazardous environmental contaminant by the EPA, but is also an investigational drug for the treatment of lactic acidosis in children with inborn errors of metabolism. Chronic administration of DCA leads to toxicity including peripheral neuropathy and ocular opacities. DCA also inhibits its own metabolism, which can be seen as early as after the first dose. The aims of the research conducted over the past four years have been to uncover the overall metabolic pathways of the metabolism of DCA and to examine hypotheses related to the mechanism of its inhibition of its own metabolism. Research into DCA metabolism has included in vivo and in vitro experiments in rats, and in vitro investigations with human liver cytosol. There were several important findings in the metabolism of DCA including the confirmation of glyoxylate as an intermediate, which had not previously been unequivocally identified, the requirement of glutathione (GSH) for DCA metabolism to glyoxylate, and the discovery of hippurate and other glycine conjugates as metabolites of DCA. Advancements in uncovering the mechanism of DCA auto-inhibition include demonstrating a decrease in the rate of in vitro DCA metabolism in hepatic cytosol prepared from DCA treated rats, a direct inhibitory effect in dialyzed rat hepatic cytosol but not dialyzed human hepatic cytosol incubated with DCA, inhibition of DCA metabolism by maleylacetone, a native substrate of GSTz, and an increase in maleylacetone levels in DCA treated rats, suggesting an interaction between DCA and the tyrosine catabolic pathway. Uncovering the interaction between DCA and the tyrosine catabolic pathway may lead to improvements in the treatment of children with lactic acidosis and insights into the mechanisms of DCA's toxicity and rodent hepatocarcinogenicity. |
