EPR Spin-Trapping Evidence for the Direct, One-Electron Reduction of tert-Butylhydroperoxide to the tert-Butoxyl Radical by Copper(II):  Paradigm for a Previously Overlooked Reaction in the Initiation of Lipid Peroxidation

Abstract

Lipid peroxidation is often initiated using Cu(II) ions. It is widely assumed that Cu(II) oxidizes preformed lipid hydroperoxides to peroxyl radicals, which propagate oxidation of the parent fatty acid via hydrogen atom abstraction. However, the oxidation of alkyl hydroperoxides by Cu(II) is thermodynamically unfavorable. An alternative means by which Cu(II) ions could initiate lipid peroxidation is by their one-electron reduction of lipid hydroperoxides to alkoxyl radicals, which would be accompanied by the generation of Cu(III). We have investigated by EPR spectroscopy, in conjunction with the spin trap 5,5-dimethyl-1-pyrroline N-oxide, the reactions of various Cu(II) chelates with tert-butylhydroperoxide. Spectra contained signals from the tert-butoxyl, methyl, and methoxyl radical adducts. In many previous studies, the signal from the methoxyl adduct has been assigned incorrectly to the tert-butylperoxyl adduct, which is now known to be unstable, releasing the tert-butoxyl radical upon decomposition. This either is trapped by 5,5-dimethyl-1-pyrroline N-oxide or undergoes beta-scission to the methyl radical, which either is trapped or reacts with molecular oxygen to give, ultimately, the methoxyl radical adduct. By using metal chelates that are known to be specific in either their oxidation or reduction of tert-butylhydroperoxide (the Cu(II) complex of bathocuproine disulfonic acid and the Fe(II) complex of diethylenetriaminepentaacetic acid, respectively) for comparison, we have been able to deduce, from the relative concentrations of the three radical adducts, that the Cu(II) complexes tested each reduce tert-butylhydroperoxide directly to the tert-butoxyl radical. These findings suggest that a previously overlooked reaction, namely the direct reduction of preformed lipid hydroperoxides to alkoxyl radicals by Cu(II), may be responsible for the initiation of lipid peroxidation by Cu(II) ions.

Absence of an effect of vitamin E on protein and lipid radical formation during lipoperoxidation of LDL by lipoxygenase

“…Various theories have been formulated to explain the initial species that triggers LDL oxidation. Vitamin E [15, 38, 39] and apo B-100 [3, 40] have been shown to reduce Cu 2+ , while lipid hydroperoxides have been shown to oxidize Cu 2+ [41]. Interestingly, LDL has multiple reduction sites with different affinities for Cu 2+ [16], which shows that the high association and integration of the different components of LDL make the analysis of the contribution of each individual component difficult.…”

Iminoxyl radicalsvs. tert-butylperoxyl radical in competitive oxidative C–O coupling with β-dicarbonyl compounds. Oxime ether formation prevails over Kharasch peroxidation

“…22,23,[62][63][64][65] Furthermore, generation of tert-butylperoxyl radical I can occur via abstraction of hydrogen atom from t-BuOOH by t-BuOc radical II. 63,65,66 Generation of iminoxyl radical IV (stage C) can occur via oxidation of oxime III with Cu 2+ , 8 as well as with radicals I and II formed from t-BuOOH. 47,67 At stage D, b-dicarbonyl compound V forms a Cu 2+ chelate complex VI, 22,68 which reacts with iminoxyl radical IV to form the nal coupling product VII (stage E).…”

Antioxidant effect of FeAOX-6 on free radical species produced during iron catalyzed breakdown oftert-butyl hydroperoxide

“…As reported by Jones and Burkitt [11] tertbutylperoxyl radicals easily decompose to tert-butoxyl FeAOX-6 effects on tBOOH-generated free radicals with the release of oxygen:…”