A large body of scientific evidence indicates that reactive free radicals are involved in many diseases, including heart disease and cancers. Cells contain many potentially oxidizable substrates such as polyunsaturated fatty acids (PUFAs), proteins, and DNA. Therefore, a complex antioxidant defence system normally protects cells from the injurious effects of endogenously produced free radicals as well as from species of exogenous origin such as cigarette smoke and pollutants.
Should our exposure to free radicals exceed the protective capacity of the antioxidant defence system, a phenomenon often referred to as oxidative stress, then damage to biologic molecules may occur. There is considerable evidence that disease causes an increase in oxidative stress; therefore, consumption of foods rich in antioxidants, which are potentially able to quench or neutralise excess radicals, may play an important role in modifying the development of such diseases.
Vitamin E is the major lipid-soluble antioxidant in the cell antioxidant defence system and is exclusively obtained from the diet. The term “vitamin E” refers to a family of eight naturally occurring homologues that are synthesised by plants from homogentisic acid. All are derivatives of 6-chromanol and differ in the number and position of methyl groups on the ring structure. The four tocopherol homologues (d-α-, d-β-, d-γ-, and d-δ-) have a saturated 16- carbon phytyl side chain, whereas the tocotrienols (d-α-, d-β-, d-γ-, and d-δ-) have three double bonds on the side chain. There is also a widely available synthetic form, dl-α- tocopherol, prepared by coupling trimethylhydroquinone with isophytol. This consists of a mixture of eight stereoisomers in approximately equal amounts; these isomers are differentiated by rotations of the phytyl chain in various directions that do not occur naturally.
For dietary purposes, vitamin E activity is expressed as α-tocopherol equivalents (α-TEs). One α-TE is the activity of 1 mg RRR-α-tocopherol (d-α-tocopherol). To estimate the α-TE of mixed diet containing natural forms of vitamin E, the number of milligrams of β-tocopherol should be multiplied by 0.5, γ-tocopherol by 0.1, and α-tocotrienol by 0.3. Any of the synthetic all-rac-α-tocopherol (dl-α-tocopherol) should be multiplied by 0.74. One milligram of the latter compound in the acetate form is equivalent to 1 IU of vitamin E.
Vitamin E is an example of a phenolic antioxidant. Such molecules readily donate the hydrogen from the hydroxyl (OH) group on the ring structure to free radicals, which then become unreactive. On donating the hydrogen, the phenolic compound itself becomes a relatively unreactive free radical because the unpaired electron on the oxygen atom is usually delocalised into the aromatic ring structure thereby increasing its stability.
The major biologic role of vitamin E is to protect PUFAs and other components of cell membranes and low-density lipoprotein (LDL) from oxidation by free radicals. Vitamin E is located primarily within the phospholipid bilayer of cell membranes. It is particularly effective in preventing lipid peroxidation, a series of chemical reactions involving the oxidative deterioration of PUFAs. Elevated levels of lipid peroxidation products are associated with numerous diseases and clinical conditions. Although vitamin E is primarily located in cell and organelle membranes where it can exert its maximum protective effect, its concentration may only be one molecule for every 2000 phospholipid molecules.
This suggests that after its reaction with free radicals it is rapidly regenerated, possibly by other antioxidants.
Absorption of vitamin E from the intestine depends on adequate pancreatic function, biliary secretion, and micelle formation. Conditions for absorption are like those for dietary lipid, that is, efficient emulsification, solubilisation within mixed bile salt micelles, uptake by enterocytes, and secretion into the circulation via the lymphatic system. Emulsification takes place initially in the stomach and then in the small intestine in the presence of pancreatic and biliary secretions.
The resulting mixed micelle aggregates the vitamin E molecules, solubilises the vitamin E, and then transports it to the brush border membrane of the enterocyte probably by passive diffusion. Within the enterocyte, tocopherol is incorporated into chylomicrons and secreted into the intracellular space and lymphatic system and subsequently into the blood stream. Tocopherol esters, present in processed foods and vitamin supplements, must be hydrolysed in the small intestine before absorption.
Vitamin E is transported in the blood by the plasma lipoproteins and erythrocytes. Chylomicrons carry tocopherol from the enterocyte to the liver, where they are incorporated into parenchymal cells as chylomicron remnants. The catabolism of chylomicrons takes place in the systemic circulation through the action of cellular lipoprotein lipase. During this process tocopherol can be transferred to high-density lipoproteins (HDLs). The tocopherol in HDLs can transfer to other circulating lipoproteins, such as LDLs and very low-density lipoproteins (VLDLs).
During the conversion of VLDL to LDL in the circulation, some α-tocopherol remains within the core lipids and thus is incorporated in LDL. Most α-tocopherol then enters the cells of peripheral tissues within the intact lipoprotein through the LDL receptor pathway, although some may be taken up by membrane binding sites recognising apolipoprotein A-I and A-II present on HDL.
Although the process of absorption of all the tocopherol homologues in our diet is similar, the α form predominates in blood and tissue. This is due to the action of binding proteins that preferentially select the α form over the others. In the first instance, a 30-kDa binding protein unique to the liver cytoplasm preferentially incorporates α-tocopherol in the nascent VLDL. This form also accumulates in non-hepatic tissues, particularly at sites where free radical production is greatest, such as in the membranes of mitochondria and endoplasmic reticulum in the heart and lungs.
Hepatic intracellular transport may be expedited by a 14.2-kDa binding protein that binds α-tocopherol in preference to the other homologues. Other proteinaceous sites with apparent tocopherol-binding abilities have been found on erythrocytes, adrenal membranes, and smooth muscle cells. These may serve as vitamin E receptors which orient the molecule within the membrane for optimum antioxidant function.
These selective mechanisms explain why vitamin E homologues have markedly differing antioxidant abilities in biologic systems and illustrates the important distinction between the in vitro antioxidant effectiveness of a substance in the stabilisation of, for example, a food product and its in vivo potency as an antioxidant. From a nutritional perspective, the most important form of vitamin E is α-tocopherol; this is corroborated in animal model tests of biopotency which assess the ability of the various homologues to prevent foetal absorption and muscular dystrophies.
Plasma vitamin E concentrations vary little over a wide range of dietary intakes. Even daily supplements of the order of 1600 IU/day for 3 weeks only increased plasma levels 2–3 times and on cessation of treatment plasma levels returned to pretreatment levels in 5 days.
Likewise, tissue concentrations only increased by a similar amount when patients undergoing heart surgery were given 300 mg/day of the natural stereoisomer for 2 weeks preoperatively. Kinetic studies with deuterated tocopherol suggest that there is rapid equilibration of new tocopherol in erythrocytes, liver, and spleen but that turnover in other tissues such as heart, muscle, and adipose tissue is much slower. The brain is markedly resistant to depletion and repletion with vitamin E. This presumably reflects an adaptive mechanism to avoid detrimental oxidative reactions in this key organ.
The primary oxidation product of α-tocopherol is a tocopheryl quinone that can be conjugated to yield the glucuronate after prior reduction to the hydroquinone. This is excreted in the bile or further degraded in the kidneys to α-tocopheronic acid and hence excreted in the bile. Those vitamin E homologues not preferentially selected by the hepatic binding proteins are eliminated during the process of nascent VLDL secretion in the liver and probably excreted via
the bile. Some vitamin E may also be excreted via skin sebaceous glands.
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