79-43-6JXTHNDFMNIQAHM-UHFFFAOYSA-NJXTHNDFMNIQAHM-UHFFFAOYSA-N
Dichloroacetic acidAcetic acid, dichloro-
Acetic acid, 2,2-dichloro-
Acide dichloroacetique
acido dicloroacetico
DCA (acid)
Dichloracetic acid
DICHLORESSIGSAEURE
Dichloressigsaure
Dichlorethanoic acid
Dichloroethanoic acid
NSC 2654
UN 1764
DTXSID2020428D000236AdenomaD002277CarcinomaPR:000023575pyruvate dehydrogenase [ubiquinone]PR:Q63065Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial (rat)D006528hepatocellular carcinomaGO:0008219cell deathGO:0001909leukocyte mediated cytotoxicityMP:0003674oxidative stressGO:0004738pyruvate dehydrogenase activityGO:0045333cellular respiration1increased2decreasedDichloroacetic Acid2016-11-29T18:42:272016-11-29T18:42:27435435Rattus sp. ABTC 4250310090mouseWCS_9606humanWikiUser_26rodentsWikiUser_25human and other cells in culture10090Mus musculus10116Rattus norvegicusIncrease, hepatocellular adenomas and carcinomasIncrease, hepatocellular adenomas and carcinomasTissueUBERON:0002107liver2016-11-29T18:41:262020-12-26T10:09:54Increase, CytotoxicityIncrease, CytotoxicityCellular<p>Reductions in cellular pH that exceed homeostatic controls leads to denatured/dysfunctional cellular apparatus (enzymes)<sup id="cite_ref-1" class="reference"><a href="#cite_note-1">[1]</a></sup> and cell death<sup id="cite_ref-2" class="reference"><a href="#cite_note-2">[2]</a></sup>.
</p><p>Cytotoxicity is measured in vitro using one of many available standardized methods, including the release of the intracellular enzyme lactate dehydrogenase<sup id="cite_ref-3" class="reference"><a href="#cite_note-3">[3]</a></sup>, alkaline phosphatase<sup id="cite_ref-4" class="reference"><a href="#cite_note-4">[4]</a></sup> cell counts <sup id="cite_ref-5" class="reference"><a href="#cite_note-5">[5]</a></sup>, mitochondrial function<sup id="cite_ref-6" class="reference"><a href="#cite_note-6">[6]</a></sup> and dye exclusion assays<sup id="cite_ref-7" class="reference"><a href="#cite_note-7">[7]</a></sup>.
Cytotoxicity is measured in vivo by histopathological evaluation of tissue. The presence of dead cells and/or cellular debris is direct evidence of cytotoxicity at the time of tissue sampling. Histological evidence of previous cytotoxicity is reported as tissue degeneration and/or atrophy.
</p><p>Cell death is the inevitable outcome of sufficient cellular disruption in any living cell. Cytotoxicity has been observed in the olfactory epithelium of rats and mice exposed by inhalation to one or more of the listed chemical initiators. Cytotoxicity is expected in humans based conserved properties of the of the olfactory epithelium across species.
</p>CL:0000255eukaryotic cellHighHighModerate<ol class="references">
<li id="cite_note-1"><span class="mw-cite-backlink"><a href="#cite_ref-1">↑</a></span> <span class="reference-text">Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326</span>
</li>
<li id="cite_note-2"><span class="mw-cite-backlink"><a href="#cite_ref-2">↑</a></span> <span class="reference-text">Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326, Izumi, Torigoe, Ishiguchi, Uramoto, Yoshida, Tanabe, Ise, Murakami, Yoshida, Nomoto and Kohno (2003). Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev. 29: 541-549, Fais (2010). Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. J Intern Med. 267: 515-525</span>
</li>
<li id="cite_note-3"><span class="mw-cite-backlink"><a href="#cite_ref-3">↑</a></span> <span class="reference-text">(2008). Principles and Methods of Toxicology. Boca Raton, FL, Taylor and Francis: 2193</span>
</li>
<li id="cite_note-4"><span class="mw-cite-backlink"><a href="#cite_ref-4">↑</a></span> <span class="reference-text">Kuykendall, Taylor and Bogdanffy (1993). Cytotoxicity and DNA-protein crosslink formation in rat nasal tissues exposed to vinyl acetate are carboxylesterase-mediated. Toxicol Appl Pharmacol. 123: 283-292</span>
</li>
<li id="cite_note-5"><span class="mw-cite-backlink"><a href="#cite_ref-5">↑</a></span> <span class="reference-text">Theiszova, Jantova, Dragunova, Grznarova and Palou (2005). Comparison the cytotoxicity of hydroxyapatite measured by direct cell counting and MTT test in murine fibroblast NIH-3T3 cells. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 149: 393-396, (2008). Principles and Methods of Toxicology. Boca Raton, FL, Taylor and Francis: 2193</span>
</li>
<li id="cite_note-6"><span class="mw-cite-backlink"><a href="#cite_ref-6">↑</a></span> <span class="reference-text">Theiszova, Jantova, Dragunova, Grznarova and Palou (2005). Comparison the cytotoxicity of hydroxyapatite measured by direct cell counting and MTT test in murine fibroblast NIH-3T3 cells. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 149: 393-396, (2008). Principles and Methods of Toxicology. Boca Raton, FL, Taylor and Francis: 2193</span>
</li>
<li id="cite_note-7"><span class="mw-cite-backlink"><a href="#cite_ref-7">↑</a></span> <span class="reference-text">Weisenthal, Dill, Kurnick and Lippman (1983). Comparison of dye exclusion assays with a clonogenic assay in the determination of drug-induced cytotoxicity. Cancer Res. 43: 258-264, Elia, Storer, Harmon, Kraynak, McKelvey, Hertzog, Keenan, DeLuca and Nichols (1993). Cytotoxicity as measured by trypan blue as a potentially confounding variable in the in vitro alkaline elution/rat hepatocyte assay. Mutat Res. 291: 193-205</span>
</li>
</ol>2016-11-29T18:41:262017-09-16T10:16:36Peptide OxidationPeptide OxidationMolecular<p>Oxidative stress corresponds to an imbalance between the rate of oxidant production and that of their degradation. The term oxidative stress indicates the outcome of oxidative damage to biologically relevant macromolecules such as nucleic acids, proteins, lipids and carbohydrates. This occurs when oxidative stress-related molecules, generated in the extracellular environment or within the cell, exceed cellular antioxidant defenses. Major reactive oxygen species (ROS), such as hydrogen peroxide (H2O2) and superoxide anion, as well as 4-hydroxy- 2,3-nonenal (HNE) and related 4-hydroxy-2,3-alkenals (HAKs), major aldehydic end-products of lipid peroxidation, can act as potential mediators able to affect signal transduction pathways as well as the proliferative and functional response of target cells. H2O2 and superoxide anion may be also generated as molecular messengers within the cell as part of the cellular response to defined growth factors, cytokines and other mediators. The final consequence at tissue, cellular and molecular level is primarily affected by the steady state concentration of oxidative stress-related molecules. The main biological targets of free radicals are proteins, lipids and DNA.</p>
<p>Major consequences of reaction of ROS, HAKs and NO with biologically relevant macromolecules that can mediate pathophysiological effects:</p>
<p>ROS: DNA: oxidation, strand breaks, genotoxicity Proteins: oxidation, fragmentation, formation of carbonyls Lipids: lipid peroxidation and degradation</p>
<p>HAKs: DNA: adducts (low doses), strand breaks, genotoxicity (high doses) Proteins: adducts (Michael type reactions on Lys, Cys and His residues)</p>
<p>NO: DNA: oxidation, strand breaks Proteins: oxidation, nitrosation, nitration (nytrosylation of tyrosine) Lipids: lipid peroxidation and degradation</p>
<p>Continued oxidative stress can lead to chronic inflammation. Oxidative stress can activate a variety of transcription factors including NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines and chemokines, which can activate inflammatory pathways. <sup><a href="#cite_note-1">[1]</a></sup> <sup><a href="#cite_note-2">[2]</a></sup> <sup><a href="#cite_note-3">[3]</a></sup></p>
<p>Glutathione (GSH) oxidation refers to the conversion of reduced glutathione to its oxidized form glutathione disulfide (GSSG) in the presence of oxidative species. GSH plays an important role as an anti-oxidant in regulating cellular redox homeostasis, and is mainly present in the cell as the reduced form (98%). Deficiency in GSH or a decrease in GSH/GSSG ratio results in decreased anti-oxidant function and increased susceptibility to oxidative stress, thus making it a marker of cellular redox status. An imbalance in GSH/GSSG ratio has been implicated in the onset and progression of human diseases, such as neurodegenerative diseases, cancers, pulmonary diseases and cardiovascular diseases (Ballatori et al., 2009; Kalinina et al., 2014)</p>
<p> </p>
<p><em><strong>measuring oxidative stress</strong> </em></p>
<p><em>Agents for <strong>ROS detection</strong> are primarily fluorescence based, but recently luminescent based detections have been introduced. The biggest difficulty reported with much of the cellular ROS research has been with the lack of reporter agents specific for discrete molecules. ROS moieties by their nature are reactive with a number of different molecules; as such designing reporter agents has been difficult. With more specific chemistries, particularly for hydrogen peroxide, the specific mechanisms for regulation will be elucidated. </em></p>
<p><em><strong>Reduced glutathione</strong> (GSH) is regenerated from its oxidized form (GSSH) by the action of an NADPH dependent reductase GSSH + NADPH + H+ à 2 GSH + NADP+ Due to the rapid nature of the reduction of GSSH relative to its synthesis or secretion, the ratio of GSH to GSSH is a good indicator of oxidative stress within cells. GSH and GSSH levels can be determined by HPLC, capillary electrophoresis, or biochemically in microplates. Several different assays have been designed to measure glutathione in samples. By using a luciferin derivative in conjunction with glutathione S-transferase enzyme the amount of GSH would be proportional to the luminescent signal generated when luciferase is added in a subsequent step. Total glutathione can be determined colorimetrically by reacting GSH with DTNB (Ellman’s reagent) in the presence of glutathione reductase. Glutathione reductase reduces GSSH to GSH, which then reacts with DTNB to produce a yellow colored 5-thio-2-nitrobenzoic acid (TNB), which absorbs at 412 nm. </em></p>
<p><em><strong>Lipid peroxidation</strong> is one of the most widely used indicators of free radical formation, a key indicator of oxidative stress. Measurement of lipid peroxidation has historically relied on the detection of thiobarbituric acid (TBA) reactive compounds such as malondialdehyde generated from the decomposition of lipid peroxidation products. While this method is controversial in that it is quite sensitive, but not necessarily specific to MDA, it remains the most widely used means to determine lipid peroxidation. This reaction, which takes place under acidic conditions at 90-100ºC, results in an adduct that can be measured colorimetrically at 532 nm or by fluorescence using a 530 nm excitation wavelength and a 550 nm emission wavelength. A number of commercial assay kits are available for this assay using absorbance or fluorescence detection technologies. The formation of F2-like prostanoid derivatives of arachidonic acid, termed F2-isoprostanes (IsoP) has been shown to be specific for lipid peroxidation. Unlike the TBA assay, measurement of IsoP appears to be specific to lipid peroxides, they are stable and are not produced by any enzymatic pathway making interpretation easier. There have been a number of commercial ELISA kits developed for IsoPs, but interfering agents in samples requires partial purification of samples prior to running the assay. The only reliable means for detection is through the use of GC/MS, which makes it expensive and limits throughput. </em></p>
<p><em><strong>Superoxide detection</strong> is based on the interaction of superoxide with some other compound to create a measurable result. The reduction of ferricytochrome c to ferrocytochrome c has been used in a number of situations to assess the rate of superoxide formation. While not completely specific for superoxide this reaction can be monitored colorimetrically at 550 nm. Chemiluminescent reactions have been used for their potential increase in sensitivity over absorbance-based detection methods. The most widely used chemiluminescent substrate is Lucigenin, but this compound has a propensity for redox cycling, which has raised doubts about its use in determining quantitative rates of superoxide production. Coelenterazine has also been used as a chemiluminescent substrate. Hydrocyanine dyes are fluorogenic sensors for superoxide and hydroxyl radical. These dyes are synthesized by reducing the iminium cation of the cyanine (Cy) dyes with sodium borohydride. While weakly fluorescent, upon oxidation their fluorescence intensity increases 100 fold. In addition to being fluorescent, oxidation also converts the molecule from being membrane permeable to an ionic impermeable moiety. The most characterized of these probes are Hydro-Cy3 and Hydro-Cy5. </em></p>
<p><em><strong>Hydrogen peroxide</strong> (H2O2) is the most important ROS in regards to mitogenic stimulation or cell cycle regulation. There are a number of fluorogenic substrates, which serve as hydrogen donors that have been used in conjunction with horseradish peroxidase (HRP) enzyme to produce intensely fluorescent products. The more commonly used substrates include diacetyldichloro-fluorescein, homovanillic acid, and Amplex® Red. In these examples, increasing amounts of H2O2 form increasing amounts of fluorescent product. </em></p>
<p><em><strong>Nitric Oxide</strong> The free radical nitric oxide (•NO) is produced by a number of different cell types with a variety of biological functions. Regardless of the source or role, the free radical •NO has a very short half life (t½= 4 seconds), reacting with several different molecules normally present to form either nitrate (NO3-) or nitrite (NO2-) A commonly used method for the indirect determination of •NO is the determination of its composition products nitrate and nitrite colorimetrically. This reaction requires that nitrate (NO3) first be reduced to nitrite (NO2), typically by the action of nitrate reductase. Subsequent determination of nitrite by a two step process provides information on the “total” of nitrate and nitrite. In the presence of hydrogen ions nitrite forms nitrous acid, which reacts with sulfanilamide to produce a diazonium ion. This then coupled to N-(1-napthyl) ethylenediamine to form the chromophore which absorbs at 543 nm. Nitrite only determinations can then be made in a parallel assay where the samples were not reduced prior to the colorimetric assay. Actual nitrate levels are then calculated by the subtraction of nitrite levels from the total. <sup><a href="#cite_note-4">[4]</a></sup> </em></p>
<p> </p>
<p>The concentrations of GSH and GSSG have been shown in tissues of human and laboratory animals, including rats, mice and cows (Chen et al., 2010; Giustarini et al., 2013).</p>
CL:0000255eukaryotic cellHighUnspecificHighAll life stagesHighHighHigh<p>Ballatori, N., Krance, S.M., Notenboom, S., Shi, S., Tieu, K., and Hammond, C.L. (2009). Glutathione dysregulation and the etiology and progression of human diseases. Biol. Chem. 390, 191–214.</p>
<p>Chen, C.-A., Wang, T.-Y., Varadharaj, S., Reyes, L.A., Hemann, C., Talukder, M.A.H., Chen, Y.-R., Druhan, L.J., and Zweier, J.L. (2010). S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468, 1115–1118.</p>
<p>Giustarini, D., Dalle-Donne, I., Milzani, A., Fanti, P., and Rossi, R. (2013). Analysis of GSH and GSSG after derivatization with N-ethylmaleimide. Nat. Protoc. 8, 1660–1669.</p>
<p>Held P., 2010 Biotek, Measurement of ROS in Cells, <a class="external free" href="http://www.biotek.com/assets/tech_resources/ROS%20Application%20Guide.pdf" rel="nofollow" target="_blank">http://www.biotek.com/assets/tech_resources/ROS%20Application%20Guide.pdf</a></p>
<p>Kalinina, E.V., Chernov, N.N., and Novichkova, M.D. (2014). Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes. Biochem. Biokhimii︠a︡ 79, 1562–1583.</p>
<p>Kamencic, H., Lyon, A., Paterson, P.G., and Juurlink, B.H. (2000). Monochlorobimane fluorometric method to measure tissue glutathione. Anal. Biochem. 286, 35–37.</p>
<p>Parola, M. and Robino, G. (2001). Oxidative stress-related molecules and liver fibrosis. J Hepatol. 35, 297-306</p>
<p>Reuter S. et al., (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med.49, 1603-1616</p>
<p>Sánchez-Valle V. et al., (2012) Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr Med Chem. 19, 4850-4860</p>
<p>Tipple, T.E., and Rogers, L.K. (2012). Methods for the Determination of Plasma or Tissue Glutathione Levels. Methods Mol. Biol. Clifton NJ 889, 315–324</p>
2016-11-29T18:41:232017-11-13T10:22:02Increased, Induction of pyruvate dehydrogenase (PDH)Increased, Induction of pyruvate dehydrogenase (PDH)Molecular2016-11-29T18:41:262016-12-03T16:37:51Inhibition, Pyruvate dehydrogenase kinase (PDK) enzymeInhibition, Pyruvate dehydrogenase kinase (PDK) enzymeCellular2016-11-29T18:41:262016-12-03T16:37:51Increase, Oxidative metabolismIncrease, Oxidative metabolismCellular2016-11-29T18:41:262016-12-03T16:37:515a4efa78-2a0b-480f-89d2-0bae1817024a05c2b538-262b-4445-9225-081e00ffc97e2016-11-29T18:41:352016-12-03T16:37:5905c2b538-262b-4445-9225-081e00ffc97e32cd9426-fdd8-47fd-aaa8-87b5af361e772016-11-29T18:41:352016-12-03T16:38:0032cd9426-fdd8-47fd-aaa8-87b5af361e770887260f-8398-4121-ae1e-74cbde09f7a72016-11-29T18:41:352016-12-03T16:38:000887260f-8398-4121-ae1e-74cbde09f7a7ca73d4a3-8ddf-4f98-b0d3-e3ad733704952016-11-29T18:41:352016-12-03T16:38:00ca73d4a3-8ddf-4f98-b0d3-e3ad7337049517559c09-f101-4965-ac1a-341efbf98a322016-11-29T18:41:352016-12-03T16:38:00Inhibition of pyruvate dehydrogenase kinase leading to hepatocellular adenomas and carcinomas (in mouse and rat)PDK inhibition- HCC<p>Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)</p>
Under Development: Contributions and Comments WelcomeUnder Development1.29<p>This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.</p>
adjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedNot SpecifiedMaleNot SpecifiedNot Specified<p>U.S. Environmental Protection Agency (Aug 2003). Toxicological Review of Dichloroacetic Acid: In Support of Summary Information on the Integrated Risk Information System (IRIS) (Vol. EPA 635/R-03/007). Washington, DC</p>
2016-11-29T18:41:162023-04-29T16:02:57