The research investigating the efficacy of vitamin E and β-carotene has shown some beneficial health properties, however many of the studies have shown no benefit or even negative health outcomes. For example, researcha investigating the effects of β-carotene and vitamin E supplements on smokers has found an increase in lung cancer in those subjects taking β-carotene, with no benefit from vitamin E. In addition, many studies investigating the effects of vitamin E on cardiovascular disease have concluded that there is no benefit to supplementation. Closer inspection of the research suggests that the contradictory outcomes may be due to the study design, which often does not take into account either the form of the vitamin found in foods, the food matrix containing the vitamin, or the synergistic effects of other antioxidants.
Vitamin E is not a single compound, but a group of structurally related isomers with similar chemical activity. Vitamin E comprises of α-, β-. γ- and δ-tocopherol and α-, β-. γ- and δ-tocotrienol. In addition, stereoisomers of all the vitamin E molecules exist such that they can be found in both laevo (L-) or dextro (D-) forms. In nature the isomers exist in the dextro forms (e.g. D-α-tocopherol) and thus all food contains only this natural form of the vitamin. Synthetic vitamin E is manufactured in such a way as there is no control over the stereoisomerism of the product and the result is a mixture of both L- and D- forms (e.g. DL-α-tocopherol). Biologically the synthetic forms of vitamin E are not as biologically active as the natural forms because the L-form is not recognised by the body.
Studies using synthetic forms of vitamin E may therefore not be properly replicating the forms of vitamin E contained within food matrices. However, the issue is further complicated because in food, vitamin E tends to occur as mixture of isomers and not as single isolated forms. The administration of high doses of single isomers is something that has developed from the testing of active ingredients in pharmaceuticals. However, foods do not work in the same way as drugs and there must be consideration taken for the properties of the nutrient in its original food matrix. In the case of vitamin E, this would be a mixture of tocopherols or a mixture of tocotrienols usually in food containing high qualities of polyunsaturated fatty acids. Studies involving the use of a high dose of synthetic DL-α-tocopherol should not be expected therefore to replicate accurately the bioactive properties of natural foods.
Naturally, vitamin E is present in most foods as a mixture of both α- and γ-tocopherol. In fact, the most abundant form of vitamin E in the average US diet is γ-tocopherol. However, cardiovascular research has focused most of its attention on the effects of α-tocopherol, with a minor role for γ-tocopherol, and almost completely ignored any other isomer of vitamin E. The structural differences between vitamin E produces different biological effects in vivo. For example, ingesting high concentration of α-tocopherol has been shown to increase plasma levels at the expense of γ-tocopherol, which is subsequently excretedb. This is important because some studies show that patients with cardiovascular disease have low levels of γ-tocopherol but normal levels of α-tocopherol. Studies supplementing with high doses of synthetic or natural α-tocopherol therefore may not be expected to benefit cardiovascular patients.
Like vitamin E, carotenoids are a family of structurally related compounds that are responsible for some of the red, orange and yellow colours in plants. Only ≈10% of the carotenoids in nature have vitamin A activity, including α-, β- and γ-carotene. These carotenes can be enzymatically hydrolysed in humans for form a molecule of vitamin A. Other carotenoids without vitamin A activity include cyptoxanthin, canthaxanthin, zeathanthin and lycopene. Like vitamin E, carotenoids can act as fat soluble antioxidants in vitro and in vivo, but their mechanism of action is not the same as vitamin E. While vitamin E can donate a hydrogen atom to lipid carbon centred radicals, carotenoids quench singlet oxygen (1O2) by transfer of its excitation to its own structure (returning oxygen to the ground state (3O2)). Following excitation of the carotenoid, stabilisation occurs and the energy is then released as heat.
Most studies interested in the properties of carotenoids have concentrated on the effects of β-carotene. However, as with vitamin E research, this is not an accurate reflection of the intake of carotenoids from foods. Carotenoids in foods occur generally as a mixture of structurally related molecules, and a normal mixed diet may provide tens of different forms of carotenoid molecules. Just as with vitamin E, there is evidence that high intake of certain carotenoids may decrease the absorption, bioavailability and tissue distribution of other carotenoids. Structural differences in the chemistry of the various carotenoids give the molecules slight nuances in their functional characteristics which may be necessary for health benefits. For example, lycopene is known to accumulate in the prostate tissue preferentially, and may provide benefits to this specific areas.
Natural β-carotene is composed of two isomers, all-trans β-carotene and 9-cis β-carotene. These two isomers have been shown to differ in both their physiochemical properties and their antioxidant activity. In contrast, synthetic laboratory produced β-carotene is made up of only the all-trans form of the vitamin. Most studies investigating the health benefits of carotenoids have administered the synthetic form of β-carotene. However, as with vitamin E studies this does not accurately reflect the isomers of the vitamin in the food matrix. In fact, research has shown that the natural form of β-carotene has superior antioxidant properties in vivo in humans, compared to the synthetic formc. Studies showing an increase in lung cancer with administration of synthetic β-carotene are therefore misleading if not taken in context. Studies should incorporate realistic food forms of carotenoids if the cellular effects are to be accurately assessed.
Some studies have noted that vitamin E may function as a pro-oxidant that disrupts the normal synergistic behaviour of in vivo antioxidants. This is because vitamin E can only behave as a lipid soluble antioxidant if there is an aqueous phase antioxidant present to recycle the vitamin E radical generated from free radical quenching. In humans, in vivo, this lipid soluble antioxidant recycling function is performed by vitamin C. Any study investigating the effects of vitamin E on cardiovascular disease must therefore ensure that all subjects are replete with vitamin C. Without this important step, vitamin E is able to oxidise LDL and create new free radical chain reactions, a detrimental process to health that could alter study outcomes to negative findings. Despite this, studies continue to supplement subjects with high doses of synthetic vitamins in drug-like trials, but interpret the findings as nutritionally relevant.
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