Dimethoxy-naphthoquinone (DMNQ)

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Dimethoxy-naphthoquinone (DMNQ)
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Executive Summary Information

Compound DMNQ (2,3-dimethoxy-1,4-naphthoquinone)
Toxicities Cytotoxicity
Mechanisms DMNQ is an oxidizing quinone with no alkylating activity. It has a relatively low reduction potential so that it can undergo redox cycling reactions. It depletes the cellular reduction potential, cause oxidation of proteins and DNA, and results ultimately in cell death.
Comments DMNQ is selected based on its chemical reactivity, representing quinones with low reduction potentials and without accompanying alkylating activity. This reactivity similar to that for doxorubicin but without affinity for DNA.
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Dimethoxy-naphthoquinone (DMNQ)
DMNQ.png
Identifiers
Leadscope Id LS-213329
CAS 6956-96-3
ChemSpider 3024
Pathway DBs
Assay DBs
PubChem CID 3136
ChEMBL 402468
Omics DBs
Properties
ToxCast Accepted no
ToxBank Accepted yes
Target MOA standard for redox cycling
Toxicities Cytotoxicity


In Vivo Data ? Compound Assessment
Adverse Events ? DMNQ is a chemical reagent used to study mechanisms of toxicity. It has not been dosed in humans.
Toxicity Mechanisms ? DMNQ is a quinone that has redox cycling but no alkylating activity. It can therefore be used as reference compound in characterizing the effects of oxidative stress. The effects of DMNQ are dependent on concentration, time, and cell type. In addition to the examples provided here, detailed analysis of the toxicity is provided below in the section on in vitro mechanisms of toxicity.

An excellent review of the chemistry behind the toxicity of redox cycling quinones is available at

References:

-Yang Song, Garry R. Buettner, “Thermodynamic and kinetic considerations for the reaction of semiquinone radicals to form superoxide and hydrogen peroxide”, Free Radical Biology & Medicine 49 (2010) 919–962.

In RINm5f pancreatic cells no effect was observed at 10 uM, apoptosis at 30 uM, necrosis at 100 uM. Apoptosis was activated only after 1-3 h of exposure. At 100 uM and 3 h, ATP was depleted to 15%, GSH to 30%, and NAD+ to 5% of control.

References:

-Jeanette M. Dypbuk, Maria Ankarcrona, Mark Burkitt, Sjoholm, Kerstin Strom, Sten Orrenius, and Pierluigi Nicotera, “Different Prooxidant Levels Stimulate Growth, Trigger Apoptosois, or Produce Necrosis of Insulin-secreting RINm5F Cells”, J. Biol. Chem. 269:30553-30560, 1994.

In rat hepatocytes, DMNQ did not cause cell death at 50 uM but rates of cell death increased linearly with higher concentrations. 50% of cells had died at 3 h and 500 uM DMNQ. There was a lag of 30 min before cell death commenced.

References:

-Timothy W. Gant, D.N. Ramakrishna Rao, Ronald P. Mason, and Gerald M. Cohen, "Redox Cycling and Sulphydryl Arylation; Their Relative Importance in the Mechanism of Quinone Cytotoxicity to Isolated Hepatocytes", Chem.-Biol. Interactions, 65 (1988) 157--173.

DMNQ is inotropic for electrically-driven guinea pig left atria. Inotropy is catecholamine-driven. Note that direct effects of DMNQ on the oxidative synthesis or degradation of catecholamines was not evaluated. DMNQ decreased contractility (left ventricular developed pressure) in perfused mouse hearts by 20% at 10 uM.

References:

-M Floreani and F Carpenedo, "Modifications of cardiac contractility by redox cycling alkylating and mixed redox cycling/alkylating quinones", J. Pharmacol. Exp. Ther. 1991 256:243-248.
-Ulrich Flögel, Axel Gödecke, Lars-Oliver Klotz, Jürgen Schrader, “Role of myoglobin in the antioxidant defense of the heart”, The FASEB Journal express article 10.1096/fj.03-1382fje.

Therapeutic Target ?

PubMed references

The following resource link will perform a PubMed query for the terms " Dimethoxy-naphthoquinone (DMNQ) " and "liver toxicity".
Dimethoxy-naphthoquinone (DMNQ) Search

The following resource link will perform a PubMed query for the terms " Dimethoxy-naphthoquinone (DMNQ) " and "cardio toxicity".
Dimethoxy-naphthoquinone (DMNQ) Search

PK-ADME ? Compound Assessment
PK parameters ?
Therapeutic window ?
Metabolically activated ? The primary metabolic route in the mouse is 2-electron reduction to the hydroquinone followed by glucuronidation. This metabolism is detoxifying.

References:

-Joel D. Parry, Amy V. Pointon, Ursula Lutz, Friederike Teichert, Joanne K. Charlwood, Pui Hei Chan, Toby J. Athersuch, Emma L. Taylor, Rajinder Singh, JinLi Luo, Kate M. Phillips, Angelique Vetillard, Jonathan J. Lyon, Hector C. Keun, Werner K. Lutz, and Timothy W. Gant, “Pivotal Role for Two Electron Reduction in 2,3-Dimethoxy-1,4-naphthoquinone and 2-Methyl-1,4-naphthoquinone Metabolism and Kinetics in Vivo That Prevents Liver Redox Stress”, Chem. Res. Toxicol. 2009, 22, 717–725.

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? Comparison of DMNQ to doxorubicin

References:

-Amy V. Pointon, Tracy M. Walker, Kate M. Phillips, Jinli Luo, Joan Riley, Shu-Dong Zhang, Joel D. Parry, Jonathan J. Lyon, Emma L. Marczylo, Timothy W. Gant, "Doxorubicin In Vivo Rapidly Alters Expression and Translation of Myocardial Electron Transport Chain Genes, Leads to ATP Loss and Caspase 3 Activation", (2010) PLoS ONE 5(9): e12733. doi:10.1371/journal.pone.0012733.

DMNQ is used as a reference standard for metallotoxin gene expression profiles.

References:

-Kawata K, Yokoo H, Shimazaki R, Okabe S. "Classification of heavy-metal toxicity by human DNA microarray analysis", Environ Sci Technol. 2007 May 15;41(10):3769-74.

Sublethal doses of DMNQ induce synthesis of GSH via increased transcription of the y-glutamylcysteine synthetase gene.

References:

-M M Shi, A Kugelman, T Iwamoto, L Tian, H J Forman, "Quinone-induced oxidative stress elevates glutathione and induces gamma-glutamylcysteine synthetase activity in rat lung epithelial L2 cells", J Biol Chem. (1994) 269:26512-7.
-Rui-Ming Liu, Michael Ming Shi, Cecilia Giulivi, and Henry Jay Forman, “Quinones increase g-glutamyl transpeptidase expression by multiple mechanisms in rat lung epithelial cells”, Am J Physiol Lung Cell Mol Physiol 274:L330-L336, 1998.

The NF-κB, ERK, c-jun and especially Nrf-2 signally pathways are sensitive to cellular reduction potential. Nrf-related gene expression has been characterized at the whole genome level, and this pathway regulates the key quinone-metabolizing NQO1 (diaphorase) gene.

References:

-Dean P. Jones and Young-Mi Go, "Redox compartmentalization and cellular stress", Diabetes Obes Metab. 2010, 12(Suppl 2): 116–125.
-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.
- Kotb Abdelmohsen, P. Arne Gerber, Claudia von Montfort, Helmut Sies, and Lars-Oliver Klotz, “Epidermal Growth Factor Receptor Is a Common Mediator of Quinone-induced Signaling Leading to Phosphorylation of Connexin-43”, J. Biol. Chem. 278:38360–38367, 2003.


DMNQ induces expression of differentiating cytokines in T-cells.

References:

-Miranda R. King, Anisa S. Ismail, Laurie S. Davis, and David R. Karp, "Oxidative Stress Promotes Polarization of Human T Cell Differentiation Toward a T Helper 2 Phenotype", The Journal of Immunology, 2006, 176: 2765–2772.

Proteomics profiles known. ? The cellular reduction potential varies from compartment to compartment. Sensitivity of compartments to redox-active toxins is generally in the order mitochondria > cytosol > nucleus. Proteomics profiles are the basis of most methods to distinguish redox effects by compartment.

References:

-Dean P. Jones and Young-Mi Go, “Redox compartmentalization and cellular stress”, Diabetes Obes Metab. 2010, 12(Suppl 2): 116–125.
-Jerome Garcia, Derick Han, Harsh Sancheti, Li Peng Yap, Neil Kaplowitz, and Enrique Cadenas, “Regulation Of Mitochondrial Glutathione Redox Status And Protein Glutathionylation By Respiratory Substrates”, JBC Papers in Press. Published on October 11, 2010 as Manuscript M110.164160.

DMNQ modulates protein phosphorylation.

References:

-Kotb Abdelmohsen, P. Arne Gerber, Claudia von Montfort, Helmut Sies, and Lars-Oliver Klotz, “Epidermal Growth Factor Receptor Is a Common Mediator of Quinone-induced Signaling Leading to Phosphorylation of Connexin-43”, J. Biol. Chem. 278:38360–38367, 2003.
-Valerie P.Wright, Peter J. Reiser and Thomas L. Clanton, “Redox modulation of global phosphatase activity and protein phosphorylation in intact skeletal muscle”, J Physiol 587.23 (2009) pp 5767–5781.
-Roger F. Duncan, Hazel Peterson, Curt H. Hagedorn, and Alex Sevanian, “Oxidative stress increases eukaryotic initiation factor 4E phosphorylation in vascular cells”, Biochem. J. (2003) 369, 213±225.

Metabonomics profiles known. ? A metabonomic profile in mice 72 h after a single dose near the MTD indicated a long-term effect on glycolytic capacity.

References:

-Joel D. Parry, Amy V. Pointon, Ursula Lutz, Friederike Teichert, Joanne K. Charlwood, Pui Hei Chan, Toby J. Athersuch, Emma L. Taylor, Rajinder Singh, JinLi Luo, Kate M. Phillips, Angelique Vetillard, Jonathan J. Lyon, Hector C. Keun, Werner K. Lutz, and Timothy W. Gant, "Pivotal Role for Two Electron Reduction in 2,3-Dimethoxy-1,4-naphthoquinone and 2-Methyl-1,4-naphthoquinone Metabolism and Kinetics in Vivo That Prevents Liver Redox Stress", Chem. Res. Toxicol. 2009, 22, 717–725.

Fluxomics profiles known. ?
Epigenomics profiles known. ? References:
-Michaela Tausendschön, Nathalie Dehne, Bernhard Brüne, “Hypoxia causes epigenetic gene regulation in macrophages by attenuating Jumonji histone demethylase activity”, Cytokine 53 (2011) 256–262.
Observed IC50 for in vitro cellular efficacy. ? The MTD for a single dose in mice is 25 mg/kg.

References:

-Joel D. Parry, Amy V. Pointon, Ursula Lutz, Friederike Teichert, Joanne K. Charlwood, Pui Hei Chan, Toby J. Athersuch, Emma L. Taylor, Rajinder Singh, JinLi Luo, Kate M. Phillips, Angelique Vetillard, Jonathan J. Lyon, Hector C. Keun, Werner K. Lutz, and Timothy W. Gant, “Pivotal Role for Two Electron Reduction in 2,3-Dimethoxy-1,4-naphthoquinone and 2-Methyl-1,4-naphthoquinone Metabolism and Kinetics in Vivo That Prevents Liver Redox Stress”, Chem. Res. Toxicol. 2009, 22, 717–725.

Observed IC50 for in vitro cellular toxicity studies. ? DMNQ reacts chemically to oxidize GSH and NADH, and the resultant reduced forms of the quinone can react further to generate reactive oxygen species, especially hydrogen peroxide.

References:

-Review of chemical reactivity: Yang Song, Garry R. Buettner, “Thermodynamic and kinetic considerations for the reaction of semiquinone radicals to form superoxide and hydrogen peroxide”, Free Radical Biology & Medicine 49 (2010) 919–962.

Enzyme-catalyzed reduction of DMNQ is much faster than the chemical reduction. In cardiac cells, reduction is dominated by flavoproteins diaphorase and complex I, which is a 2-electron reduction. One-electron oxidation catalyzed by P450 reductases is slow in rat cardiac tissue. Kinetics in cell lysates at 37⁰, 150 uM NAD(P)H are listed in Table 1. Vmax values can be compared to the rate of glycolysis, approximated by the rate of glucose uptake, which in turn is represents the replenishment of NADH. While the rate of re-oxidation of the dihydroquinone was not explicitly studied, it was shown to be catalyzed by cytochrome c. DMNQ, therefore, can replace ubiquinone in the electron transport chain.

Table 1. Kinetics of enzyme-catalyzed reactions in rat cardiac subcellular fractions.

Vmax (nmol/g cells/min) Km (uM)
Cytosol (diaphorase)3101.7
Mitochondria (complex I) 2407.2
Microsomes (P450 reductases) 108.5
Glucose uptake (mouse heart) 350

References:

-Maura Floreani and Francesca Carpenedo, “Metabolism of Simple Quinones in Guinea Pig and Rat Cardiac Tissue”, Gen. Pharmac. 26:1757-1764 (1995).
-Raymond R. Russell III, Ji Li, David L. Coven, Marc Pypaert, Christoph Zechner, Monica Palmeri, Frank J. Giordano, James Mu, Morris J. Birnbaum, and Lawrence H. Young, “AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury”, J. Clin. Invest. 114:495–503 (2004).

Reduction of quinones via DT-diaphorase (the NQO1 gene product) generates the dihydroquinone. The dihydroquinone can react with O2 or other oxidizing agents to form reactive free radical species, but on balance 2-electron reduction protects against cell death. For quinones such as menadione and NAPQI, which are alkylating agents, reduction blocks the alkylation reaction since the reduced hydroquinone is not alkylating. This protective effect is also observed for DMNQ, which is not alkylating, but to a lesser extent. Protection is not complete for either class of quinones, but the rate of cell death may be shifted from minutes at low diaphorase levels to hours at high levels. Since cellular diaphorase levels can vary markedly for cell lines from the same organ type, the diaphorase expression level is a key parameter in characterizing cell lines as “wild type” with respect to human tissues..

References:

-Jurgen M. Karczewski, Janny G. P. Peters and Jan Noordhoek, “Quinone Toxicity in DT-Diaphorase-Efficient and -Deficient Colon Carcinoma Cell Lines”, Biochemical Pharmacology, Vol. 57, pp. 27–37, 1999.

The ability of non-alkylating quinones to substitute for ubiquinone in the electron transport pathway has been demonstrated by showing that quinones can rescue cells from blockage of ATP synthesis at complex I by rotenone and that this rescue is reversed by inhibition of complex II/III by antimycin A (in glucose-free medium). Rescue was linearly dependent on diaphorase (NQO1) expression, which can vary 100-fold, across multiple cell lines. This implies that flux is driven by reduced DMNQ formed in the cytosol. Note that dicoumoral is useful as an inhibitor of diaphorase in evaluating the function of this enzyme.

References:

-Haefeli RH, Erb M, Gemperli AC, Robay D, Courdier Fruh I, et al. (2011), “NQO1-Dependent Redox Cycling of Idebenone: Effects on Cellular Redox Potential and Energy Levels”, PLoS ONE 6(3): e17963.

In rat hepatocytes, DMNQ caused rapid oxidation of GSH that plateaued within 5 min and slower cell death that progressed over at least 4 h. There was a lag of 30 min before cell death commenced. Table 2 compares the rate of cell death to the extent of GSH oxidation. The cellular redox potential in Table 2 was calculated from the redox potential for GSH. As a rough guide, a potential of -250 mV is normal for proliferating cells, -200 mV for resting cells, and -150 for apoptotic cells. Note that extracellular media serves as a reservoir for oxidized quinone and a sink for reduced hydroquinone, and that glycolysis continually replenishes reduced NAD(P)H and GSH. The cellular redox potential in the presence of DMNQ is, therefore, determined by rates of diffusion in addition to thermodynamics of the oxidation reactions.

Table 2. Concentration dependence of cell death, cellular redox potential, and mitochondrial function in cultured rat hepatocytes.

DMNQ (uM) % Cell Death (4 h) % GSH oxidized (10 min) Calculated Cellular Reduction Potential (mV)
10----
25----
50027-209
1001136-202
2003748-192
5007474-167

References:

-Timothy W. Gant, D.N. Ramakrishna Rao, Ronald P. Mason, and Gerald M. Cohen, “Redox Cycling and Sulphydryl Arylation; Their Relative Importance in the Mechanism of Quinone Cytotoxicity to Isolated Hepatocytes”, Chem.-Biol. Interactions, 65 (1988) 157-173.
-Yang Song, Garry R. Buettner, “Thermodynamic and kinetic considerations for the reaction of semiquinone radicals to form superoxide and hydrogen peroxide”, Free Radical Biology & Medicine 49 (2010) 919–962.
-Dongxiao Shen, Timothy P. Dalton, Daniel W. Nebert, and Howard G. Shertzer, “Glutathione Redox State Regulates Mitochondrial Reactive Oxygen Production”, J. Biol. Chem. 280:25305–25312, 2005. [redox potential calculated for pH 7.8 and 8 mM total glutathione]
-Tak Yee Aw, “Cellular Redox: A Modulator of Intestinal Epithelial Cell Proliferation”, News Physiol Sci 18: 201204, 2003.

Also in rat hepatocytes, cyt P450 inhibitors increased the rate of cell death. The explanation offered to explain this is that inhibiting P450 will decouple P450 reductase from the P450 itself and increase the 1-electron oxidation of DMNQ by the reductase. This 1-electron oxidation is assumed to be a major contributor to toxicity.

References:

- Yasuhiro Ishihara, Dai Shiba, Norio Shimamoto, “Enhancement of DMNQ-induced hepatocyte toxicity by cytochrome P450 in”, Toxicology and Applied Pharmacology 214 (2006) 109–117.

In RINm5f pancreatic cells, DMNQ effects are concentration dependent: no effect at 10 uM, apoptosis at 30 uM, necrosis at 100 uM. Apoptosis was activated only after 1-3 h of exposure. At 100 uM, ATP was depleted to 15%, GSH to 30%, and NADtotal to 5% of control at 3 h. The marked depletion of NADtotal is ascribed to hydrolysis to species of ADP-ribose. Similarly, 50 uM DMNQ caused depletion of NADtotal in K562 leukemia cells and rat hepatocytes.

References:

-Jeanette M. Dypbuk, Maria Ankarcrona, Mark Burkitt, Sjoholm, Kerstin Strom, Sten Orrenius, and Pierluigi Nicotera, “Different Prooxidant Levels Stimulate Growth, Trigger Apoptosois, or Produce Necrosis of Insulin-secreting RINm5F Cells”, J. Biol. Chem. 269:30553-30560, 1994.
-Winston A. Morgan, “Napthoquinone-induced DNA damage in the absence of oxidative stress”, Biochem. Soc. Trans. (1995) 23:225S.
-Winston A. Morgan, “Pyridine nucleotide hydrolysis and interconversion in rat hepatocytes during oxidative stress”, Biochem. Pharm. 49:1179-1184 (1995).

DMNQ (100 uM) modulates protein phosphorylation via the ERK pathway in WB-F344 rat liver epithelial cells within 60 min. It is often assumed that changes in phosphorylation are driven by changes in cellular reduction potential, particularly because protein tyrosine phosphatase (PTPase) is sensitive to redox regulation (see above for a tabulation of ‘omics references). DMNQ activates the ERK pathway without significant modulation of GSH levels or PTPase activity in these cells, however. The pathway that links quinone to ERK activation is not clear.

References:

-Kotb Abdelmohsen, P. Arne Gerber, Claudia von Montfort, Helmut Sies, and Lars-Oliver Klotz, “Epidermal Growth Factor Receptor Is a Common Mediator of Quinone-induced Signaling Leading to Phosphorylation of Connexin-43”, J. Biol. Chem. 278:38360–38367, 2003.

DMNQ at 250 uM causes 67% oxidation of GSH in rat platelets after 2 h. There is no significant cell death in platelets (LDH release) compared to controls under the same conditions. The simplest interpretation of the lack cell death is that cell death is DNA-mediated, either via activation of transcription or a response to DNA damage.

References:

-N. Bresgen, G. Karlhuber, I. Krizbai, H. Bauer, H.C. Bauer, and P.M. Eckl, “Oxidative Stress in Cultured Cerebral Endothelial Cells Induces Chromosomal Aberrations, Micronuclei, and Apoptosis”, Journal of Neuroscience Research 72:327–333 (2003).

The toxicity of DMNQ in A549-S human alveolar epithelial cells was antagonized by extracellular catalase. It was inferred that a major route of toxicity is the diffusion of the reduced hydroquinone species out of the cell, where comproportionation with the oxidized quinone form occurs, followed by reaction of the semiquinone with oxygen to generate H2O2. This implies that DMNQ catalyzes the reduction of O2to H2O2with glucose as the source reducing equivalents. 100 uM extracellular H2O2 was generated with 5 mM glucose and 100 uM DMNQ within 30 min in this system. However, in porcine cerebral endothelial cells, toxicity is increased at low glucose levels. Although seemingly contradictory, concomitant measurements of H2O2 were not made in these experiments.

References:

-Nobuo Watanabe and Henry Jay Forman, “Autoxidation of extracellular hydroquinones is a causative event for the cytotoxicity of menadione and DMNQ in A549-S cells”, Arch Biochem Biophys. 2003 March 1; 411(1): 145–157.
-N. Bresgen, G. Karlhuber, I. Krizbai, H. Bauer, H.C. Bauer, and P.M. Eckl, “Oxidative Stress in Cultured Cerebral Endothelial Cells Induces Chromosomal Aberrations, Micronuclei, and Apoptosis”, Journal of Neuroscience Research 72:327–333 (2003).

Table 3. LD50’s in assorted cell types.

Cells LD50 (uM) Time (h) Comments
Mouse aortic smooth muscle1016Apoptosis, protected by protein phosphatase I
Mouse neural stem5-1024 P53, caspase 2 – dependent apoptosis
Bovine aortic endothelial153Apoptosis; DMNQ supports O2 consumption via the electron transport system
Rat hepatocytes100-3004
Rat hepatocytes15001
RINm5f pancreatic30,10024,8Apoptosis, Necrosis
Newborn mouse astrocytes10 (EC10), 20 (EC50)24, 24Apoptosis and Necrosis, Necrosis
A549-S human alveolar epithelial cells256Dose response very steep with plateau at 25 uM
Porcine cerebral microvascular endothelial10 (IC50)48 P53-mediated apoptosis
Rat platelets>>2502

References:

-Igor Tchivilev, Nageswara R. Madamanchi, Aleksandr E. Vendrov, Xi-Lin Niu, and Marschall S. Runge, “Identification of a Protective Role for Protein Phosphatase 1c1 against Oxidative Stress-induced Vascular Smooth Muscle Cell Apoptosis”, J. Biol. Chem., VOL. 283, NO. 32, pp. 22193–22205, August 8, 2008
-Christoffer Tamm, Boris Zhivotovsky, Sandra Ceccatelli, “Caspase-2 activation in neural stem cells undergoing oxidative stress-induced apoptosis”, Apoptosis (2008) 13:354–363.
-Brian P. Dranka, Bradford G. Hill, and Victor M. Darley-Usmar, “Mitochondrial reserve capacity in endothelial cells: the impact of nitric oxide and reactive oxygen species”, Free Radic Biol Med. 2010 April 1; 48(7): 905–914.
-Timothy W. Gant, D.N. Ramakrishna Rao, Ronald P. Mason, and Gerald M. Cohen, “Redox Cycling and Sulphydryl Arylation; Their Relative Importance in the Mechanism of Quinone Cytotoxicity to Isolated Hepatocytes”, Chem.-Biol. Interactions, 65 (1988) 157-173.
-Yasuhiro Ishihara, Dai Shiba, Norio Shimamoto, “Enhancement of DMNQ-induced hepatocyte toxicity by cytochrome P450 in”, Toxicology and Applied Pharmacology 214 (2006) 109–117.
-Jeanette M. Dypbuk, Maria Ankarcrona, Mark Burkitt, Sjoholm, Kerstin Strom, Sten Orrenius, and Pierluigi Nicotera, “Different Prooxidant Levels Stimulate Growth, Trigger Apoptosois, or Produce Necrosis of Insulin-secreting RINm5F Cells”, J. Biol. Chem. 269:30553-30560, 1994.
-Nikolaus Bresgen, Heidi Jaksch, Hans-Chr. Bauer, Peter Eckl, Istvan Krizbai, and Herbert Tempfer, “Astrocytes Are More Resistant Than Cerebral Endothelial Cells Toward Geno- and Cytotoxicity Mediated by Short-Term Oxidative St”, Journal of Neuroscience Research 84:1821–1828 (2006).
-Nobuo Watanabe and Henry Jay Forman, “Autoxidation of extracellular hydroquinones is a causative event for the cytotoxicity of menadione and DMNQ in A549-S cells”, Arch Biochem Biophys. 2003 March 1; 411(1): 145–157.
-N. Bresgen, G. Karlhuber, I. Krizbai, H. Bauer, H.C. Bauer, and P.M. Eckl, “Oxidative Stress in Cultured Cerebral Endothelial Cells Induces Chromosomal Aberrations, Micronuclei, and Apoptosis”, Journal of Neuroscience Research 72:327–333 (2003).
-Tala R. Henry á Kendall B. Wallace, “Differential mechanisms of cell killing by redox cycling and arylating quinones”, Arch Toxicol (1996) 70: 482-489.

At this stage it is clear that the dominant reaction of DMNQ within the cell is 2-electron reduction to the hydroquinone. It is not clear whether 1-electron free radical side reactions are what cause toxicity. It is not clear whether cell death is caused by disruption of cellular redox potential/metabolism, protein oxidation, or DNA degradation. LD50 measurements have been measured at times from 1 h to 24 h, resulting in 100-fold variation in LD50’s. In addition, and the levels of a primary metabolizing enzyme, diaphorase, may vary by 100-fold from cell to cell. It is possible that with such large variation in basic parameters, multiple mechanisms of toxicity may be reflected in various investigations. To the extent these factors are not clear for DMNQ, they are not clear generally for redox cycling activities. Based on the aggregate of the above results, a complete profile of the effect of DMNQ on cells would include the following:


-GSH/GSSG ratio (cellular reduction potential)
-Intermediates of glycolysis pre- and post- glyceraldehyde phosphate (GAPDH enzyme is highly sensitive to oxidation)
-Total GSH (some cells secrete GSSG if the GSH/GSSG ratio decreases)
-Total NAD (depletion, presumably via ADP-ribosylation reactions, is observed in some cells)
-Protein oxidation state (methods referenced in the Iodoacetamide data table)
-Formation of 8-oxodG oxidation products in DNA and DNA strand breakage
-Markers for ROS damage
-Diaphorase, complex I, and P450 reductase expression
-H2O2 release

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. ?
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? estimated intrinsic solubility : 7.6979e-2 mg/ml


estimated solubility in pure water at pH 7: 7.6979e-2 mg/ml
estimated solubility in water at pH 7.4: 7.6979e-2 mg/ml
(Calculations performed using ACD/PhysChem v 12.0)

Solubility in DMSO 100 times buffer solubility. ? 10 mg/ml Sigma Aldrich (D5439) Specification Sheet
Vessel binding properties. ?
Vapor pressure. (Non-volatile) ? Estimated vapor pressure (25°C): 1.29E-005 mmHg


(Calculation performed using EPI Suite v4.1)

Authors of this ToxBank wiki page

David Bower, Egon Willighagen
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