Dichloroacetate (DCA) is an environmentally important xenobiotics, widely distributed in our biosphere. It is also employed as an investigational drug for treatment of congenital forms of lactic acidosis (CLA). The cardinal manifestations of chronic DCA exposure are reversible hepatotoxicity and peripheral neuropathy (PN) in humans and hepatic neoplasia and reversible neurotoxicity in rodents. The etiologies of these adverse effects are obscure as in the relevance of the toxicological findings in animals to human risk assessment. DCA is dehalogenated by a glutathione transferase that is identical to maleylacetoacetate isomerase (MAAI), a key enzyme in tyrosine catabolism. Inhibition of MAAI by DCA causes accumulation of certain tyrosine catabolites, such as maleylacetone (MA), and heme precursors, such as ((-aminolevulinate ((-ALA) that may be responsible for its toxicity. The principal objective of this competitive renewal application is to elucidate the molecular mechanisms of DCA toxicity in rodents and humans by addressing the following specific aims and hypotheses:
Specific Aim 1 : Quantify the changes in tyrosine and heme metabolism in the urine of humans following exposure to DCA alone or in combination with pharmacologic inhibition of tyrosine catabolism.
This aim tests the postulate that the chemical NTBC, which inhibits an early step in tyrosine catabolism, will prevent or mitigate the clinical toxicity of DCA.
Specific Aim 2 : Determine the mechanism of DCA neurotoxicity in peripheral nerves of dosed humans undergoing treatment with DCA. These studies test the hypotheses 1) that the PN from DCA exposure is primarily due to selected disruption of neuronal cell metabolism, as a result of a direct effect of DCA and from accumulation of catabolites and (-ALA, and 2) that inhibition of this latter effect by NTBC mitigates neurologic damage.
Specific Aim 3 : Determine the mechanism of DCA neurotoxicity in peripheral nerves of dosed rats and in cultures of neuronal cells from rodents.
This aim will address the postulate that DCA induces neuropathology in rats by the same basic mechanisms as occurs in humans. It will also test the hypothesis that susceptibility to DCA PN is age-dependent, being increased in young animals in whom myelination of peripheral nerves is an active, ongoing process. ? ? ?
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