Fenton Chemistry and Iron Chelation under Physiologically Relevant Conditions: Electrochemistry and Kinetics
- 27 September 2006
- journal article
- research article
- Published by American Chemical Society (ACS) in Chemical Research in Toxicology
- Vol. 19 (10), 1263-1269
- https://doi.org/10.1021/tx060101w
Abstract
The goal of iron-chelation therapy is to reduce the levels of labile plasma iron, and intravenously administered desferrioxamine is the gold standard of therapeutic agents. Hydroxypyridinones, e.g., CP20 (3-hydroxy-1,2-dimethylpyridin-4(1H)-one), are used or are under investigation as orally administered iron chelators. We determined electrode potentials of CP20, the related hydoxypyridones CP361, CP363, and CP502, and ICL670 (4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid) under physiologically relevant conditions to address the question of whether iron in the presence of these chelating agents can carry out Fenton chemistry in vivo. We found that iron(III) but not iron(II) binds tightly to both CP20 and ICL670 at pH 7 and higher, compared to nearly complete binding of 1 μM iron(II) to 10 μM desferrioxamine at pH 7.4 The electrode potentials of the hydroxypyridinones shift to more negative values with decreasing pKa values at lower concentrations of iron(III) (0.02 mM) and ligand (0.1 mM). The electrode potential of the iron−CP20 system decreases as a function of increasing pH, with a minimum near pH 10.5. We estimate an electrode potential for the ascorbyl radical/ascorbate couple under physiological conditions of +105 mV, which is higher than the electrode potential of the iron(III) complex of CP20 at all concentrations of iron. The rate of oxidation of iron(II) in the presence of CP20 by hydrogen peroxide increases with the concentrations of both ligand and peroxide. Although iron(II) is oxidized by hydrogen peroxide, the thus-formed FeIII(CP20)3 complex cannot be reduced by ascorbate. Therefore, the tight binding of iron(III) by this class of chelators prevents redox cycling.Keywords
This publication has 14 references indexed in Scilit:
- Metallothionein protects against oxidative stress-induced lysosomal destabilizationBiochemical Journal, 2006
- Role of compartmentalized redox-active iron in hydrogen peroxide-induced DNA damage and apoptosisBiochemical Journal, 2005
- Redox Properties of the Iron Complexes of Orally Active Iron Chelators CP20, CP502, CP509, and ICL670Helvetica Chimica Acta, 2004
- Thiyl Radicals Abstract Hydrogen Atoms from the αC−H Bonds in Model Peptides: Absolute Rate Constants and Effect of Amino Acid StructureJournal of the American Chemical Society, 2003
- Iron-hydroxypyridone redox chemistry: kinetic and thermodynamic limitations to Fenton activityInorganica Chimica Acta, 1996
- Stabilities of the iron(III) chelates of 1,2-dimethyl-3-hydroxy-4-pyridinone and related ligandsInorganica Chimica Acta, 1991
- Solar PowerScience, 1989
- Pulse Radiolysis of Catalase in Solution. I. Reactions of O−2with Catalase and Its Compound IInternational Journal of Radiation Biology, 1988
- Rate constants for reaction of hydroxyl radicals with Tris, Tricine and Hepes buffersFEBS Letters, 1986
- Equilibrium between hydroxyl radicals and thallium(II) and the oxidation potential of hydroxyl(aq)The Journal of Physical Chemistry, 1984