Abstract
The use of N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED) for iron chelation therapy is currently being tested. Besides its affinity for iron, bioavailability, and efficacy in relieving iron overload, it is important to assess its anti- and/or pro-oxidant activity. To address these questions, the antioxidant/pro-oxidant effects of HBED in a cell-free solution and on cultured Chinese hamster V79 cells were studied using UV-VIS spectrophotometry, oximetry, spin trapping, and electron paramagnetic resonance (EPR) spectrometry. The results indicate that HBED facilitates Fe(II) oxidation but blocks O2(.-)-induced reduction of Fe(III) and consequently pre-empts production of .OH or hypervalent iron through the Haber-Weiss reaction cycle. The efficacy of HBED as a 1-electron donor (H-donation) was demonstrated by reduction of the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate)-derived nitrogen-centered radical cation (ABTS(.+)), accompanied by formation of a short-lived phenoxyl radical. HBED also provided cytoprotection against toxicity of H2O2 and t-BuOOH. Our results show that HBED can act both as a H-donating antioxidant and as an effective chelator lacking pro-oxidant capacity, thus substantiating its promising use in iron chelation therapy.
MeSH terms
-
Animals
-
Antioxidants / chemistry
-
Antioxidants / metabolism*
-
Antioxidants / pharmacology
-
Benzothiazoles
-
Cell Death / drug effects
-
Cell Line
-
Cell Survival / drug effects
-
Chromans / metabolism
-
Cricetinae
-
Cricetulus
-
Cyclic N-Oxides / metabolism
-
Cytoprotection / drug effects
-
Edetic Acid / analogs & derivatives
-
Edetic Acid / chemistry
-
Edetic Acid / metabolism*
-
Edetic Acid / pharmacology
-
Electron Spin Resonance Spectroscopy
-
Hydrogen / metabolism
-
Hydrogen Peroxide / antagonists & inhibitors
-
Hydrogen Peroxide / metabolism
-
Hydrogen Peroxide / pharmacology
-
Hydroxyl Radical / metabolism
-
Iron Chelating Agents / chemistry
-
Iron Chelating Agents / metabolism*
-
Iron Chelating Agents / pharmacology
-
Oxidation-Reduction
-
Oxygen / metabolism
-
Phenols / metabolism
-
Spectrophotometry
-
Spin Labels
-
Sulfonic Acids / metabolism
-
Superoxides / metabolism
-
tert-Butylhydroperoxide / antagonists & inhibitors
-
tert-Butylhydroperoxide / metabolism
-
tert-Butylhydroperoxide / pharmacology
Substances
-
Antioxidants
-
Benzothiazoles
-
Chromans
-
Cyclic N-Oxides
-
Iron Chelating Agents
-
Phenols
-
Spin Labels
-
Sulfonic Acids
-
Superoxides
-
2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid
-
phenoxy radical
-
Hydroxyl Radical
-
N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid
-
Hydrogen
-
tert-Butylhydroperoxide
-
Edetic Acid
-
Hydrogen Peroxide
-
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
-
Oxygen
-
tempol