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Oxidative Pathways for Catecholamines in the Genesis of Neuromelanin and Cytotoxic Quinones
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“When iron is present in the cytosol (as may occur more frequently with ageing)265,266, dopamine can be oxidized into dopamine quinone (DAQ), which is highly reactive and toxic267,268.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [267]
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“The monoamines, particularly DA and norepinephrine (NE) have the ability to spontaneously oxidize in the cytosol, potentially damaging cellular machinery [21].”
BackgroundProteasomal activity in brain differs between species and brain regions and changes with age.
Zeng, B.-Y., Medhurst, A. D., Jackson, M., Rose, S., & Jenner, P. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.01.008 · Cited by 113
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“On the other hand, toxic e ects of dopamine may result via either oxidative deamination by MAO or autoxidation (Graham, 1978; Michel & Hefti, 1990; Rosenberg, 1988).”
BackgroundResultInfluentialVulnerability of mitochondrial complex I in PC12 cells exposed to manganese
Galvani, P., Fumagalli, P., & Santagostino, A. (1995) · European Journal of Pharmacology Environmental Toxicology and Pharmacology · doi:10.1016/0926-6917(95)90058-6 · Cited by 112
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“However, excessive levels of cytosolic DA outside the vesicles in damaged DA neurons is thought to induce neurotoxicity through the generation of ROS and reactive DA quinones (15, 16).”
BackgroundDecreased brain dopamine cell numbers in human cocaine users
Little, K. Y., Ramssen, E., Welchko, R. M., Volberg, V., Roland, C. J., & Cassin, B. J. (2009) · Psychiatry Research · doi:10.1016/j.psychres.2008.10.034 · Cited by 113
“Dopamine is known to spontaneously oxidize both de novo, or via an enzyme-catalyzed reaction in vivo, to form reactive oxygen species which are damaging to cellular components such as lipids, proteins, and DNA (Graham, 1978).”
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Dopamine D1 Receptors, Regulation of Gene Expression in the Brain, and Neurodegeneration
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“The manner by which DA exerts its toxic effects have been attributed, mainly, to the production of reactive quinones and other reactive species that are generated by oxidative DA metabolism [151-153].”
BackgroundChemicals and Drugs Forming Reactive Quinone and Quinone Imine Metabolites
Klopčič, I., & Dolenc, M. S. (2018) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.8b00213 · Cited by 112
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l-dopa-induced dopamine synthesis and oxidative stress in serotonergic cells
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“It is likely that dopa and synthesized dopamine can spontaneously oxidize to their quinones (Asanuma et al., 2003; Basma et al., 1995; Graham, 1978; Stokes et al., 1999) and produce damage to 5-HT neurons.”
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Modulation of Antioxidant Defense Systems by the Environmental Pesticide Maneb in Dopaminergic Cells
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“Oxidation of dopamine generates electron-deficient quinones and reactive, partially reduced oxygen species.(6,30,31) Further oxidation and polymerization of dopamine leads to the formation of neuromelanin, an insoluble granular pigment thought to be protective in that it sequesters reactive dopamine derivatives.”
BackgroundFelix, K., Manna, S. K., WISE, K. C., Barr, J. L., & Ramesh, G. T. (2005) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.20062 · Cited by 103
“Second, the catechol ring of DA can undergo oxidation to form DA quinine and ROS such as H2O2 and superoxide anion ( ) in a reaction that can occur either spontaneously in the presence of transition of metals or enzymatically [20,21].”
BackgroundLiu, F., Hindupur, J., Nguyen, J. L., Ruf, K. J., Zhu, J., Schieler, J. L., Bonham, C. C., Wood, K. V., Davisson, V. J., & Rochet, J. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.03.022 · Cited by 102
“Dopaminergic neurons of the substantia nigra contain relatively high basal levels of ROS resulting from dopamine metabolism and auto-oxidation [10].”
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“The subsequent oxidation of 5-S-cysteinyl DA produces a number of neurotoxic compounds [17].”
BackgroundNature of methamphetamine-induced rapid and reversible changes in dopamine transporters
Kokoshka, J. M., Vaughan, R. A., Hanson, G. R., & Fleckenstein, A. E. (1998) · European Journal of Pharmacology · doi:10.1016/s0014-2999(98)00741-9 · Cited by 102
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Oxidative damage in substantia nigra and striatum of rats chronically exposed to ozone
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“Stable o-quinones were formed by oxidizing DA or N-acetyl-DA with one equivalent of NaIO4 immediately before addition to cells (Graham, 1978; Graham et al., 1978).”
MethodEnvironmental Chemistry and Chemical Ecology of “Green Tide” Seaweed Blooms
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Impaired iron homeostasis in Parkinson’s disease
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“It has been known since the mid 1970s that superoxide interacts with catecholamines (these are, in fact, considered as antioxidants), converting them to adrenochromes (100, 101).”
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Interaction of Human Substantia Nigra Neuromelanin with Lipids and Peptides
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Astrocyte-derived metallothionein protects dopaminergic neurons from dopamine quinone toxicity
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“The monoamines, particularly DA and NA have the ability to undergo spontaneous oxidation in the cytosol, which is potentially damaging to cellular structures (Graham 1978; Antkiewicz-Michaluk et al. 2006; Wąsik et al. 2009).”
BackgroundLevodopa: Effect on cell death and the natural history of Parkinson's disease
Olanow, C. W. (2014) · Movement Disorders · doi:10.1002/mds.26119 · Cited by 95
“In addition, both L-dopa and dopamine can undergo auto-oxidation to form potentially toxic semiquinones.(3,4) Indeed, in the SNc of patients with PD, iron levels, which promote oxidation, are increased,(5) GSH levels, which defend against oxidation, are reduced,(6) cysteinyldopa levels, which provide an index of autox…”
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Levodopa Is Toxic to Dopamine Neurons in an in Vitro but Not an in Vivo Model of Oxidative Stress
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“The addition of levodopa under these conditions could add to the pro-oxidant environment in the SNc by way of the formation of reactive oxygen species formed during the autoxidation or metabolism of levodopa and/or dopamine (Graham, 1978).”
BackgroundPeripheral Blood Markers of Oxidative Stress in Parkinson’s Disease
Younes, S., Frih-Ayed, M., Kerkeni, A., Bost, M., & Chazot, G. (2007) · European Neurology · doi:10.1159/000103641 · Cited by 92
Dopamine quinones interact with α-synuclein to form unstructured adducts
Bisaglia, M., Tosatto, L., Munari, F., Tessari, I., de Laureto, P. P., Mammi, S., & Bubacco, L. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.03.044 · Cited by 94
“The oxidation of DA leads to both toxic reactive oxygen species (ROS) and dopamine-quinones (DAQ) [4].”
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“Alternatively, it can be enzymatically deaminated by monoamine oxidase to produce toxic dopamine metabolites and ROS, such as superoxide and hydroxyl radicals (Graham 1978; Maker et al. 1981).”
Storch, A., Kaftan, A., Burkhardt, K., & Schwarz, J. (2000) · Journal of Neural Transmission · doi:10.1007/s007020050023 · Cited by 93
“At physiological pH 6-OHDA reacts with molecular oxygen to form quinones as well as radical oxygen species (Graham, 1978), including hydrogen peroxide (H2O2), anion superoxide O22 and hydroxyl radical (OH).”
BackgroundNo evidence for systemic oxidant stress in Parkinson's or Alzheimer's disease
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Pharmacological treatment of Parkinson’s disease
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Dopamine-glutamate interactions in methamphetaminc-induced neurotoxicity
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“Oxidation products of DA include neurotoxins such as 6-hydroxydopamine (Seiden and Vosmer, 1984), quinones of dopamine (Graham, 1978; Rosengren etal., 1985; Fornstedt etal., 1990), or oxygen radicals (Cohen, 1990).”
BackgroundBilska‐Wilkosz, A., Dubiel, M., ewicz, M. S. O.-J., Lorenc‐Koci, E., & Włodek, L. B. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.04.002 · Cited by 91
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“DA was also converted enzymatically to the aminochrome by tyrosinase, and finally, N-acetyl-DA was oxidized by NaIO 4 to the more stable o-quinone (Graham, 1978; Graham et al., 1978).”
BackgroundMethodInfluentialManganese Homeostasis and Transport
Roth, J. A., Ponzoni, S., & Aschner, M. (2012) · Metal ions in life sciences · doi:10.1007/978-94-007-5561-1_6 · Cited by 94
Oxidative stress in Parkinson's disease
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Drug treatment of Parkinson’s disease
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“Catalase provides a secondary source of H O removal only when glutathione levels are severely depleted (71).”
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“DA can oxidize spontaneously in vitro or through an enzyme-catalyzed reaction in vivo to form ROS and quinones (Cohen and Heikkila, 1974; Graham, 1978; Hastings, 1995).”
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“As previously reported [7], during the Ty-mediated oxidation of DA at physiological pH and 25 °C only AC is detectable in the optical spectra with no evidence for the presence of DQ.”
BackgroundInfluentialNeurotoxicity of MDMA: Neurochemical Effects
SCHMID, C. J., & Kehne, J. H. (1990) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1990.tb16917.x · Cited by 84
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“…prevents the acute METHinduced decrease in TPH activity (Schmidt et al., 1985); and 2) dopamine may have oxidative consequences by causing formation of hydrogen peroxide, superoxide, dopamine quinones (Graham, 1978; Baez et al., 1995) or the neurotoxin 6-hydroxydopamine (Seiden and Vosmer, 1984).”
Neurotoxicity of Endogenous Cysteinylcatechols
Montine, T. J., Picklo, M. J., Amarnath, K., et al. (1997) · Experimental Neurology · doi:10.1006/exnr.1997.6662 · Cited by 83
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Free radical production induced by methamphetamine in rat striatal synaptosomes
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Loss of dopaminergic neurons in parkinsonism: possible role of reactive dopamine metabolites
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“Spontaneous DA oxidation at neutral pH of the cytosol yields DA-o-quinone and dopaminochrome (Graham, 1978; Sulzer and Zecca, 2000), which can then react with free cysteine and exposed cysteine residues of proteins and glutathione producing 5-Scystenyl-DA.”
BackgroundIncreased α-synuclein phosphorylation and nitration in the aging primate substantia nigra
McCormack, A. L., Mak, S. K., & Monte, D. A. D. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.50 · Cited by 80
“A pro-oxidant environment characterizes dopaminergic neurons and is reflected by their accumulation of neuromelanin, a product of dopamine oxidative metabolism.(24)”
BackgroundOxidative stress and Parkinson's disease
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“First,blockade of post-synapticneuronsby the antipsychoticdrug increasestheproductionandmetabolismof dopamine, whichmayleadto increasedformationof dopamine quinones (Graham, 1978) as well as hydrogen peroxide (Cohen, 1984),both of which cangenerate free radicals.”
BackgroundMolecular Events Underlying Parkinson’s Disease – An Interwoven Tapestry
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“For SN dopaminergic neurons, the vulnerability toward oxidative stress is further enhanced by the abundance of redox-active iron in this region of the brain, as well as by the presence of DA, whose oxidation products are potentially cytotoxic (Graham, 1978).”
BackgroundExposure, epidemiology, and mechanism of the environmental toxicant manganese
Chen, P., Culbreth, M. E., & Aschner, M. (2016) · Environmental Science and Pollution Research · doi:10.1007/s11356-016-6687-0 · Cited by 79
“In dopaminergic (DAergic) neurons, Mn can catalyze autoxidation of dopamine (DA), producing DA-o-quinone, ROS, and hydrogen peroxide (H2O2) (Donaldson et al. 1982; GRAHAM 1978; Reaney and Smith 2005).”
BackgroundKato, T., Ito, S., & Fujita, K. (1986) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(86)90034-6 · Cited by 79
6-Hydroxydopamine: a far from simple neurotoxin
Varešlija, D., Tipton, K. F., Davey, G. P., & McDonald, A. G. (2020) · Journal of Neural Transmission · doi:10.1007/s00702-019-02133-6 · Cited by 80
“The high reduction potential of 6-OHDA (+ 154 mV at pH 6.8; Graham 1978) is sufficient for releasing iron in its ferrous Fe(II) from the iron-storage protein ferritin (Gerlach et al.”
BackgroundInfluentialFast, M. D., Ross, N. W., Craft, C., et al. (2004) · Experimental Parasitology · doi:10.1016/j.exppara.2004.04.001 · Cited by 78
Duce, J. A., Wong, B. X. W., Durham, H., Devedjian, J.-C., Smith, D. P., & Devos, D. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0186-8 · Cited by 81
“Alternatively, DA can be spontaneously oxidised in the presence of oxygen to yield DA-o-quinone, H2O2 and superoxide [11].”
Dopamine and Iron Induce Apoptosis in PC12 Cells
Velez‐Pardo, C., Jiménez-Del-Río, M., Verschueren, H., Ebinger, G., & Vauquelin, G. (1997) · Pharmacology & Toxicology · doi:10.1111/j.1600-0773.1997.tb00287.x · Cited by 77
DNA damage in rats after treatment with methylphenidate
Andreazza, A. C., Frey, B. N., Valvassori, S. S., Zanotto, C., Gomes, K. M., Comim, C. M., Cassini, C., Stertz, L., Ribeiro, L. C., Quevedo, J., et al. (2007) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2007.05.012 · Cited by 76
α-Synuclein and Dopamine Metabolism
Yu, S., Uéda, K., & Chan, P. (2005) · Molecular Neurobiology · doi:10.1385/mn:31:1-3:243 · Cited by 77
“DA can also undergo spontaneous autoxidation, at normal intracellular pH and in the presence of molecular oxygen, into toxic and reactive DA quinones, superoxide free radicals, and hydrogen peroxide (30).”
Metadata
- Authors
- GRAHAM, D. G.
- Affiliations
- Duke Medical Center (US)
- Corresponding author
- GRAHAM, DOYLE G.
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 1978-07
- Volume
- 14
- Issue
- 4
- Pages
- 633-643
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2211987820
- Cited by
- 1,126
- References
- 0
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 6 · 2023: 11 · 2022: 13 · 2021: 20 · 2020: 23 · 2019: 26 · 2018: 29 · 2017: 30 · 2016: 26 · 2015: 29 · 2014: 26 · 2013: 26 · 2012: 49
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- catecholamines, autoxidation, periodate oxidation, 6-hydroxydopamine, dopamine, norepinephrine, epinephrine, aminochrome, adrenochrome, o-quinones, p-quinones, cyclization, tautomerism, neuromelanin
- MeSH terms
- Catecholamines, Dopamine, Epinephrine, Hydroxydopamines, Melanins, Norepinephrine, Oxidation-Reduction, Quinones, Monophenol Monooxygenase
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