Superfund Research Program

Dichloroacetate Kinetics, Metabolism and Human Toxicology

Project Leader: Peter W. Stacpoole
Grant Number: P42ES007375
Funding Period: 1995 - 2000

Project-Specific Links

Final Progress Reports

Year:   1999 

Last year's progress included recruitment of the final patients to the phase III clinical trial of dichloroacetate (DCA) for the treatment of children with congenital lactic acidosis (CLA). Each patient will be studied for two years on the General Clinical Research Center (GCRC) and the pharmacokinetics, biotransformation, pharmacodynamics and toxicology of DCA will be evaluated. The study blind will be broken in September, 2001. Recruitment continued for the study of healthy adult volunteers involving the kinetics and biotransformation of DCA, at doses spanning environmental and clinical exposure levels. All patients taking clinically relevant doses of DCA have been enrolled and enrollment is in progress for subjects who will receive environmental and intermediate doses of the chemical. Finally, last year led to the discovery, in rats, that DCA markedly inhibits the activity and amount of the enzyme glutathione-S-transferase zeta (GSTz), which biotransforms DCA into glyoxylate. Moreover, project investigators found that this enzyme, which is identical to maleylacetoacetate isomerase (MAAI), a key enzyme in tyrosine catabolism, leads to accumulation of tyrosine breakdown products that may be toxic and could explain, at least in part, the adverse effects of chronic DCA on liver and peripheral nerves, target organs of toxicity in humans.