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Cited by 105Redox biology and oxidative stressFree Radicals and AntioxidantsMetal-Catalyzed Oxygenation Mechanisms

Oxidation of serotonin by superoxide radical: Implications to neurodegenerative brain disorders

Wrona, Monika Z., Dryhurst, Glenn·1998·Chemical Research in Toxicology
DOI 10.1021/tx970185w
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Abstract

Many new lines of evidence implicate both superoxide anion radical (O2*-) and biogenic amine neurotransmitters in the pathological mechanisms that underlie neuronal damage caused by methamphetamine (MA), glutamate-mediated oxidative toxicity, ischemia-reperfusion, and other neurodegenerative brain disorders. In this investigation the oxidation of 5-hydroxytryptamine (5-HT, serotonin) by an O2*--generating system (xanthine/xanthine oxidase) in buffered aqueous solution at pH 7.4 has been studied. The major product of the O2*--mediated oxidation of 5-HT is tryptamine-4,5-dione (T-4, 5-D). However, O2*- and H2O2, cogenerated by the xanthine oxidase-mediated oxidation of xanthine to uric acid, together react with trace levels of iron that contaminate buffer constituents to give a chemically ill-defined oxo-iron species. This species mediates the oxidation of 5-HT to a C(4)-centered carbocation intermediate that reacts with 5-HT to give 5,5'-dihydroxy-4, 4'-bitryptamine (4,4'-D) and with uric acid to give 9-[3-(2-aminoethyl)-5-hydroxy-1H-indol-4-yl]-2,6,8-triketo-1H,3H, 7H-purine (7) as the major products. These products differ from those formed in the HO*-mediated oxidation of 5-HT under similar conditions. When the reaction is carried out in the presence of the intraneuronal nucleophile glutathione (GSH), T-4,5-D is scavenged to give 7-(S-glutathionyl)tryptamine-4,5-dione, whereas the putative carbocation intermediate is scavenged to give 4-(S-glutathionyl)-5-hydroxytryptamine. T-4,5-D also reacts with the sulfhydryl residues of a model protein, alcohol dehydrogenase, and inhibits its activity. Previous investigators have proposed that T-4, 5-D is a serotonergic neurotoxin. This raises the possibility that T-4,5-D and perhaps other putative intraneuronal metabolites formed by the O2*-/H2O2/oxo-iron-mediated oxidations of 5-HT might be endotoxins that contribute to neurodegeneration in brain regions innervated by serotonergic neurons caused by MA, ischemia-reperfusion, and other neurodegenerative brain disorders.

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  • Trp• reacts very rapidly with O2•− with second-order rate constants k in the range 0.7-2.2 × 10^9 M−1 s−1, mainly giving hydroperoxides in almost quantitative yields.

    “Trp• reacts very rapidly with O2•− with second order rate constants, k, in the range 0.7–2.2 × 109 M−1 s−1, the main initial products being hydroperoxides, in almost quantitative yields [145,146,147,148,149,150,151], Figure 56.”

    From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [147]

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Authors
Wrona, M. Z., & Dryhurst, G.
Affiliations
University of Oklahoma (US)
Corresponding author
Dryhurst, Glenn
Venue
Chemical Research in Toxicology
Publisher
American Chemical Society (ACS)
Published
1998-05-05
Volume
11
Issue
6
Pages
639-650
ISSN
  • 0893-228X (ISSN-L)
  • 1520-5010
DOI
10.1021/tx970185w
OpenAlex
W2054091982
Cited by
105
References
28
Citations by year
2025: 2 · 2024: 2 · 2023: 6 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 7 · 2013: 1 · 2012: 5
FWCI
1.05
Type
journal article
Language
en
Open access
closed
Locations
  • Chemical Research in Toxicology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01gm032367-20)
  • National Institute of General Medical Sciences (GM32367)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Physical Sciences › Chemistry › Organic Chemistry › Free Radicals and Antioxidants
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Keywords
serotonin oxidation, superoxide, xanthine/xanthine oxidase, uric acid, iron-catalyzed oxidation, hydrogen peroxide, glutathione, alcohol dehydrogenase inhibition, neurodegeneration
MeSH terms
Antioxidants, Brain Diseases, Free Radicals, Glutathione, Humans, Iron Chelating Agents, Oxidation-Reduction, Protein Binding, Serotonin, Superoxides, Tryptamines, Free Radical Scavengers, Neurodegenerative Diseases, Indolequinones

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