Mechanism of dichloroacetate-induced hypolactatemia in humans with or without cirrhosis.
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.
Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University and Veterans Administration Medical Center, Portland 97239-3098, USA.
Robert E
RE
Shangraw
Farook
F
Jahoor
D000328:Adult; D000409:Alanine / Q000097:blood; D002096:C-Peptide / Q000097:blood; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005934:Glucagon / Q000097:blood; D006801:Humans; D007328:Insulin / Q000097:blood; D007700:Kinetics; D007773:Lactates / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000097:blood*; D008297:Male; D010084:Oxidation-Reduction; D019289:Pyruvic Acid / Q000097:blood
D002096:C-Peptide; D007328:Insulin; D007773:Lactates; D019289:Pyruvic Acid; D005934:Glucagon; D003999:Dichloroacetic Acid; D000409:Alanine