Iodoacetamide

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Iodoacetamide
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Executive Summary Information

Compound Iodoacetamide
Toxicities Cytotoxicity
Mechanisms Iodoacetamide is representative of alkylating reagents that are selective for thiols. Enzymes that use cysteine as a catalytic nucleophile may be 2-3 orders of magnitude more sensitive to alkylation by this reagent than is GSH. Glyceraldehyde phosphate dehydrogenase is rapidly inactivated, and blockage of glycolysis is a major mechanism of toxicity. Iodoacetamide rapidly increases the GSSG/GSH ratio, which is inferred to result from an increase in the NAD/NADH ratio associated with inhibition of glycolysis. Caspases are also known to be sensitive, and enzymes that transfer the CoASH cofactor in fatty acid synthesis and oxidation are expected to be sensitive. Tagged derivatives of iodoacetamide are used in proteomic analysis of protein redox states.
Comments Iodoacetamide is selected based on its chemical reactivity, representing thiol alkylating agents without accompanying redox activity.
Feedback Contact Gold Compound Working Group (GCWG)
Iodoacetamide
Iodoacetamide.png
Identifiers
Leadscope Id LS-7458
CAS 144-48-9
ChemSpider 3596
UNII ZRH8M27S79
Pathway DBs
Assay DBs
PubChem CID 3727
ChEMBL 276727
Omics DBs
Properties
ToxCast Accepted yes
ToxBank Accepted yes
Target MOA standard for thiol alkylation
Toxicities Cytotoxicity


In Vivo Data ? Compound Assessment
Adverse Events ? Iodoacetamide has been recognized for more than a century as cytotoxic in all organisms and was one of the reagents instrumental in unraveling the pathways of glycolysis.

References:

-Lundsgaard E., “Untersuchungen uber muskelkontraktionen ohne milchsaurebildung”, Biochem. Z. 217:162-177, 1930.
Toxicity Mechanisms ? The major mechanism of toxicity is via alkylation of thiols, both protein thiols and GSH.

References:

-Frank Dickens, “CLII. Interaction of Hoalogenacetates and SH Compounds. The Reactio of Halogenacetic Acids with Glutathione and Cysteine. The Mechanism of Iodoacetate Poisoning of Glyoxylase.” Biochem (1933) 27: 1141-1151.

Iodoacetamide blocks glyceraldehyde phosphate dehydrogenase at 1 mM with glucose as energy source and blocks creatine kinase at 19 mM with pyruvate as the energy source in the perfused rat heart, both within 15 min. The higher concentration used to show inhibition of creatine kinase is consistent with the slower rate of inhibition of this enzyme (see below) although this property was not systematically investigated in a head-to-head experiment.

References:

-John R. Williamson, “Glvcolvtic Control Mechanisms III. Effects of Iodoacetamide and Fluoroacetate on Glucose Metabolism in the Perfused Rat Heart”, J. Biol. Chem. 242:4476-4485,1967.
-Baron L. Hamman, John A. Bittl, William E. Jacobus, Paul D. Allen, Richard S. Spencer, Rong Tian, and Joanne S. Ingwall, “Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts”, Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H1030-H1036, 1995.

Iodoacetamide can be used in conjunction with rotenone, actinomycin, and KCN to distinguish toxicity profiles corresponding to selective inhibition of glycolysis and individual steps in oxidative phosphorylation. (The reference cited is for the largely equivalent toxin iodoacetate.)

References:

-Nicola J. Allen, Ragnhildur Ka´rado´ttir, and David Attwell, “A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells”, The Journal of Neuroscience, January 26, 2005 • 25(4):848–859.

Glyceraldehyde phosphate dehydrogenase is highly sensitive to inhibition by iodoacetamide, and this reagent is a potent inhibitor of glycolysis. For example, in cultured astrocytes, cell death is observed after 60 min of exposure at I mM inhibitor. Alkylation of glutathione occurred more slowly, consistent with the 100-fold higher reactivity of the enzyme towards the inhibitor. However, the ratio of oxidized to reduced glutathione increased, consistent with results described below associated with induction of HSP70.

References:

-Maike M. Schmidt and Ralf Dringen, “Differential effects of iodoacetamide and iodoacetate on glycolysis and glutathione metabolism of cultured astrocytes”, Frontiers in Neuroenergetics, 1:1-10 (2009).

Iodoacetamide induces expression of HSP70 in LLC-PK1 cells. As discussed in the section on in vitro IC50’s below, this may reflect blockage of glycolysis. It activates the Nrf2 pathway in human HEK293T kidney and Hepa-1c1c7 mouse hepatoma cell lines.

References:

-Hong Liu, Richard Lightfoot, and James L. Stevens, “Activation of Heat Shock Factor by Alkylating Agents Is Triggered by Glutathione Depletion and Oxidation of Protein Thiols”, J. Biol. Chem. Vol. 271:4805–4812, 1996.
-Copple IM, Goldring CE, Jenkins RE, Chia AJ, Randle LE, Hayes JD, Kitteringham NR, Park BK, “The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system”, Hepatology. 2008 Oct;48(4):1292-301.

Iodoacetamide blocks apoptosis via caspase-dependent pathways, consistent with the very high reactivity of this reagent with cysteine proteases.

References:

-Mingyu Zhang, Michael J. Blake, Peter W. Gout, Donna J. Buckley, and Arthur R. Buckley, “Proteolysis of Heat Shock Transcription Factor Is Associated with Apoptosis in Rat Nb2 Lymphoma Cells”, Cell Growth & Differentiation, 10: 759–767, 1999.

Glyceraldehyde phosphate dehydrogenase, which is highly sensitive to inhibition by iodoacetamide, has multiple functions outside of glycolysis and its oxidative inactivation is pro-apoptotic. Although not directly confirmed with iodoacetamide as the apoptotic stimulant, the direct involvement this enzyme in apoptosis must be relevant to the induction of apoptosis by iodoacetamide. Note that the facile inhibition of caspases by this reagent implies that these proteases are not required for this apoptotic pathway.

References:

-Dastoor, Z. & Dreyer, J. L., “Potential role of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in apoptosis and oxidative stress”, J. Cell Sci. 114, 1643–1653 (2001).
-Hara MR, Agrawal N, Kim SF, et al. (2005). "S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding". Nat. Cell Biol. 7 (7): 665–74.
Therapeutic Target ?

PubMed references

The following resource link will perform a PubMed query for the terms " Iodoacetamide " and "liver toxicity".
Iodoacetamide Search

The following resource link will perform a PubMed query for the terms " Iodoacetamide " and "cardio toxicity".
Iodoacetamide Search

PK-ADME ? Compound Assessment
PK parameters ? Not applicable.
Therapeutic window. ? Not applicable.
Metabolically activated ? Activation not required. The major detoxification mechanism is via reaction with GSH.

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? Glyceraldehyde phosphate dehydrogenase, which is highly sensitive to inhibition by iodoacetamide, has multiple functions outside of glycolysis, including protein phosphorylation and direct regulation of DNA replication and translation. An effect on gene expression is implied by specific examples are not given.

References:

-Dastoor, Z. & Dreyer, J. L., “Potential role of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in apoptosis and oxidative stress”, J. Cell Sci. 114, 1643–1653 (2001) and references therein.

Iodoacetamide induces expression of HSP70 in LLC-PK1 cells. The extent of GSH loss observed in these cells is much faster than expected from chemical rates of alkylation (see below) and is attributed to alkylation, perhaps reflecting a decrease in the NADH/NAD ratio in response to blocking glycolysis.

References:

-Hong Liu, Richard Lightfoot, and James L. Stevens, “Activation of Heat Shock Factor by Alkylating Agents Is Triggered by Glutathione Depletion and Oxidation of Protein Thiols”, J. Biol. Chem. Vol. 271:4805–4812, 1996.
-James L. Stevens, Hong Liu, Margaretann Halleck, Russell C. Bowes III, Qin Mary Chen, Bob van de Water, “Linking gene expression to mechanisms of toxicity”,

Nrf-2 is activated by thiol alkylating agents, and Nrf-related gene expression has been characterized at the whole genome level.

References:

-Anja Wilmes, Daniel Crean, Sonia Aydin, Walter Pfaller , Paul Jennings, Martin O. Leonard, “Identification and dissection of the Nrf2 mediated oxidative stress pathway in human renal proximal tubule toxicity” Toxicology in Vitro 25 (2011) 613–622.
-Liam Baird and Albena T. Dinkova-Kostova, “The cytoprotective role of the Keap1–Nrf2 pathway”, Arch Toxicol (2011) 85:241–272.
Proteomics profiles known. ? Iodoacetamide is routinely used in proteomics to distinguish protein oxidation states. The compound with a radioactive or fluorescent tag is used label reduced thiols. Any oxidized thiols are then reduced chemically and iodoacetamide with a different tag is used to label the formerly oxidized thiols. These reactions may be carried out in intact cells or in cell lysates.

References:

-Sascha Hoogendoorn, Lianne Willems, Bogdan Florea, and Herman Overkleeft, “Hypersensitive Response to Over-reactive Cysteines”, Angew. Chem. Int. Ed. 2011, 50, 5434 – 5436.
-Eranthie Weerapana, Chu Wang, Gabriel M. Simon, Florian Richter, Sagar Khare, Myles B. D. Dillon, Daniel A. Bachovchin, Kerri Mowen, David Baker, & Benjamin F. Cravatt, “Quantitative reactivity profiling predicts functional cysteines in proteomes”, Nature 468: 790–795 (2010).
-James Bardwell, “Thiol modifications in a snapshot”, Nature Biotechnology, 23:42-43 (2005).

Iodoacetamide reacts more rapidly with some proteins compared to others or to reaction with GSH (see the section below on in vitro toxicity studies). This property has been used with fluorescent tags attached to iodoacetamide to identify reactive thiols in the proteome.

References:

-Sascha Hoogendoorn, Lianne Willems, Bogdan Florea, and Herman Overkleeft, “Hypersensitive Response to Over-Reactive Cysteines”, Angew. Chem. Int. Ed. 2011, 50, 5434–5436.
-Eranthie Weerapana, Chu Wang, Gabriel M. Simon, Florian Richter, Sagar Khare, Myles B. D. Dillon, Daniel A. Bachovchin, Kerri Mowen, David Baker, & Benjamin F. Cravatt, “Quantitative reactivity profiling predicts functional cysteines in proteomes”, Nature 468: 790–795 (2010).
-Kimberly J. Nelson, Amanda E. Daya, Bubing B. Zeng, S. Bruce King, and Leslie B. Poole, “Isotope-coded, iodoacetamide-based reagent to determine individual cysteine pKa values by MALDI-TOF mass spectrometry”, Anal Biochem. 2008 April 15; 375(2): 187–195.

The above procedures will facilitate comparison of the reactivity profiles of alkylating toxins such as NAPQI (the acetaminophen metabolite) with iodoacetamide. Time and concentration dependence will be important in interpreting such patterns. Examples of this type of comparative study are provided in:

References:

-Nah-Young Shin, Qinfeng Liu, Sheryl L. Stamer, and Daniel C. Liebler, “Protein Targets of Reactive Electrophiles in Human Liver Microsomes”, Chem Res Toxicol. 2007 June ; 20(6): 859–867.
-Hansen L. Wong and Daniel C. Liebler, “Mitochondrial Protein Targets of Thiol-Reactive Electrophiles”, Chem. Res. Toxicol. 2008, 21, 796–804.
-Dennehy MK, Richards KA, Wernke GR, Shyr Y, Liebler DC, “Cytosolic and nuclear protein targets of thiol-reactive electrophiles”, Chem Res Toxicol. 2006 19:20-9.
-Lin D, Saleh S, Liebler DC, “Reversibility of covalent electrophile-protein adducts and chemical toxicity”, Chem Res Toxicol. 2008 Dec;21(12):2361-9.
-Aaron T. Jacobs and Lawrence J. Marnett, “Systems Analysis of Protein Modification and Cellular Responses Induced by Electrophile Stress”, Acct. Chem. Res. 43:673-683, 2010.

Iodoacetamide is selective for thiols but will react with other nucleophilic groups at longer reaction times or high pH.

References:

-Zhihua Yang, Athula B. Attygalle, “LC/MS characterization of undesired products formed during iodoacetamide derivatization of sulfhydryl groups of peptides”, Journal of Mass Spectrometry, 42:233–243, 2007.
Metabonomics profiles known. ? Extensive early literature describes the use of iodoacetamide to unravel the pathways of glycolysis.

References:

-Lundsgaard E., “Untersuchungen uber muskelkontraktionen ohne milchsaurebildung”, Biochem. Z. 217:162-177, 1930.
-John R. Williamson, “Glvcolvtic Control Mechanisms III. Effects of Iodoacetamide and Fluoroacetate on Glucose Metabolism in the Perfused Rat Heart”, J. Biol. Chem. 242:4476-4485,1967.
-Baron L. Hamman, John A. Bittl, William E. Jacobus, Paul D. Allen, Richard S. Spencer, Rong Tian, and Joanne S. Ingwall, “Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts”, Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H1030-H1036, 1995.
-Nicola J. Allen, Ragnhildur Ka´rado´ttir, and David Attwell, “A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells”, The Journal of Neuroscience, January 26, 2005 • 25(4):848–859.
-Maike M. Schmidt and Ralf Dringen, “Differential effects of iodoacetamide and iodoacetate on glycolysis and glutathione metabolism of cultured astrocytes”, Frontiers in Neuroenergetics, 1:1-10 (2009).
-N. G. M. Palmen and C. T. A. Evelo, “Glutathione Depletion in Human...
Fluxomics profiles known. ?
Epigenomics profiles known. ?
Observed IC50 for in vitro cellular efficacy. ?
Observed IC50 for in vitro cellular toxicity studies. ? Iodoacetamide reacts more rapidly with some proteins compared to others or to reaction with GSH. This means that some proteins will be inactivated before GSH is depleted by reaction with this reagent.

Relative reactivities towards iodoacetamide are listed in Table 1 below. Proteins with catalytic thiols are generally most sensitive to iodoacetamide. Based on these rates, for example, 99% of glyceraldehyde phosphate dehydrogenase would be inhibited, completely blocking glycolysis, before there is detectable alkylation of glutathione. These rate constants are key to identifying the mechanism of toxicity for this and related alkylating agents

Table 1. Half-lives for reaction of proteins with I mM iodoacetamide in cell-free systems at pH 7.0
Iodoacetamide (alkylation)NAPQI (oxidation)
Glutathione150 min (37⁰)0.008 min (25⁰)
Glyceraldehyde phosphate dehydrogenase0.18 min (25⁰)
Aldehyde dehydrogenase1.3 min (25⁰)
Caspase 31.6 min (25⁰)
Fatty acid synthase5 min (0⁰)
Creatine Kinase20 min (30⁰)
HMG-CoA reductase18 min (37⁰)
GSH synthesis18 min (30⁰)
Lipoamide dehydrogenase120 min (25⁰)

References:

-Maike M. Schmidt and Ralf Dringen, “Differential effects of iodoacetamide and iodoacetate on glycolysis and glutathione metabolism of cultured astrocytes”, Frontiers in Neuroenergetics, 1:1-10 (2009).
-Hasan Shayani-Jam and Davood Nematollahi, “Electrochemical evidences in oxidation of acetaminophen in the presence of glutathione and N-acetylcysteine”, Chem. Commun., 2010, 46, 409–411.
-Allan Fenselau, “Nicotinamide Adenine Dimucleotide As an Active Site Director in Glyceraldehyde S-Phosphate Dehydrogenase Modification”, J. Biol. Chem. 245: 1239-1246, 1970.
-John D. Hempel and Regina Pietruszko, “Selective Chemical Modification of Human Liver Aldehyde Dehydrogenases El and E2 by Iodoacetamide”, JBC 256: 10889-10896, 1981.
-Pratap Karki, Jungsup Lee, Song Yub Shin, Byungyun Cho, Il-Seon Park, “Kinetic comparison of procaspase-3 and caspase-3”, Archives of Biochemistry and Biophysics 442 (2005) 125–132.
-James K. Stoops and Salih J. Wakil, “Yeast fatty acid synthetase: Structure-function relationship and nature of the β-ketoacyl synthetase site”, Proc. Nati. Acad. Sci. USA, Vol. 77, No. 8, pp. 4544-4548, August 1980.
-I. Kumudavalli, B. H. Moreland and D. C. Watts, “Properties and Reaction with Iodoacetamide of Adenosine 5'-Triphosphate-Creatine Phosphotransferase from Human Skeletal Muscle”, Biochem. J. (1970) 117,513-523.
-Rowena G. Matthews, David P. Ballou, Colin Thorpe, And Charles H. Williams, Jr., “Ion Pair Formation in Pig Heart Lipoamide Dehydrogenase”, (1977) J. Biol. Chem. 252, 3199-3207.
-Robert L. Beamer, Owen W. Griffith, Jerald D. Gass, Mary E. Anderson, and Alton Meister, “Interaction of L- and D-3-Amino-1-chloro-2-pentanone with y-Glutamylcysteine Synthetase”, J. Biol. Chem. 255:11732-ll736, 1980.
-Joseph Roitelman and Ishaiahu Shechter, “Studies on the catalytic site of rat liver HMG-CoA reductase: interaction with CoA-thioesters and inactivation by iodoacetamide”, J Lipid Res. 1989. 30: 97-107.
-Spencer L. Shames, Alan H. Fairlamb, Anthony Cerami, and Christopher T. Walsh, “Purification and Characterization of Trypanothione Reductase from Crithidia fasciculata, a Newly Discovered Member of the Family of Disulfide-Containing Flavoprotein Reductases”, Biochemistry 1986, 25, 3519-3526.

A recommended approach to studying the variable sensitivity of proteins to iodoacetamide is to use a dose response in a 15 minute pulse. If glyceraldehyde phosphate dehydrogenase is inhibited, depletion of ATP can be expected within 7 min depending on the cell type and assuming glucose is the energy source. Cell death is observed after 60 min if ATP is depleted.

References:

-James L. Stevens, Hong Liu, Margaretann Halleck, Russell C. Bowes III, Qin Mary Chen, Bob van de Water, “Linking gene expression to mechanisms of toxicity”, Toxicology Letters 112–113 (2000) 479–486.
-Nicola J. Allen, Ragnhildur Ka´rado´ttir, and David Attwell, “A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells”, The Journal of Neuroscience, January 26, 2005 • 25(4):848–859.
-Maike M. Schmidt and Ralf Dringen, “Differential effects of iodoacetamide and iodoacetate on glycolysis and glutathione metabolism of cultured astrocytes”, Frontiers in Neuroenergetics, 1:1-10 (2009).
Table 2. Iodoacetamide reactivity in cell culture.
Concn.TimeCell TypeEffect
1 mM60 minastrocytesinhibition of glycolysis without alkylation of GSH
2 mM13 minhippocampaldepolarization via inhibition of glycolysis without inhibition of oxidative phosphorylation
2 mM60 minerythrocytes97% depletion of GSH
- Maike M. Schmidt and Ralf Dringen, “Differential effects of iodoacetamide and iodoacetate on glycolysis and glutathione metabolism of cultured astrocytes”, Frontiers in Neuroenergetics, 1:1-10 (2009).
- Nicola J. Allen, Ragnhildur Ka´rado´ttir, and David Attwell, “A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells”, The Journal of Neuroscience, January 26, 2005 • 25(4):848–859.
-N. G. M. Palmen and C. T. A. Evelo, “Glutathione Depletion in Human Erythrocytes and Rat Liver: a Study on the Interplay Between Bioactivation and Inactivation Functions of Liver and Blood”, Toxicology in Vitro 10 (1996) 273-281.

Bromocrotonate, a chemical analogue of iodoacetamide, preferentially inhibits 3-ketoacyl-CoA thiolase and acetoacetyl-CoA thiolase in the fatty acid beta-oxidation pathway, without reacting with CoASH. This suggests that these proteins belong to the class of iodoacetamide-sensitive proteins such as the aldehyde dehydrogenases and thiol proteases.

·

References:

-Yetunde Olowe and Horst Schulz, “4-Bromocrotonic Acid, an Effective Inhibitoorf Fatty Acid Oxidation and Ketone Body Degradation in Rat Heart Mitochondri”, J. Biol. Chem. 257:548-5413, 1982.

Iodoacetamide induces expression of HSP70 in LLC-PK1 cells. Gene expression is maximum at 2 hours and is observable at iodoacetamide concentrations of 50 uM and higher. 75 uM [14C]iodoacetamide alkylates only 0.3% of protein thiols but causes a total loss 22% of protein thiols and 85% of reduced GSH within 15 min in these cells. The extent of GSH loss observed in these cells is much faster than expected from chemical rates of alkylation of GSH and, together with the apparent oxidation of a major fraction of protein, implies that iodoacetamide induces a very rapid change in cellular reduction potential, perhaps reflecting a change in the NADH/NAD ratio in response to blocking glycolysis.

·

References:

-Hong Liu‡, Richard Lightfoot, and James L. Stevens, “Activation of Heat Shock Factor by Alkylating Agents Is Triggered by Glutathione Depletion and Oxidation of Protein Thiols”, J. Biol. Chem. Vol. 271:4805–4812, 1996.
-James L. Stevens, Hong Liu, Margaretann Halleck, Russell C. Bowes III, Qin Mary Chen, Bob van de Water, “Linking gene expression to mechanisms of toxicity”, Toxicology Letters 112–113 (2000) 479–486.

Iodoacetamide at 5 uM causes depletion of 50% of GSH within 1 hour in rat hepatocytes, presumably via oxidation rather than alkylation, as discussed in the paragraph above. No further depletion is observed after 1 h. In the same system, acetaminophen requires 24 h at 100 uM for 50% depletion.

·

References:

-David B. Mitchell, Daniel Acosta, and James V. Bruckner, “Role Of Glutathione Depletion In The Cytotoxicity Of Acetaminophen In A Primary Culture System Of Rat Hepatocytes”, Toxicology, 37 (1985) 127-146.

30 uM iodoacetamide is equivalent to 100 uM NAPQI (acetaminophen active metabolite) at inducing activation of Nrf2 in human HEK293T kidney and Hepa-1c1c7 mouse hepatoma cell lines. Cell death at these concentrations progressed over a period of 24 h.

References:

-Copple IM, Goldring CE, Jenkins RE, Chia AJ, Randle LE, Hayes JD, Kitteringham NR, Park BK, “The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system”, Hepatology. 2008 Oct;48(4):1292-301.

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? No - Not included in ToxCast Phase I and II Chemicals List.
Substance stability. ? Sensitive to light and moisture. Prepare aqueous solutions immediately before use and do not use stored solutions.
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Water solubility 0.5 M at 20°C Sigma I1149 Product details


estimated intrinsic solubility : 70.5323 mg/ml
estimated solubility in pure water at pH 7: 70.5323 mg/ml
estimated solubility in water at pH 7.4: 70.53 mg/ml
(Calculations performed using ACD/PhysChem v 12.0)

Solubility in DMSO 100 times buffer solubility. ?
Vessel binding properties. ? Insignificant binding to plasticware
Vapor pressure. (Non-volatile) ? Estimated vapor pressure (25°C): 0.0025 mmHg (Calculation performed using EPI Suite v4.1)

Authors of this ToxBank wiki page

David Bower, Egon Willighagen
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