Disease relevance of Dichloroacetate

• Stable isotope tracer methodology and indirect calorimetry was used to determine the rates of intermediary carbohydrate metabolism and oxygen use in five severely septic patients with lactic acidosis and six healthy volunteers before and after administration of DCA [1].
• Patients with acquired deficiency of GSTZ1-1 caused by therapeutic exposure to dichloroacetic acid for the clinical treatment of lactic acidosis may be at increased risk of drug- and chemical-induced toxicity [2].
• In contrast, the depressed PDHC activity at 15 min following ischemia was not affected by the DCA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)[3]
• Dichloroacetic acid (DCA) has recently been shown to increase significantly the incidence of hepatic adenomas (HAs) and hepatocarcinomas (HCs) in male B6C3F1 mice [4].
• Its expression is increased by several treatments/conditions that are associated with hepatocarcinogenesis (peroxisome proliferators, iron overload, dichloroacetic acid) [5].

High impact information on Dichloroacetate

• In vivo administration of dichloroacetic acid suppresses spontaneous apoptosis in murine hepatocytes [6].
• Glutathione transferase zeta (GSTZ1-1) is the major enzyme that catalyzes the metabolism of alpha-halo acids such as dichloroacetic acid, a carcinogenic contaminant of chlorinated water [7].
• E2 activation of PDK2 resulted in a greatly enhanced sensitivity to inhibition by pyruvate or DCA; pyruvate was effective at significantly lower levels than DCA [8].
• Dichloroacetate (DCA) binds at the pyruvate binding site in the center of the R domain, which together with ADP, induces significant changes at the active site [9].
• We previously established that activation of the pyruvate dehydrogenase complex (PDC) using dichloroacetate (DCA) reduced the reliance on substrate-level phosphorylation (SLP) at the onset of exercise, with normal and reduced blood flow [10].

Chemical compound and disease context of Dichloroacetate

• Studies of the TCE metabolites dichloroacetic acid (DCA) , trichloroacetic acid (TCA) , and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans [11].
• These data also indicate that MA and FA may covalently modify and inactivate other proteins that have accessible cysteine residues and may, thereby, contribute to dichloroacetic acid-induced or hypertyrosinemia type-I-associated toxicities [12].
• These studies demonstrate that the mouse is more sensitive than the rat with respect to the enhancement of liver peroxisome proliferation by TCA and DCA and suggest that if peroxisome proliferation is critical for the induction of hepatic cancer by TCA and DCA, then the rat should be less sensitive or refractory to tumor induction [13].
• Prevention by methionine of dichloroacetic acid-induced liver cancer and DNA hypomethylation in mice [14].
• Dichloroacetate (DCA) also does and was shown to improve exercise capacity in animals, but it has long-term toxicity problems [15].

Biological context of Dichloroacetate

• Dichloroacetic acid (DCA), a disinfection by-product of chlorination found in drinking water, is a hepatocarcinogenic in the B6C3F1 mouse [16].
• Detection of early gene expression changes by differential display in the livers of mice exposed to dichloroacetic acid [17].
• Consistent with our earlier conclusions, DCA pretreatment reduces muscle fatigue only when SLP is attenuated [10].
• The frequency and mutation spectra of proto-oncogene activation in hepatocellular neoplasms induced by tetrachloroethylene, trichloroethylene and dichloroacetic acid were examined to help define the molecular basis for their carcinogenicity [18].
• Glutathione transferase zeta-catalyzed biotransformation of dichloroacetic acid and other alpha-haloacids [19].

Anatomical context of Dichloroacetate

• Using canine skeletal muscle, one group was infused with saline while the other was pretreated with 300 mg (kg body mass)(-1) DCA [10].
• Chronic DCA treatment significantly improved the metabolic function of PDHC in digitonin-permeabilized R378C and R88C fibroblasts [20].
• In this study, we investigated the response to DCA in various PDHC-deficient cell lines and tried to determine the mechanism involved [20].
• Metabolic regulation of collagen I in fibroblasts isolated from normal peritoneum and adhesions by dichloroacetic acid [21].
• Dichloroacetic acid: metabolism in cytosol [22].

Associations of Dichloroacetate with other chemical compounds

• Glutathione transferase zeta catalyses the oxygenation of the carcinogen dichloroacetic acid to glyoxylic acid [23].
• Cancer dose metrics provided in the model include the area under the concentration curve (AUC) for TCA and DCA in the plasma, the peak concentration and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney [24].
• However, the formation of corresponding dihaloacetic acids, dichloroacetic acid and dibromoacetic acid, could not be detected in vitro at all [25].
• GSTZ1-1-catalyzed biotransformation of fluorine-lacking alpha,alpha-dihaloalkanoic acids, including dichloroacetic acid (DCA), results in the mechanism-based inactivation and covalent modification of the enzyme [26].
• Cytochrome P450 (CYP)-dependent metabolism of TRI produces chloral hydrate (CH) and is rate limiting in the ultimate production of trichloro- and/or dichloroacetic acid from TRI [27].

Gene context of Dichloroacetate

• Regulation of matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1 by dichloroacetic acid in human fibroblasts from normal peritoneum and adhesions [28].
• Thus, DCA- and TCA-promoted carcinogenesis appears to include decreased methylation and increased expression of c-jun and c-myc genes in the presence of increased DNA MTase activity [29].
• Hypomethylated and over-expression of c-jun and c-myc genes were found in DCA- and TCA-promoted liver tumors [29].
• H-ras codon 61 activation was not significantly different among dichloroacetic acid- and trichloroethylene-induced and combined historical and concurrent control hepatocellular tumors (62%, 51% and 69% respectively) [18].
• Regulation of transforming growth factor-beta, type III collagen, and fibronectin by dichloroacetic acid in human fibroblasts from normal peritoneum and adhesions [30].

Analytical, diagnostic and therapeutic context of Dichloroacetate

• Helix--coil transitions of an alternating copolypeptide poly(gamma-benzyl epsilon-carbobenzoxy-L-lysyl-L-glutamate) (poly[Lys(Z)-Glu(OBzl)]) in binary mixtures of dichloroacetic acid (DCA) and ethylene dichloride (EDC) were investigated by optical rotatory dispersion (ORD) [31].
• Analysis of dichloroacetic acid in rat blood and tissues by hydrophilic interaction liquid chromatography with tandem mass spectrometry [32].
• The induction of DNA strand breaks by these agents was measured by alkaline single-cell gel electrophoresis (SCGE, comet assay) and the rank order in decreasing genotoxicity was BA >> MX > CA > DBA > TBA > EMS > KBrO(3), while DCA and TCA were refractory [33].
• We investigated metabolic factors related to the recovery of myocardial function during ischemia and after reperfusion using dichloroacetic acid (DCA) in canine models with repeated 10-min regional ischemia and reperfusion [34].
• Because of the known neurotoxicity of the analogue, dichloroacetic acid, both natural breeding and artificial inseminations were evaluated in untreated females to distinguish between possible behavioral and spermatogenic effects [35].

References