Antioxidant Functions of Vitamin E

Vitamin E functions as a lipid antioxidant both in vitro and in vivo; a number of synthetic antioxidants will prevent or cure most of the signs of vitamin E deficiency in experimental animals. Polyunsaturated fatty acids undergo oxidative attack by hydroxyl radicals and superoxide to yield alkylperoxyl (alkyl-dioxyl) radicals, which perpetuate a chain reaction in the lipid-withpotentially disastrous consequences for cells. Similar oxidative radical damage can occur to proteins (especially in a lipid environment) and nucleic acids.

Phenolic compounds can break such chain reactions by trapping the radicals, with the formation of stable nonradical products from the oxidized lipid and phenoxyl radicals that are relatively unreactive because they are stabilized by resonance. The phenoxyl radical may either react with a further alkylperoxyl radical to yield nonradical products, or it may be reduced back to the starting phenol by reaction with a water-soluble reducing agent.

Vitamin E is one of the most active radical-trapping, chain-breaking antioxidant phenols that has been investigated, and is the major lipid-soluble antioxidant in tissues (Burton and Ingold, 1984). As shown in Figure 4.4, the a- and ^-tocopheroxyl radicals have three resonance forms compared with two for the y - and S-radicals, and are therefore more stable and have a greater antioxidant activity. In simple solution, a-tocopherol and a-tocotrienol are equipotent as antioxidants. In vitro, when it is incorporated into liposomes or microsome preparations, a-tocotrienol has greater antioxidant activity. This is probably because the unsaturated side chain causes more membrane perturbation, and tocotrienol is able to distribute more uniformly through the resonance forms of the a- and p-tocopherol and tocotrienol radicals resonance forms of the a- and p-tocopherol and tocotrienol radicals

CH3 CH3 CH:

chromanoxyl radical chromanoi methide radical chromanone radical

CH3 CH3 CH:

chromanoxyl radical chromanoi methide radical chromanone radical resonance forms of the y- and 5-tocopherol and tocotrienol radicals resonance forms of the y- and 5-tocopherol and tocotrienol radicals chromanoxyl radical chromone radical

Figure 4.4. Resonance forms of the vitamin E radicals.

chromanoxyl radical chromone radical

Figure 4.4. Resonance forms of the vitamin E radicals.

membrane, with a greater chance of interacting with lipid peroxides. However, the poor retention of tocotrienols in tissues means that in vivo tocotrienols have lower antioxidant activity than tocopherols (Packer et al., 2001).

Tocopherol can act catalytically as a chain-breaking lipophilic antioxidant in membranes and plasma lipoproteins, because the tocopheroxyl radical formed by reaction of a-tocopherol with a lipid peroxide radical can be reduced to tocopherol in four main ways:

1. By reaction with ascorbate to yield the monodehydroascorbate radical, which in turn can either be reduced to ascorbate or can undergo dismutation to yield dehydroascorbate and ascorbate (Section 13.4.7.1). In vitro, the formation of the tocopheroxyl radical can be demonstrated by the appearance of its characteristic absorbance peak, which normally has a decay time of 3 msec; in the presence of ascorbate, the tocopheroxyl peak has a decay time of 10 ^sec, and its disappearance is accompanied by the appearance of the monodehydroascorbate peak. There is an integral membrane oxidoreductase that uses ascorbate as the preferred electron donor, linked either directly to reduction of tocopheroxyl radical or via an electron transport chain involving ubiquinone (see no. 4 below; May, 1999).

2. By reaction with glutathione, catalyzed by a membrane-specific isoenzyme of glutathione peroxidase, which is a selenoenzyme. Thus, in

Figure 4.5. Role of vitamin E as a chain-perpetuating prooxidant.

addition to its role in removing products of lipid peroxidation (Section 4.3.2), selenium has a direct role in the recycling of tocopherol.

3. By reaction with other lipid-soluble antioxidants in the membrane or lipoprotein, including ubiquinone (Section 14.6), which is present in large amounts in all membranes as part of an electron transport chain, not just the mitochondrial inner membrane (Thomas etal., 1995; Crane and Navas, 1997; Thomas and Stocker, 2000; Villalba and Navas, 2000).

4. In mitochondria by reaction with the electron transport chain linked to the oxidation of NADH, succinate, or reduced cytochrome c (Maguire etal., 1989).

4.3.1.1 Prooxidant Actions of Vitamin E Most of the studies of the antioxidant activity of vitamin E have used relatively strong oxidants as the source of oxygen radicals to produce lipid peroxides in lipoproteins or liposomes in vitro. Studies oflipoproteins treated in vitro withlow concentrations of sources of the perhydroxyl radical suggest that vitamin E may have a prooxidant action. Over 8 hours, there was 10-fold more formation of cholesterol ester hydroperoxide (anindexoflipidperoxidation) in native LDL than in vitamin E-depleted LDL (Bowry et al., 1992). This is perhaps unsurprising; vitamin E and other radical-trapping antioxidants are effective because they form stable radicals that persist long enough to undergo reaction to nonradical products. It is therefore to be expected that they are also capable of perpetuating the radical chain reaction deeper into lipoproteins or membranes, as shown in Figure 4.5,

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