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United States Department of Agriculture

Agricultural Research Service

Title: Mechanism of Dichlor0acetate-Induced Hypolactatemia in Humans with Or Without Cirrhosis

Authors
item Shangraw, Robert - OREGON HEALTH/SCI UNIV
item Jahoor, Farook

Submitted to: Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 11, 2004
Publication Date: August 1, 2004
Citation: Shangraw, R.E., Jahoor, F. 2004. Mechanism of dichloracetate-induced hypolactatemia in humans with or without cirrhosis. Metabolism. 53(8):1087-1094.

Interpretive Summary: Lactic acid is one of the products of pyruvate metabolism, and its concentration rises when there is a lack of oxygen (to oxidize pyruvate to carbon dioxide, water and energy) because of underperfusion of tissues (e.g., hypodynamic sepsis) or when the liver cannot remove lactic acid from the circulation (e.g., patients with end-stage liver disease). High blood lactic acid levels can be lethal in patients with end stage liver disease. An experimental drug called dichloroacetate (DCA) has been used as an experimental treatment for lactic acidosis because it lowers blood lactic acid concentration. How DCA lowers blood lactic acid remains unclear. This study tested whether DCA lowers lactic acid by decreasing lactate production from pyruvate, increasing its clearance from blood, or decreasing the rate of production of pyruvate from glucose in healthy humans and in patients with end-stage cirrhosis. Plasma isotopic enrichment was measured using gas chromatography and mass spectrometry. Studies were performed in 6 healthy volunteers and 7 cirrhotic patients to measure lactate production and clearance. DCA decreased blood lactate concentrations, decreased pyruvate production, increased its oxidation, and markedly decreased conversion of pyruvate to lactate. These results indicate that DCA reduces blood lactic acid concentrations by inhibiting production, via stimulating pyruvate oxidation and inhibiting pyruvate production, rather than increasing clearance. In addition, end-stage cirrhosis does not alter either the mechanism or the magnitude of the metabolic response to DCA.

Technical Abstract: Dichloroacetate (DCA) has been used as an experimental treatment for lactic acidosis because it lowers plasma lactic acid concentration. Three potential mechanisms could underlie the hypolactatemic action of DCA, but the dominant mechanism in vivo remains unclear. This study tested whether DCA-induced hypolactatemia occurs via decreased lactate production, increased lactate clearance, or decreased rate of glycolysis in healthy humans and in patients with end-stage cirrhosis. Cirrhosis is associated with decreased hepatic pyruvate dehydrogenase (PDH) content. Six healthy volunteers and 7 cirrhotic patients received a primed, constant infusion of 1-13C-pyruvate and 15N-alanine for 5 hours. DCA (35 mg/kg intravenously) was administered at 2 hours. Plasma isotopic enrichment was measured by gas chromatography/mass spectrometry (GC/MS), and exhaled CO2 enrichment by isotope ratio mass spectrometry. Pyruvate and alanine production rates (Ra) were determined by isotope dilution, and pyruvate oxidation calculated as 13CO2 production from 13C-pyruvate. Ra lactate was calculated as the difference between Ra pyruvate and its disposal by oxidation to CO2 and conversion to alanine. Baseline plasma lactate kinetics in cirrhotic patients did not differ from controls. DCA decreased lactate concentration in both groups by approximately 53%. DCA decreased glycolysis (Ra pyruvate) by 24%, increased the fraction of pyruvate oxidized to CO2 by 26%, and decreased pyruvate transamination to alanine by 25%. DCA also inhibited lactate production by 85%, but decreased plasma lactate clearance by 60% in both groups. DCA reduces plasma lactic acid concentration by inhibiting production, via stimulating pyruvate oxidation and inhibiting glycolysis, rather than increasing clearance. In addition, end-stage cirrhosis does not alter either the mechanism or the magnitude of the metabolic response to DCA.

Last Modified: 9/22/2014
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