A-tocopheroxyl radical

It has been proposed that the a-tocopheroxyl radical can be recycled back to tocopherol by ascorbate producing the ascorbyl radical (Packer etal., 1979 Scarpa et al., 1984). The location of a-tocopherol, with its phytyl tail in the membrane parallel to the fatty acyl chains of the phospholipids and its phenolic hydroxyl group at the memisrane-water interface near the polar headgroups of the phospholipid bilayer, enables ascorbate to donate hydrogen atoms to the tocopheroxyl radical. The suitability for ascorbate and tocopherol as chain-breaking antioxidants is exemplified (Buettner,... 

In contrast to the a-tocopheroxyl radical (2) and chromanoxylium cation 4 for which the oxidation allows only one structure to form, generation of an o-QM from a-tocopherol could proceed, theoretically, involving either of the two methyl groups C-5a or C-7a. The reason for the large selectivity of o-QM formation, that is, the nearly exclusive involvement of position 5a, will be discussed in more detail in Section 6.3.1. The overall formation of the o-QM from the parent phenol a-tocopherol means a loss of H2, or more detailed, of two electrons and two protons. In which order and as which species those are released, for example, as protons, H-atoms, or hydride ions, will have major implications on o-QM formation and chemistry, which is discussed in Section 6.3.2. 

The third fact that seemed to argue in favor of the occurrence of radicals 10 was the observation that reactions of a-tocopherol under typical radical conditions, that is, at the presence of radical initiators in inert solvents or under irradiation, provided also large amounts of two-electron oxidation products such as o-QM 3 and its spiro dimerization product 9 (Fig. 6.8).16,25,26 This was taken as support of a disproportionation reaction involving a-tocopheroxyl radical 2 and its hypothetical tautomeric chromanol methide radical 10, affording one molecule of o-QM 3 (oxidation) and regenerating one molecule of 1 (reduction). The term disproportionation was used here to describe a one-electron redox process with concomitant transfer of a proton, that is, basically a H-atom transfer from hypothetical 10 to radical 2. 

The initiator-derived radical products generate a-tocopheroxyl radicals (2) from a-tocopherol (1). The radicals 2 are further oxidized to ort/io-quinone methide 3 in a formal H-atom abstraction, thereby converting benzoyloxy radicals to benzoic acid and phenyl radicals to benzene. The generated o-QM 3 adds benzoic acid in a [ 1,4] -addition process, whereas it cannot add benzene in such a fashion. This pathway accounts for the observed occurrence of benzoate 11 and simultaneous absence of a 5 a-phenyl derivative and readily explains the observed products without having to involve the hypothetical C-centered radical 10. 

Bisby, R.H. and Parker, A.W. 1995. Reaction of ascorbate with the a-tocopheroxyl radical in micellar and bilayer membrane systems. Arch. Biochem. Biophys. 317 170-178. 

Low-density lipoprotein oxidation. A detailed EPR study of LDL oxidation by HRP has been reported by Pietraforte and colleagues, who reported the direct observation of the a-tocopheroxyl radical and a protein radical (g = 2.003), assigned tentatively to a tyrosyl radical and also trapped with MNP.295 Another study reported the observation of the probucol phenoxyl radical in LDL undergoing oxidation by lipoxygenase. This finding supports the assertion... 

FIGURE 29.1 Pathways of the chain-breaking action of vitamin E in lipid peroxidation and its subsequent regeneration. LOOH lipid hydroperoxide, LOO lipid peroxyl radical, vitamin C ascorbate radical (semi-dehydroascorbate), vitamin E a-tocopheroxyl radical. The lipid peroxyl radical is reduced to lipid hydroperoxide by tocopherol. The resulting tocopheroxyl radical can be re-reduced by ascorbate. The thus formed ascorbate radical can be reduced to ascorbate by the NADH-dependent semidehydroascorbate reductase. 

The rate constant for the bimolecular decay of the a-tocopheroxyl radical is only 3.5x 102M-1 s . Therefore, its half-life is several hours in chloroform at ambient temperature. This implies that vitamin E free radical can react with a second peroxyl radical. In biological membranes, a-tocopherylquinone is generally believed to be the major end-product, but the mechanism of its production remains controversial. It may arise either from the decomposition of a-tocopherone, or from dismutation of a-tocopheroxyl radicals. However, the steady-state concentration of a-tocopherylquinone is usually too low to be measurable ex vivo when tissue homogenization and extraction are performed in the presence of pyrogallol and butylated hydroxytoluene, respectively,... 

Reduction of the Vitamin E Radical by Ascorbate Asdiscussed in Section 4.3.1, one of the major roles of vitamin E is as a radical-trapping antioxidant in membranes and lipoproteins. a-Tocopherol reacts with lipid peroxides forming the a-tocopheroxyl radical, which reacts with ascorbate in the aqueous phase, regenerating a-tocopherol, and forming monodehydroascorbate. Vitamin C may have a vitamin E-sparing antioxidant action, coupling lipophilic and hydrophilic reactions. 

In contrast with all the described antioxidant properties of vitamin E, it has been shown that lipid peroxidation of LDL is faster in the presence a-tocopherol, and is substantially accelerated by enrichment of the vitamin in LDL, either in vitro or in vivo [10, 11]. It was thus proposed that peroxidation is propagated within lipoprotein particles by the vitamin E radical i.e. a-tocopheroxyl radical) unless it became reduced by vitamin C or ubiquinol-10 [12]. However, the importance of pro-oxidation reactions of a-tocopherol in vivo, under physiological conditions, appears to be questionable. 

SCHEME 3. Oxidation products of a-tocopheroxyl radical with peroxyl radicals, R = C16H33... 

Ascorbate protects membranes through two mechanisms. First, ascorbate reacts with peroxyl radicals formed in the cytoplasm before they can reach the membrane, thereby preventing lipid peroxidation. Second, ascorbate enhances the antioxidant activity of vitamin E by regenerating reduced a-tocopherol from the a-tocopheroxyl radical (Figure 10.23). Ascorbate is then regenerated by reacting with GSH. 

L-Ascorbate, a water-soluble molecule, protects membranes from oxidative damage by regenerating a-tocopherol from a-tocopheroxyl radical. The ascorbyl radical formed in this process is reconverted to L-ascorbate during a reaction with GSH. 

Coenzyme Q (Q) in its reduced form (ubiquinol) is known to inhibit LPO in subcellular membranes (Mellors and Tappel, 1966 Forsmak et al., 1991), either by reducing the a-tocopheroxyl radical (TO) back to a-tocopherol (TOH) (Kagan et al., 1990) or by reacting directly with radicals. However, by far the most information exists, to date, for vitamin E and vitamin C (ascorbate). 

May directly scavenge O radicals and regenerate a-tocopherol from the a-tocopheroxyl radical Interrupts chain-reaction lipid peroxidation Scavenges singlet oxygen May scavenge O radicals directly regenerates oxidized ascorbic acid... 

In its reactions with free radicals, vitamin E is converted to the a-tocopheroxyl radical. By regenerating vitamin E, ascorbic acid becomes involved in protecting the membranes indirectly. The mechanism whereby water-soluble ascorbic acid regenerates fat-soluble vitamin E has not yet been elucidated. Regeneration reactions would have to take place at the interface between hydrophilic and hydrophobic sites (Lambe-let et aL, 1985). It is suggested that ascorbate functions to recycle vitamin E... 

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