DICHLOROACETIC ACID - METABOLISM IN CYTOSOL

Dichloroacetic acid (DCA) arises from the chlorination of drinking wat er and the metabolism of trichloroethylene (TRI) and is used therapeut ically. The toxicity of TRI exposure is dependent on metabolism, and D CA has been proposed to be one contributor to this toxicity. Beyond th e identification of some metabolites of DCA and some pharmacokinetic s tudies, little is known about the tissue distribution and enzymology o f DCA metabolism. We present data that indicate that DCA degradation o ccurs primarily in the cytosol. Low molecular weight components of cyt osol are required for the reaction, including nicotinamide cofactor an d glutathione (GSH). GSH plays a role in the removal of DCA from cytos ol, although not through transferase-mediated conjugation. In rat cyto sol, the K-M is approximately 0.3 mM, and the apparent V-max approxima tes 12 nmoles/min/mg cytosolic protein. These results set DCA apart fr om other chlorinated compounds that are metabolized by the cytochrome P450 enzyme family.