Vitamin E is the collective name for the tocopherols and tocotrienols — the fat-soluble vitamins that are the primary antioxidants in the lipid phase of cell membranes and that protect the polyunsaturated fatty acids (PUFAs) of the cell membrane from peroxidation by free radicals. The most biologically active form of vitamin E is alpha-tocopherol, which is the predominant form in human tissues and which is the form that is maintained at the highest concentration in the blood and in the cell membranes. Vitamin E is unique among the antioxidants in that it is both a direct scavenger of lipid peroxyl radicals (it reacts directly with the peroxyl radicals that initiate the chain reaction of lipid peroxidation) and a substrate for the antioxidant enzymes that regenerate it — the vitamin E can be reduced back to its active form by the vitamin C, by the ubiquinol (the reduced form of CoQ10), and by the glutathione-dependent vitamin E reductase system. This regenerative capacity of vitamin E is one of the most important features of the antioxidant network, and it allows a small amount of vitamin E to protect a large amount of lipid from peroxidation.
Lipid Peroxidation and the Antioxidant Defence System
Lipid peroxidation is the process by which free radicals attack the polyunsaturated fatty acids (PUFAs) of the cell membrane, initiating a chain reaction that produces lipid hydroperoxides (LOOH) and reactive aldehydes that are more toxic than the original radicals that initiated the reaction. The PUFAs of the cell membrane — including arachidonic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) — are particularly susceptible to peroxidation because they contain multiple double bonds with weakened C-H bonds that are easily attacked by radicals. When a radical abstracts a hydrogen atom from a PUFA, a lipid radical (L*) is formed; this lipid radical reacts rapidly with oxygen to form a lipid peroxyl radical (LOO*), which can then attack adjacent PUFAs and propagate the chain reaction. Vitamin E (specifically alpha-tocopherol) interrupts this chain reaction by reacting directly with the lipid peroxyl radical, forming a lipid hydroperoxide (LOOH) and a vitamin E radical (alpha-tocopheroxyl radical); the vitamin E radical is then reduced back to alpha-tocopherol by vitamin C, by ubiquinol, or by the glutathione-dependent system.
The clinical importance of vitamin E as a lipid-phase antioxidant is underscored by the observation that vitamin E deficiency produces a characteristic neurological syndrome — the ataxia with vitamin E deficiency (AVED) syndrome — which is characterised by progressive spinocerebellar degeneration, peripheral neuropathy, and retinal degeneration. AVED is caused by mutations in the alpha-tocopherol transfer protein (alpha-TTP) gene, which impair the incorporation of alpha-tocopherol into the VLDL particle in the liver and lead to the rapid loss of vitamin E from the blood and tissues. The neurological manifestations of AVED are the direct result of the accumulation of lipid peroxidation products in the nervous system when vitamin E is not available to protect the neuronal membrane PUFAs from peroxidation. The treatment of AVED with high-dose vitamin E (at 800-2,000 IU daily of alpha-tocopherol) halts the progression of the neurological disease and prevents the further accumulation of oxidative damage to the nervous system.
Vitamin E and Cardiovascular Disease
The role of vitamin E in cardiovascular disease has been extensively studied, with initially promising observational data suggesting that high vitamin E intake was associated with reduced cardiovascular risk, followed by large randomised controlled trials that showed no benefit of vitamin E supplementation for the prevention of cardiovascular events. The discrepancy between the observational data and the trial data is thought to reflect the fact that the observational data were confounded by the healthy user effect — people who take vitamin E supplements are generally healthier and have healthier lifestyles than people who do not, and this confounding by lifestyle factors explains the apparent protective effect of vitamin E in observational studies. The large trials that failed to show a cardiovascular benefit of vitamin E (including the HOPE trial and the GISSI trial) used natural-source vitamin E (RRR-alpha-tocopherol) at doses of 400-800 IU daily, which is a dose that is higher than the RDA but lower than the doses used in the early interventional studies.
Practical Application
For general vitamin E supplementation, the evidence-based approach is to supplement with 400-800 IU of natural-source alpha-tocopherol daily (as RRR-alpha-tocopherol, which is the naturally occurring form and which is more bioavailable than the synthetic all-rac-alpha-tocopherol). For people with AVED or with other conditions that impair vitamin E absorption (including cystic fibrosis, cholestatic liver disease, and abetalipoproteinemia), higher doses may be required and should be supervised by a physician. For comprehensive antioxidant support, vitamin E pairs well with vitamin C (which regenerates vitamin E from its radical form), with selenium (which is required for the glutathione peroxidase enzymes that reduce lipid hydroperoxides), with CoQ10 (which regenerates vitamin E and which has independent cardiovascular benefits), and with the omega-3 fatty acids (which are the PUFAs that are most susceptible to peroxidation and which are protected by adequate vitamin E status).
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