Prostaglandin H Synthase-1-Catalyzed Bioactivation of Neurotransmitters, Their Precursors, and Metabolites: Oxidative DNA Damage and Electron Spin Resonance Spectroscopy Studies

Gonçalves, Leônor; Ramkissoon, Annmarie; Wells, Peter G.

doi:10.1021/tx800423s

Cited by 17 publications

(34 citation statements)

References 62 publications

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“…NaH 2 PO 4 and Tricine were from Research Products International (Mount Prospect, IL), and Cambridge Isotope Laboratories (Andover, MA) provided deuterated solvents and trimethylsilylpropanoate-d 4 . Human recombinant COX-2 (EC 1.14.99.1; 10,636.25 units/mg) and arachidonic acid were from Cayman Chemicals (Ann Arbor, MI), and DMSO, K 3 Fe(CN) 6 , and perchloric acid were from Thermo Fisher Scientific. All other chemicals were from Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

“…The spectra in D 2 O were referenced to trimethylsilylpropanoate-d 4 (0.0 ppm), whereas samples in 1:4 D 2 O/acetone-d 6 were referenced internally to acetone-d 6 (2.05 ppm).…”

Section: Methodsmentioning

confidence: 99%

“…The reaction was repeated with 10 mM NaH 2 PO 4 (pD 7.5 in D 2 O), and with a 4-fold excess of acetoned 6 . For structure determination experiments, the reaction mixture was diluted 1:4 with acetone-d 6 (prechilled on dry ice) 60 s after the addition of NaIO 4 , and then transferred into an NMR tube and immediately analyzed at Ϫ20°C. The oxidation product was characterized via a variety of one-and two-dimensional homonuclear and heteronuclear experiments ( 10.0 ppm; TD, 4k; TD1, 400; NS, 40; DS, 128).…”

Section: Methodsmentioning

confidence: 99%

“…DA may act as a source of cellular oxidative stress and is known to undergo oxidation (Scheme 1) to cytotoxic radicals and quinones (5)(6)(7)(8). Such oxidations can occur spontaneously or via metal-or enzyme-catalyzed mechanisms (9).…”

mentioning

confidence: 99%

“…Such oxidations can occur spontaneously or via metal-or enzyme-catalyzed mechanisms (9). One-electron oxidation of DA produces a radical capable of interfering with DA storage and causing oxidative protein and DNA modifications (5,6,10). Similarly, two-electron oxidation of DA to an ortho-quinone results in reactivity with cellular nucleophiles such as thiols and proteins (8,11).…”

mentioning

confidence: 99%

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Oxidation of 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopaminergic Metabolite, to a Semiquinone Radical and an ortho-Quinone

Anderson

Mariappan

Buettner

et al. 2011

Journal of Biological Chemistry

122

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The oxidation and toxicity of dopamine is believed to contribute to the selective neurodegeneration associated with Parkinson disease. The formation of reactive radicals and quinones greatly contributes to dopaminergic toxicity through a variety of mechanisms. The physiological metabolism of dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL) via monoamine oxidase significantly increases its toxicity. To more adequately explain this enhanced toxicity, we hypothesized that DOPAL is capable of forming radical and quinone species upon oxidation. Here, two unique oxidation products of DOPAL are identified. Several different oxidation methods gave rise to a transient DOPAL semiquinone radical, which was characterized by electron paramagnetic resonance spectroscopy. NMR identified the second oxidation product of DOPAL as the ortho-quinone. Also, carbonyl hydration of DOPAL in aqueous media was evident via NMR. Interestingly, the DOPAL quinone exists exclusively in the hydrated form. Furthermore, the enzymatic and chemical oxidation of DOPAL greatly enhance protein cross-linking, whereas auto-oxidation results in the production of superoxide. Also, DOPAL was shown to be susceptible to oxidation by cyclooxygenase-2 (COX-2). The involvement of this physiologically relevant enzyme in both oxidative stress and Parkinson disease underscores the potential importance of DOPAL in the pathogenesis of this condition. Parkinson disease (PD)2 involves specific loss of dopaminergic nuclei in the substantia nigra of the brain (1). Although the exact causes of this selective degeneration are unknown (2), the role of affected cells as centers of dopamine (DA) synthesis, storage, and metabolism suggests that DA may be an endogenous neurotoxin (3, 4) that contributes to the pathogenesis of PD. DA may act as a source of cellular oxidative stress and is known to undergo oxidation (Scheme 1) to cytotoxic radicals and quinones (5-8). Such oxidations can occur spontaneously or via metal-or enzyme-catalyzed mechanisms (9). One-electron oxidation of DA produces a radical capable of interfering with DA storage and causing oxidative protein and DNA modifications (5, 6, 10). Similarly, two-electron oxidation of DA to an ortho-quinone results in reactivity with cellular nucleophiles such as thiols and proteins (8, 11). Both species are capable of redox cycling, which could deplete cellular oxidative defenses. Also, in the presence of transition metals and/or O 2 , such oxidations could result in the production of ROS capable of inducing lipid peroxidation and damage to other cellular macromolecules (12). Another potential mechanism of toxicity for DA is its physiological metabolism to 3,4-dihydroxyphenylacetaldehyde (DOPAL) (13).DOPAL is a very reactive aldehyde that is 100 -1000-fold more toxic than DA both in vivo and in vitro (14,15). Physiological levels of DOPAL in the substantia nigra are ϳ2 M; levels as low as 6 M can exert significant toxicity (16). Reactivity with proteins, presumably via Schiff base formation, is an important mechanism o...

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Section: Methodsmentioning

confidence: 99%

“…The spectra in D 2 O were referenced to trimethylsilylpropanoate-d 4 (0.0 ppm), whereas samples in 1:4 D 2 O/acetone-d 6 were referenced internally to acetone-d 6 (2.05 ppm).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Oxidation of 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopaminergic Metabolite, to a Semiquinone Radical and an ortho-Quinone

Anderson

Mariappan

Buettner

et al. 2011

Journal of Biological Chemistry

122

View full text Add to dashboard Cite

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Neurodegeneration from Drugs and Aging‐Derived Free Radicals

Ramkissoon¹,

Shapiro²,

Loniewska³

et al. 2013

Molecular Basis of Oxidative Stress

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Fetal oxidative stress mechanisms of neurodevelopmental deficits and exacerbation by ethanol and methamphetamine

Wells

Bhatia

Drake

et al. 2016

Birth Defects Research Pt C

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In utero exposure of mouse progeny to alcohol (ethanol, EtOH) and methamphetamine (METH) causes substantial postnatal neurodevelopmental deficits. One emerging pathogenic mechanism underlying these deficits involves fetal brain production of reactive oxygen species (ROS) that alter signal transduction, and/or oxidatively damage cellular macromolecules like lipids, proteins, and DNA, the latter leading to altered gene expression, likely via non-mutagenic mechanisms. Even physiological levels of fetal ROS production can be pathogenic in biochemically predisposed progeny, and ROS formation can be enhanced by drugs like EtOH and METH, via activation/induction of ROS-producing NADPH oxidases (NOX), drug bioactivation to free radical intermediates by prostaglandin H synthases (PHS), and other mechanisms. Antioxidative enzymes, like catalase in the fetal brain, while low, provide critical protection. Oxidatively damaged DNA is normally rapidly repaired, and fetal deficiencies in several DNA repair proteins, including oxoguanine glycosylase 1 (OGG1) and breast cancer protein 1 (BRCA1), enhance the risk of drug-initiated postnatal neurodevelopmental deficits, and in some cases deficits in untreated progeny, the latter of which may be relevant to conditions like autism spectrum disorders (ASD). Risk is further regulated by fetal nuclear factor erythroid 2-related factor 2 (Nrf2), a ROS-sensing protein that upregulates an array of proteins, including antioxidative enzymes and DNA repair proteins. Imbalances between conceptal pathways for ROS formation, versus those for ROS detoxification and DNA repair, are important determinants of risk. Birth Defects Research (Part C) 108:108-130, 2016. © 2016 Wiley Periodicals, Inc.

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Prostaglandin H Synthase-1-Catalyzed Bioactivation of Neurotransmitters, Their Precursors, and Metabolites: Oxidative DNA Damage and Electron Spin Resonance Spectroscopy Studies

Cited by 17 publications

References 62 publications

Oxidation of 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopaminergic Metabolite, to a Semiquinone Radical and an ortho-Quinone

Oxidation of 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopaminergic Metabolite, to a Semiquinone Radical and an ortho-Quinone

Neurodegeneration from Drugs and Aging‐Derived Free Radicals

Fetal oxidative stress mechanisms of neurodevelopmental deficits and exacerbation by ethanol and methamphetamine

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