Superfund Research Program
Comparative Metabolism Studies of Dichloroacetate
Dichloroacetate (DCA) is a chemical with seemingly paradoxical features. Many environmental scientists are familiar with DCA as a by-product of drinking water disinfection and a degradation product of trichloroethylene and perchloroethylene, two of the most prevalent groundwater contaminants on hazardous waste sites in the United States. Once DCA was recognized as a widespread contaminant, toxicological studies were performed in rodents to determine the chemical's possible health effects. DCA was found to cause liver cancer in both rats and mice; thus, it has been flagged as a possible human carcinogen. Although these rodent toxicity studies are significant, there is considerable uncertainty about how the findings relate to humans because the mechanism of carcinogenicity is unknown.
What makes DCA so unusual, especially in comparison to other environmental contaminants, is that the pharmacology of this compound has been under study since the 1950s. As a result of extensive research into its clinical potential, there is a substantial body of knowledge about the pharmacological and therapeutic properties of DCA. Because it can facilitate the break down of lactic acid in the body, the compound is now an investigational drug undergoing testing for use in children with congenital lactic acidosis (CLA), an inherited metabolic disorder that causes lactic acid to accumulate to high, sometimes life-threatening levels in the body. The therapeutic doses of DCA (12.5 to 50 mg/kg of body weight) are much higher than the likely environmental exposures and, to date, few side effects have been noted. In addition to its clinical potential for children with CLA, DCA is being investigated for the treatment of ischemic heart disease, stroke, and malaria.
Whether regarded as a potentially useful drug or as a potential public health hazard, there are still many gaps in our knowledge about the fate and metabolism of DCA in the body. Because few details are known about the biochemistry of DCA, including the enzymes involved in its metabolism and its mode of action in the body, it has been difficult to evaluate whether DCA poses significant health risks to the general population, and whether it is a safe pharmaceutical agent. To help resolve these issues, scientists at the University of Florida are conducting a detailed investigation of the in vivo and in vitro metabolism of DCA in humans and rodents. This is the first comparative study of the chemical and it will aid both environmental scientists and biomedical researchers in evaluating the possible health effects of this important chemical.
To date, in vivo metabolism investigations have been performed in 36 children with CLA, 18 healthy adult volunteers, and in male Sprague-Dawley rats. A significant finding of these metabolic studies is that the major pathway for initial metabolism of DCA has been elucidated. In both humans and rats, DCA is metabolized in the liver to glyoxylate, a non-chlorinated, two carbon metabolic intermediate that the body can convert to several substances. Glyoxylate was identified in the plasma of both humans and rodents who were treated with radiolabeled 13C-DCA. This finding is significant because, prior to this study, there was no direct evidence of the initial step in DCA metabolism.
The enzyme responsible for catalyzing the dechlorination of DCA is now under investigation. Based on in vitro studies, the conversion of DCA to glyoxylate was found to occur in the cytosol of liver cells in both rats and humans. Although the dechlorinating enzyme has not yet been characterized, the researchers have determined that it requires glutathione, a compound that the cell often uses to stabilize metabolic intermediates in order to prevent them from reacting with vital cellular components. This information will lead the researchers closer to understanding the functions of the enzyme and the mechanism of DCA dechlorination.
Both the in vivo and in vitro studies show that the initial pathway for metabolism of DCA is similar in humans and rodents. The findings of these studies, in addition to results obtained in studies investigating the pharmacokinetics of DCA in rats and humans, suggest the rat is a suitable model for understanding the fate of DCA in humans. Moreover, these results are the first step in elucidating the dechlorination of DCA in the body. Characterizing the mechanism of dechlorination and the metabolic fate of DCA will provide insight into the various biological effects of this chemical -- to include DCA's mode of carcinogenicity in the rodent model -- and will ultimately assist the process of regulating environmental exposures to DCA.
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To learn more about this research, please refer to the following sources:
- James MO, Yan Z, Cornett R, Jayanti VK, Henderson GN, Davydova N, Katovich MK, Pollock B, Stacpoole PW. 1998. Pharmacokinetics and metabolism of [14C] dichloroacetate (DCA) in the male Sprague-Dawley rat: identification of the glycine conjugates, including hippuric, as urinary metabolites of DCA. Drug Metab Dispos 26(11):1134-1143.
- Stacpoole PW, Henderson GN, Yan Z, Cornett R, James MO. 1998. Pharmokinetics, metabolism and toxicology of dichloroacetate. J Mol Biol 30(3):499-539. PMID:9710704
- James MO, Cornett R, Yan Z, Henderson GN, Stacpoole PW. 1997. Glutathione-dependent conversion to glyoxylate, a major pathway of dichloroacetate biotransformation in hepatic cytosol from humans and rats, is reduced in dichloroacetate-treated rats. Drug Metab Dispos 25(11):1223-1227. PMID:9351896
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