Skip to main content
PMC home page
Redox Report : Communications in Free Radical Research logoLink to Redox Report : Communications in Free Radical Research
. 2013 Jul 19;15(1):29–35. doi: 10.1179/174329210X12650506623087

Bioavailability and catalytic properties of copper and iron for Fenton chemistry in human cerebrospinal fluid

Ivan Spasojević, Miloš Mojović, Zorica Stević, Snežana D Spasić, David R Jones, Arian Morina, Mihajlo B Spasić
PMCID: PMC7067315  PMID: 20196926

Abstract

A breakdown in homeostasis of redox-active metals represents an important factor for neurodegeneration. We have used EPR spectroscopy and BMPO spin-trap to investigate the catalytic properties and ligand modulation of redox activity of copper and iron in human cerebrospinal fluid (CSF). In contrast to iron, copper supplementation provoked a statistically significant increase in hydroxyl free radical generation in CSF treated with H2O2. However, in a binary copper/iron containing Fenton system, iron catalytically activated copper. The chelator EDTA, which represents a model of physiological metal ligands, completely prevented copper's redox activity in CSF, while iron chelation led to a significant increase in hydroxyl radical generation, indicating that copper and iron do not only have diverse catalytic properties in the CSF but also that their redox activities are differently modulated by ligands. The application of DDC reduced hydroxyl radical generation in the CSF containing catalytically active metals (free Cu2+ or Fe3+-EDTA complex). We conclude that chelators, such as DDC, are capable of preventing the prooxidative activity of both metals and may be suitable for reducing hydroxyl radical formation in certain pathophysiological settings.

Keywords: COPPER, IRON, FENTON REACTION, CEREBROSPINAL FLUID, DIETHYLDITHIOCARBAMATE

Full Text

The Full Text of this article is available as a PDF (240.6 KB).

References

  • 1.Smith MA, Harris PLR, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox generated free radicals. Proc Nat! Acad Sci USA 1997; 94: 9866–9868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Koppenol WH. Fenton chemistry and iron chelation under physiologically relevant conditions: electrochemistry and kinetics. Chem Res Toxicol 2006; 19: 1263–1269. [DOI] [PubMed] [Google Scholar]
  • 3.Cui K, Luo X, Xu K, Murthy MRV. Role of oxidative stress in neurodegeneration: recent developments in assay methods for oxidative stress and nutraceutical antioxidants. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 771–799. [DOI] [PubMed] [Google Scholar]
  • 4.Boll MC, Alcaraz-Zubeldia M, Montes S, Rios C. Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NOx content in the CSF. A different marker profile in four neurodegenerative diseases. Neurochem Res 2008; 33: 1717–1723. [DOI] [PubMed] [Google Scholar]
  • 5.Liu D, Wen J, Liu J, Li L. The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids. FASEB J 1999; 13: 2318–2328. [DOI] [PubMed] [Google Scholar]
  • 6.Huang X, Atwood CS, Hartshorn MA et al. The A13 peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 1999; 38: 7609–7616. [DOI] [PubMed] [Google Scholar]
  • 7.Takahashi S, Takahashi I, Sato H, Kubota Y, Yoshida S, Muramatsu Y Age-related changes in the concentrations of major and trace elements in the brain of rats and mice. Biol Trace Elem Res 2001; 80: 145–158. [DOI] [PubMed] [Google Scholar]
  • 8.Valko M, Morris H, Cronin MTD. Metals, toxicity and oxidative stress. Curr Med Chem 2005; 12: 1161–1208. [DOI] [PubMed] [Google Scholar]
  • 9.Barnham KJ, Masters CL, Bush AT. Neurodegenerative diseases and oxidative stress. Nat Rev 2004; 3: 205–214. [DOI] [PubMed] [Google Scholar]
  • 10.Cookson MR, Shaw PJ. Oxidative stress and motor neurone disease. Brain Pathol1999; 9: 165-186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885–890. [DOI] [PubMed] [Google Scholar]
  • 12.Nakamura M, Shishido N, Nunomura A et al. Three histidine residues of amyloid-13 peptide control the redox activity of copper andiron. Biochemistry 2007; 46: 12737–12743. [DOI] [PubMed] [Google Scholar]
  • 13.Shapira AHV, Mann VM, Cooper JM, Krige D, Jenner PJ, Marsden CD. Mitochondrial function in Parkinson's disease. Ann Neurol 1992; 32: S116–S124. [DOI] [PubMed] [Google Scholar]
  • 14.Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 1988; 334: 345–348. [DOI] [PubMed] [Google Scholar]
  • 15.Wakamatsu K, Fujikawa K, Zucca FA, Zecca L, Ito S. The structure of neuromelanin as studied by chemical degradative methods. J Neurochem 2003; 86: 1015–1023. [DOI] [PubMed] [Google Scholar]
  • 16.Gerard C, Chehhal H, Hugel RP. Complexes of iron(III) with ligands of biological interest: dopamine and 8-hydroxyquinoline-5-sulfonic acid. Polyhedron 1994; 13: 591–597. [Google Scholar]
  • 17.Opazo C, Huang X, Chemy RA et al. Metalloenzyme-like activity of Alzheimer's disease 13-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H202. J Biol Chem 2002; 277: 40302–40308. [DOI] [PubMed] [Google Scholar]
  • 18.Oba H, Araki T, Ohtomo K et al. Amyotrophic lateral sclerosis: T2 shortening in motor cortex at MR imaging. Radiology 1993; 189: 843–846. [DOI] [PubMed] [Google Scholar]
  • 19.Ihara Y, Nobukuni K, Takata H, Hayabara T. Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu,Zn-superoxide dismutase mutation. Neurol Res 2005; 27: 105–108. [DOI] [PubMed] [Google Scholar]
  • 20.Sedlak DL, Hoigne J. The role of copper and oxalate in the redox cycling of iron in atmospheric waters. Atmos Environ 1993; 27: 2173–2185. [Google Scholar]
  • 21.Buettner GR, Jurkiewicz BA. Catalytic metals, ascorbate and free radicals: combinations to avoid. Radic Res 1996; 145: 532–541. [PubMed] [Google Scholar]
  • 22.Bacic G, Spasojevic I, Secerov B, Mojovic M. Spin-trapping of oxygen free radicals in chemical and biological systems: new traps, radicals and possibilities. Spectrochim Acta A 2008; 69: 1354–1366. [DOI] [PubMed] [Google Scholar]
  • 23.Teixeira MC, Telo JP, Duarte NF, Sá-Correiaa I. The herbicide 2,4-dichlorophenoxyacetic acid induces the generation of free-radicals and associated oxidative stress responses in yeast. Biochem Biophys Res Commun 2004; 324: 1101–1107. [DOI] [PubMed] [Google Scholar]
  • 24.Lentner C. Geigy Scientific Tables, vol 1, 8th edn. Basel: Ciba-Geigy, 1981.
  • 25.Barb WG, Baxendale JH, George P, Hargrave KR. Reactions of ferrous and ferric ions with hydrogen peroxide. Part 1. - The ferrous ion reaction. Trans Farad Soc 1951; 47: 462–500. [Google Scholar]
  • 26.Gutteridge JMC, Wilkins S. Copper salt-dependent hydroxyl radical formation damage to proteins acting as antioxidants. Biochim Biophys Acta 1983; 759: 38–41. [DOI] [PubMed] [Google Scholar]
  • 27.Yamamoto K, Kawanishi S. Hydroxyl free radical is not the main active species in site-specific DNA damage induced by copper (II) ion and hydrogen peroxide. J Biol Chem 1989; 264: 15435–15440. [PubMed] [Google Scholar]
  • 28.Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O'Halloran TV. Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 1999; 284: 805–808. [DOI] [PubMed] [Google Scholar]
  • 29.Graf E, Mahoney JR, Bryant RG, Eaton JW. Iron-catalyzed hydroxyl radical formation: stringent requirement for free iron coordination site. J Biol Chem 1984; 259: 3620–3624. [PubMed] [Google Scholar]
  • 30.Michelson AM, Maral J. Carbonate anions; effects on the oxidation of luminal, oxidative hemolysis, y-irradiation and the reaction of activated oxygen species with enzymes containing various active centres. Biochimie 1983; 65: 95–104. [DOI] [PubMed] [Google Scholar]
  • 31.Engelmann MD, Bobier RT, Hiatt T, Cheng IF. Variability of the Fenton reaction characteristics of the EDTA, DTPA, and citrate complexes of iron. Biometals 2003; 16: 519–527. [DOI] [PubMed] [Google Scholar]
  • 32.Fong KL, McCay PB, Poyer JL. Evidence for superoxide dependent reduction of Fe3* and its role in enzyme generated hydroxyl radical formation. Chem Biol Interact 1976; 15: 77–89. [DOI] [PubMed] [Google Scholar]
  • 33.Nikolic-Kokic A, Stevie Z, Stojanovic S et al. Biotransformation of nitric oxide in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. Redox Rep 2005; 10: 265–270. [DOI] [PubMed] [Google Scholar]
  • 34.Taqui Khan MM, Martell AE. Metal ion and metal chelate catalyzed oxidation of ascorbic acid by molecular oxygen. I Cupric and ferric ion catalyzed oxidation. J Am Chem Soc 1967; 89: 4176–4185. [DOI] [PubMed] [Google Scholar]
  • 35.Ghosh SK, Gould ES. Electron transfer. 98. Copper(II) and vanadium(IV) catalysis of the reduction of peroxide-bound chromium(IV) with ascorbic acid. Inorg Chem 1989; 28: 1948–1951. [Google Scholar]
  • 36.Merkofer M, Kissner R, Hider R, Brunk UT, Koppenol WH. Fenton chemistry and iron chelation under physiologically relevant conditions: electrochemistry and kinetics. Chem Res Toxicol 2006; 19: 1263–1269. [DOI] [PubMed] [Google Scholar]
  • 37.Orescanin-Dusic Z, Milovanovic S, Nikolic-Kokic A, Radojcic R, Spasojevic I, Spasic M. Diethyldithiocarbamate potentiates the effects of protamine sulphate in the isolated rat uterus. Redox Rep 2009; 14: 48–54. [DOI] [PubMed] [Google Scholar]
  • 38.Van Faassen E, Vanin AF. (eds) Radicals for life. The various forms of nitric oxide, 1st edn. Amsterdam: Elsevier, 2007. [Google Scholar]

Articles from Redox Report : Communications in Free Radical Research are provided here courtesy of Taylor & Francis

RESOURCES