Prolonged hypolactatemia and increased total pyruvate dehydrogenase activity by dichloroacetate

Abstract

Dichloroacetate (DCA) given gastrically as a single dose to healthy, fed rats caused transient lowering of blood glucose, lactate, and pyruvate. Chronic daily dosing caused lowering of these metabolites and a delay in the return of lactate to basal levels for 48 hr after the final dose. DCA caused activation of the pyruvate dehydrogenase complex (PDHC), with acute multiple dosing or chronic daily dosing. The elevated active PDHC persisted for 12 hr following the final dose. In addition, total PDHC activity was increased with chronic dosing and persisted for 48 hr following the final dose. This increase was not blocked by protein synthesis inhibitors. DCA increased isolated hepatocyte [14C-1]pyruvate oxidation and activated hepatocyte PDHC. Glyoxylate and oxalate, hepatic metabolites of DCA, were inhibitory at similar concentrations.