Dichloroacetic acid: metabolism in cytosol

Dichloroacetic acid (DCA) arises from the chlorination of drinking water and the metabolism of trichloroethylene (TRI) and is used therapeutically. The toxicity of TRI exposure is dependent on metabolism, and DCA has been proposed to be one contributor to this toxicity. Beyond the identification of some metabolites of DCA and some pharmacokinetic studies, little is known about the tissue distribution and enzymology of DCA metabolism. We present data that indicate that DCA degradation occurs primarily in the cytosol. Low molecular weight components of cytosol are required for the reaction, including nicotinamide cofactor and glutathione (GSH). GSH plays a role in the removal of DCA from cytosol, although not through transferase-mediated conjugation. In rat cytosol, the KM is approximately 0.3 mM, and the apparent Vmax approximates 12 nmoles/min/mg cytosolic protein. These results set DCA apart from other chlorinated compounds that are metabolized by the cytochrome P450 enzyme family.