Disease relevance of Dichloroacetate

• Treatment of lactic acidosis with dichloroacetate [1].
• Toxicity of chronic dichloroacetate [2].
• Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia [3].
• We therefore, examined the effects of dichloroacetate, which can alter resting metabolism, on canine gracilis muscle contractile function during constant flow ischemia [4].
• Dichloroacetate was administered intravenously over 30 minutes as two 50 mg/kg body weight doses separated by 2 hours [5].

Psychiatry related information on Dichloroacetate

• Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington's disease [6].

High impact information on Dichloroacetate

• A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group [7].
• Uncontrolled studies have suggested that dichloroacetate, which stimulates the oxidation of lactate to acetyl-coenzyme A and carbon dioxide, might reduce morbidity and improve survival among patients with this condition [7].
• The metabolic effects of dichloroacetate were evaluated in 11 patients [1].
• The cytochrome P450 pathway generates tri- and dichloroacetate as metabolites of Perc, and these are associated with hepatic toxicity and carcinogenicity [8].
• In this study we characterized the metabolic effects of dichloroacetate in a human model of peripheral muscle ischemia [9].

Chemical compound and disease context of Dichloroacetate

• We conducted a placebo-controlled, randomized trial of intravenous sodium dichloroacetate therapy in 252 patients with lactic acidosis; 126 were assigned to receive dichloroacetate and 126 to receive placebo [7].
• In conclusion, dichloroacetate enhanced contractile function during ischemia, independently of blood flow, such that it appears oxidative ATP regeneration is limited by pyruvate dehydrogenase complex activity and acetyl group availability [4].
• The effect of dichloroacetate on brain lactate levels following incomplete ischemia in the hyperglycemic rat [10].
• Subjects with cirrhosis exhibit neither exaggerated inhibition of glucose production nor increased risk of hypoglycemia as a result of acute dichloroacetate-induced hypolactatemia [11].
• BACKGROUND: Sodium dichloroacetate has been used to treat patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) [12].

Biological context of Dichloroacetate

• Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle [13].
• Coenzyme Q10, Gingko biloba, nicotinamide, riboflavin, carnitine, lipoic acid, and dichloroacetate are other agents which may have beneficial effects on energy metabolism, but the preclinical and clinical evidence for efficacy in neurological diseases remains limited [14].
• Effects of dichloroacetate on lipid metabolism in isolated rat liver cells [15].
• In contrast, dichloroacetate had no effect on exercise time (control 15.2 +/- 6.0 versus dichloroacetate 15.9 +/- 6.2 min) or peak exercise oxygen consumption (control 1,280 +/- 498 ml/min versus dichloroacetate 1,312 +/- 530 ml/min) (both p = NS) [16].
• Cori cycle activity was depressed by 63% after dichloroacetate administration [17].

Anatomical context of Dichloroacetate

• We have demonstrated previously that dichloroacetate can attenuate skeletal muscle fatigue by up to 35% in a canine model of peripheral ischemia (Timmons, J.A., S.M. Poucher, D. Constantin-Teodosiu, V. Worrall, I.A. Macdonald, and P.L. Greenhaff. 1996. J. Clin. Invest. 97:879-883) [9].
• Finally, reductase activity was inhibited by dichloroacetate, a compound known to lower plasma cholesterol in man and inhibit the human leukocyte enzyme in vitro [18].
• Incubation with dichloroacetate increased activity of the pyruvate dehydrogenase complex (PDHC) in disrupted fibroblasts from controls but not from two patients with autopsy-proved Leigh disease [19].
• OBJECTIVE: To determine whether dichloroacetate (DCA) treatment can increase pyruvate dehydrogenase (PDH) activity in PDH-deficient cell lines harboring pathogenic mutations in the PDH E1alpha gene [20].
• Dichloroacetate demonstrates low grade mutagenicity in the Ames Salmonella/mammaltan microsome mutagenicity test [21].

Associations of Dichloroacetate with other chemical compounds

• Acetylcarnitine concentration fell during contraction by 5.4 +/- 1.8 mmol.kg-1 dm in the dichloroacetate group but increased by 10.0 +/- 1.9 mmol.kg-1 dm in the control group [4].
• Postischemic hearts with augmented pyruvate oxidation (dichloroacetate-treated) sustained improved mechanical function throughout 40 minutes of reperfusion [22].
• This decrease in cardiac efficiency was accompanied by a substantial production of H+ from glucose metabolism DCA caused a 2.2-fold increase in glucose oxidation, a 46 +/- 17% decrease in H+ production, a 1.6-fold increase in cardiac efficiency, and a 2.0-fold increase in cardiac work during reperfusion (n = 17) [23].
• PDK3 was poorly inhibited by pyruvate or dichloroacetate (DCA) [24].
• In contrast, the hepatocyte carrier had lower Km values than MCT1 for glycolate, chloroacetate, dichloroacetate, and 2-hydroxy-2-methylpropionate [25].

Gene context of Dichloroacetate

• During E2-aided catalysis, PDK2 had approximately 3 times more ADP than ATP bound at its active site, and the pyruvate analogue, dichloroacetate, led to 16-fold more ADP than ATP being bound (no added ADP) [26].
• However, the elevated concentration of NPY in the VMH of anorectic TB rats was also normalized by the DCA treatment [27].
• Increased expression of c-myc and c-Ha-ras in dichloroacetate and trichloroacetate-induced liver tumors in B6C3F1 mice [28].
• Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases DeltaPsim, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism [29].
• Effects of dichloroacetate in three patients with MELAS [30].

Analytical, diagnostic and therapeutic context of Dichloroacetate

• After 20-min contraction the control group had demonstrated an approximately 40% reduction in isomeric tension whereas the dichloroacetate group had fatigued by approximately 25% (P < 0.05) [4].
• Values of dP/dt were also consistently higher, by as much as 185%, during reperfusion with dichloroacetate [22].
• Dichloroacetate (1-50 mg/kg) was infused over 30 min to 16 healthy subjects and plasma drug concentrations were followed by gas chromatography over the next 8 h [31].
• We report here the trapping of the dichloroacetate radical with the spin-trapping agent PBN, and its identification by GC/MS [32].
• Numerous studies using adult animal models suggest that dichloroacetate (DCA) may have neuroprotective properties by virtue of its ability to increase rates of metabolism and, therefore, clearance of brain lactic acidosis, which may accumulate during cerebral ischemia [33].

References