Multifunctional antioxidant activity of HBED iron chelator

• Published in: Free radical biology & medicine Vol. 30; no. 2; pp. 170 - 177
• Main Authors: Samuni, Ayelet M., Afeworki, Mobae, Stein, William, Yordanov, Alexander T., DeGraff, William, Krishna, Murali C., Mitchell, James B., Brechbiel, Martin W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-01-2001
• Subjects: Animals; Antioxidant; 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; Cytoprotection - drug effects; Edetic Acid - analogs & derivatives; Edetic Acid - chemistry; Edetic Acid - metabolism; Edetic Acid - pharmacology; Electron Spin Resonance Spectroscopy; Free radicals; H-donation; 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; Iron chelator; Metal ions; Oxidation-Reduction; Oxidative damage; Oxygen - metabolism; Phenols - metabolism; Redox-activity; Spectrophotometry; Spin Labels; Sulfonic Acids - metabolism; Superoxides - metabolism; tert-Butylhydroperoxide - antagonists & inhibitors; tert-Butylhydroperoxide - metabolism; tert-Butylhydroperoxide - pharmacology; DTPA; Free radicals; Oxidative damage; EPR; HRP; Redox-activity; DMPO; Tempol; t-BuOOH; SOD; Antioxidant; DFO; H-donation; Iron chelator; HX; PB; Mb; Trolox; XO; HBED; Tempol-H; ABTS; Metal ions; Cytoprotection
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/S0891-5849(00)00459-7

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 O
2
•−-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 H
2O
2 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.