title: Multifunctional antioxidant activity of HBED iron chelator.
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.
authors.affiliation: Radiation Biology Branch, Radiation Oncology Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Samuni
authors.forename: M
authors.initials: M
authors.lastname: Afeworki
authors.forename: W
authors.initials: W
authors.lastname: Stein
authors.forename: A T
authors.initials: AT
authors.lastname: Yordanov
authors.forename: W
authors.initials: W
authors.lastname: DeGraff
authors.forename: M C
authors.initials: MC
authors.lastname: Krishna
authors.forename: J B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: M W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D052160:Benzothiazoles; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003497:Cyclic N-Oxides / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004492:Edetic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D006859:Hydrogen / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010636:Phenols / Q000378:metabolism; D013053:Spectrophotometry; D013113:Spin Labels; D013451:Sulfonic Acids / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D052160:Benzothiazoles; D002839:Chromans; D003497:Cyclic N-Oxides; D007502:Iron Chelating Agents; D010636:Phenols; D013113:Spin Labels; D013451:Sulfonic Acids; D013481:Superoxides; C002502:2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid; C042329:phenoxy radical; D017665:Hydroxyl Radical; C037740:N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid; D006859:Hydrogen; D020122:tert-Butylhydroperoxide; D004492:Edetic Acid; D006861:Hydrogen Peroxide; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D010100:Oxygen; C001803:tempol