Abstract
A new hypothesis describing the role of the redox inactive Ca2+ ion in the expression of physiological oxidative damage is described. The hypothesis is based on the optimization of the chelation characteristics of iron complexes for pro-oxidant activity. In a previous investigation it was found that an excess of ligand kinetically hindered the Fenton reaction activity of the FeII/IIIEDTA complex (Bobier et al. 2003). EDTA, citrate, NTA, and glutamate were selected as models for the coordination sites likely encountered by mobile iron, i.e. proteins. The optimal [EDTA]:[FeIII] ratio for Fenton reaction activity as measured by electrocatalytic voltammetry in a solution was found to be 1:1. An excess of EDTA in the amount of 10:1 [ligand]:[metal] suppresses the Fenton reaction activity to nearly the control. It is expected that the physiological coordination characteristics of mobile Fe would have a very large excess of [ligand]:[metal] and thus not be optimized for the Fenton reaction. Introduction of Ca2+ in to a ratio of 10:10:1 [Ca2+]:[EDTA]:[FeIII] to the system reinvigorated the Fenton reaction activity to nearly the value of the optimal 1:1 [EDTA]:[FeIII] complex. The pH distribution diagrams of Ca2+ in the presence of EDTA and FeII/III indicate that Ca2+ has the ability to uptake excess EDTA without displacing either FeII of FeIII from their respective complexed forms. The similarity in the presence for hard ligand sites albeit with a lower binding constant for Ca2+ accounts for this action.
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Alderighi L, Gans P, Ienco A, Peters D, Sabatini A, Vacca A. 1999 'Hyperquad simulation and speciation (HySS): a utility program for the investigation of equilibria involving soluble and partially soluble species', Coord Chem Rev 184: 311–318
Arouma OI, Halliwell B. 1988 'The Iron-Binding and Hydroxyl Radical Scavenging Action of Anti-inflammatory Drugs', Xen-obiotica, 18: 459–470.
Atlante A, Calissano C, Bobba A, Giannatassio S, Marra E, Passer-ella S. 2001 'Glutamate Neurotoxicity, Oxidative Stress, and Mitochondria.' FEBS Letters 497: 1–5
Avila L, Huang H, Rodriguez JC, Moënne-Loccoz, P, Rivera M. 2000 'Oxygen Activation by Axial Ligand Mutants of Mito-chondrial Cytochrome b 5: Oxidation of Heme to Veroheme and Bilverdin' J Am Chem Soc 122: 7818–7619
Babior BM. 2000 'Phagocytes and Oxidative Stress' Amer J Med 109: 33–44
Bard AJ, Faulkner LR. 2001 In: Electrochemical Methods: Funda-mentals and Applications, 2nd Edition. John Wiley and Sons, New York, p. 501?
Berlett BS, Chock PB, Yim MB, Stadtman ER. 1990 'Manganese(II)-bicarbonate-mediated catalytic activity for hydrogen peroxide dismutation and amino acid oxidation: detection of free radical intermediates.' Proc Nat Acad Sci USA 87(1): 389–393.
Blokhina O, Virolainen E, Fagerstedt KV. 2003 Antioxidants, Oxid-ative Damage and Oxidation Deprivation Stress: a Review' Ann Bot 91: 179–194
Bobier RT, Engelmann MD, Hiatt T, Cheng IF. 2003 'Variability of the Fenton Reaction Characteristics of the EDTA, DTPA, and Citrate Complexes of Iron' Biometals 16: 519–527
Caro AA, Cederbaum AI. 2002a 'Role of Calcium-activated Pro-teases in CYP2E1-dependent Toxicity in HEPG2 Cells' J Biol Chem 277: 104–113
Caro AA, Cederbaum. 2002b A.I. 'Ca 2 +-dependent and Independ-ent Mitochondrial Damage in HepG2 Cells that Overexpress CYP2E1' Arch Biochem Biophys 408: 162–170
Cheng IF, Breen K. 2000 'On the Ability of Four Flavanoids, Baicilein, Luteolin, Naringenin and Quercetin, to Suppress the Fenton Reaction of the Iron-ATP Complex.' Biometals 13: 77–83
Chiueh CC. 2001 'Iron overload, oxidative stress, and axonal distrophy in brain disorders.' Pediatr Neurol 25(2): 138–47
Collins TJ. 2002 'TAML oxidant activators: a new approach to the activation of hydrogen peroxide for environmentally significant problems.' Acc Chem Res 35: 782–90
Comporti M, Signorini C, Buonocore G, Ciccoli L. 2002 'Iron re-lease, oxidative stress and erythrocyte ageing.' Free Radic Biol Med 32: 568–76
Crichton RR, Pierre J-L. 2001 'Old Iron, Young Copper: fro Mars to Venus' Biometals 14: 99–112
Fahn S, Cohen G. 1992 'The oxidant stress hypothesis in Par-kinson's disease: evidence supporting it.' Ann of Neurol 32: 802–812
Forsén S., Kördel J. 1994 Calcium in Biological Systems, In: Bertini I, Gray HB, Lippard SJ, Valentine JS, eds Bioinorganic Chemistry, University Science Books, Mills Valley, California, Chapter 3.
Frey CM, Stuehr J. 1974, in Metal Ions in Biological Systems,Sigel H, ed. Marcel Dekker, New York, 1, 51.
Galley HF, Webster NR. 1996 'Elevated serum bleomycin-detectable iron concentrations in patients with sepsis syndrome.' Intensive Care Med 22: 226–229
Gutteridge JMC, Mumby S, Koizumi M, Taniguchi N. 1996a 'Free Iron in Neontal Plasa Activates Aconitase: Evidence for Biologically Reactive Iron' Biochem Biophys Res Comm 229: 806–809
Gutteridge JMC, Mumby GJ, Quinlan GJ, Chung KF, Evans TW. 1996b 'Pro-oxidant Iron in Human Pulmonary Epithelial Lining Fluid: Implications for Oxidative Stress in the Lung.' Biochem Biophys Res Comm 220: 1024–1027
Harris WR, Wan Z, Brook C, Yang B, Islam A. 2003 'Kinetics of Metal Ion Exchange between Citric Acid and Serum Transferrin.' Inorg Chem 42(19): 5880–5889
Kakhlon O, Cabantchik ZI. 2002 'The labile iron pool: characteriz-ation, measurement, and participation in cellular processes' Free Radic Biol Med 33: 1037–46
Krebs J. 1998 'The Role of Calcium in Apoptosis' Biometals 11: 375–382
Lee C-C, Kang J-J. 2002 'Extract of Motorcycle Exhaust Particles Induced Macrophages Apoptosis by Calcium-Dependent Man-ner' Chem Res Toxicol 15: 1534–1542
Lehnen-Beyel I, Groot HD, Rauen U. 2002 'Enhancement of iron toxicity in L929 cells by D-glucose: accelerated(re-)duction.' Biochem J 368(Pt2): 517–26
Lipscomb DC, Gorman LG, Traystman RJ, Hurn PD. 1998 'Low molecular weight iron in cerebral ischemic acidosis in vivo.' Stroke 29: 487–492
Lobner D, Golner S, Hjelmhaug J. 2003 'Neurotrophic factor ef-fects on oxidative stress-induced neuronal death.' Neurochem Res 28(5): 749–56
Petrat F, de Groot H, Sustmann R, Rauen U. 2002 'The chelatable iron pool in living cells: a methodically defined quantity.' Biol Chem 383(3–4): 489–502
Richards MP, Dettman MA. 2003 'Comparitive Analysis of Dif-ferent Hemoglobins: Autoxidation, Reaction with Peroxide, and Lipid Oxidation.' J Agric Food Chem 51: 3886–3891
Sergent O, Anger JP, Lescoat G, Pasdeloup N, Gillard P, Cillard J. 1997 'EPR determination of low molecular weight iron content applied to whole rat hepatocytes.' Cell Molec Biol (Noisy-le-grand) 43: 793–800
Shi X, Dalal NS, Jain AC. 1991 'Antioxidant Behavior of Caffeine: Efficient Scaveging of Hydroxyl Radicals.' Food Chem Toxicol 29: 1–6
Smith MA, Harris PL, Sayre LM, Perry G. 1997 'Iron Accumula-tion in Alzheimer Disease is a Source of Redox Generated Free Radicals.' Proc Nat Acad Sci USA 94: 9866–9868
Walling C, Kurz M, Schugar HJ. 1970 'The Iron(III)-Ethylenediaminetetraacetic Acid-Peroxide System' Inorg Chem 9(4): 931–937
Wang J, Ortiz De Montellano PR. 2002 'The binding sites on human heme oxygenase-1 for cytochrome P450 reductase and biliverdin reductase.' J BiolChemin press 2003
Welch KD, Davis TZ, Van Eden ME, Aust SD. 'Deleterious iron-mediated oxidation of biomolecules.' Free Radic Biol Med 32: 577–83
Wiseman H, Halliwell B. 1996 'Damage to DNA by Reactive Oxy-gen and Nitrogen Species: Roles in Inflammatory Disease and Progression to Cancer.' Biochem J 313: 17–29
Weaver J, Pollack S. 1989 'Low-Mr iron isolated from guinea pig re-ticulocytes as AMP-Fe and ATP-Fe complexes.' Biochem J 261: 787–792
Weaver J, Pollack S. 1990 'Two types of receptors for iron on mitochondria.' Biochem J 271: 463–466
Zhan H, Gupta RK, Weaver J, Pollack S. 1990 'Iron bound to low MW ligands: interactions with mitochondria and cytosolic proteins.' Europ J Haematol 44: 125–131
Zhao CP, Galazka M, Cheng IF. 1994 'Electrocatalytic Reduction of Hydrogen Peroxide by Iron-Adenosine Nucleotide Complexes.' J Electroanalyt Chem 379: 501–503
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Hutcheson, R., Engelmann, M.D. & Cheng, I.F. A hypothesis for the basis of the pro-oxidant nature of calcium ions. Biometals 17, 605–613 (2004). https://doi.org/10.1007/s10534-004-1225-9
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DOI: https://doi.org/10.1007/s10534-004-1225-9