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Vitamin E

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Vitamin E is a fat soluble chemical found in the diet in varying amounts. Discovered in 1922, the term vitamin E is used to refer to all tocol and trienol derivatives. The tocols are alpha-, beta-, gamma- and delta-tocopherols and the trienols are alpha-, beta-, gamma- and delta-tocotrienols. All these substances are found in plants and have vitamin E activity, but alpha-tocopherol is the most active form of vitamin E. In the human body, vitamin E is present primarily as alphatocopherol. Vitamin E can be isolated from natural sources (plants, vegetables and meat) or can be made in the laboratory. Therefore, vitamin E is sold commercially as a natural or synthetic preparation. Naturally occurring alpha tocopherol is now referred to as RRR-alpha tocopherol (formerly d-alpha tocopherol), whereas synthetic alpha tocopherol is referred to as all-rac-alpha tocopherol (formerly dl-alpha-tocopherol). The esterified forms of vitamin E such as alpha tocopherol acetate, alpha tocopherol succinate and alpha tocopherol nicotinate are made in the laboratory and are also sold commercially.

Vitamin E is essential for our growth and survival. However, the human body does not make this vitamin. We depend primarily on diet or supplement for our vitamin E needs. About 20% of ingested vitamin E is absorbed from the intestine. It is now known that vitamin E undergoes very little degradation in the body. The main degradation products of vitamin E are tocopheryl quinone, tocopheryl hydroquinone, dimers, trimers and some water soluble substances. The major route of excretion is through the feces. Adipose tissue, liver and muscle are major areas for the deposit of vitamin E. The consumption of higher amounts of vitamin E increases its level in all tissues. Vitamin E is present within the cells in its free form as well as bound to proteins. These vitamin E binding proteins are present in the membrane, cytosol (soluble protein) and nucleus. The role of these vitamin E binding proteins in the mechanism of action of vitamin E is unknown.

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Method of Action

The chemical formula of alpha tocopherol is C29H5002. At least 8 compounds having vitamin E activity have been isolated from plant sources. All have a 6-chromonal ring structure and a side chain. The tocols have a phytol side chain, whereas the trienols have a similar structure, with double bonds at the 3', 7', and 11' positions of the side chain. Both tocols and trienols occur as a variety of isomers which differ from one another by the number and location of methyl groups on the chromonal ring. Alpha tocopherol is the most active form and the side chain is essential for full biological activity of vitamin E.

Vitamin E has more than one mechanism in the body. One of the most well established mechanisms is its capacity to destroy free radicals generated as a part of the oxidation reaction in the human body or by exogenous agents. This antioxidation mechanism of vitamin E has been demonstrated both in vitro and in vivo. Vitamin E has been shown to stabilize membranes by physiochemical interaction between its phytol side chain and the fatty acid chain of polyunsaturated phospholipids. It inhibits the synthesis of prostaglandins and prevents platelet aggregation in vitro and in vivo. There are some data which show that vitamin E reduces the synthesis of thromboxane and increases the formation of prostacyclin. Thromboxane is considered the most potent platelet aggregating factor; therefore, further study on the role of vitamin E in regulating the metabolism of arachidonic acid is needed.

Recent studies show that alpha tocopheryl succinate treatment induces cell differentiation in some cancer (melanoma cells in vitro); however, it inhibits the growth of other tumor cells (murine neuroblastoma, rat glioma and human prostrate) in vitro. On the other hand, alpha tocopherol, alpha tocopheryl acetate and alpha tocopheryl nicotinate at similar concentrations were ineffective. However butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), which have antioxidant properties similar to those of vitamin E, were only partially effective in producing the above changes. Thus the effects of vitamin E succinate on cancer cells, in part, are mediated by its antioxidant mechanism. Alpha tocopherol also causes differentiation of mouse myeloid leukemia in vitro.

Recent in vitro studies have demonstrated a novel mechanism of action of vitamin E in which its antioxidant role is not involved. Vitamin E succinate treatment of cancer cells (neuroblastoma) and normal fibroblasts (murine L-cells) inhibits prostaglandin (PG) E1- and PGA2- stimulated adenylate cyclase (converts ATP to adenosine 3', 5'-cyclic monophosphate) activity. This effect is primarily due to an inhibition of the catalytic protein activity of adenylate cyclase. Because of the involvement of prostaglandins in the carcinogenic events, it has been proposed that one of the mechanisms of cancer prevention by vitamin E may involve a reduction in adenylate cyclase response to prostaglandins. Since the production of excess of prostaglandins is associated with suppression of the immune system and platelet aggregation, the above mechanism of vitamin E may be involved in vitamin E-induced stimulation immunity and inhibition of platelet aggregation. In a recent study, it has been observed that vitamin E treatment of neuroblastoma cells increases the expression of c-mye gene (normal cellular gene) by about five-fold (Sharna & Prasad, unpublished observation). This is the first demonstration that vitamin E can enhance the transcription of a particular sequence of DNA. The significance of this observation in the control of growth, differentiation and malignancy is unknown at this time

The relative efficacy of natural and synthetic forms of vitamin E has not been adequately studied. In vitro experimental systems, the natural and synthetic forms of vitamin E were equally effective in causing growth inhibition of neuroblastoma an melanoma cells. However, d-form of vitamin E was more potent than dl-form in inhibiting the growth of glioma cells.

The studies discussed in this chapter show that vitamin E has a direct role in the regulation of gene expression both at the levels of transcription and translation. The maximal potential of vitamin E for maintaining an optimal health and for disease prevention remains to be determined. The above goal cannot be realized until we know how vitamin E works on cellular molecular levels. Future vitamin E research will focus on this issue and at the same time will continue to emphasize the evaluation of the role of vitamin E in human health and disease prevention and treatment.

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Properties and Uses

In recent years, consumers have been advised to use polyunsaturated fats instead of saturated fats in order to reduce the risk of heart disease. Some preliminary data suggest that this advice is having a favorable impact in reducing the risk of heart disease. It has been reported that in animals, the dietary need for vitamin E increases when the intake of polyunsaturated fatty acids becomes greater. Nutrition scientists have established that cellular membranes containing polyunsaturated fats are more easily damaged by free radicals than those which contain saturated fats. In order to protect membranes which contain high levels of polyunsaturated fats, the increased consumption of vitamin E is not only justified but essential.

In chickens, selenium deficiency causes poor absorption of vitamin E from the digestive tract. Vitamin E enhances the cancer preventive effect of selenium on chemical-induced breast cancer in rats. The relevance of this observation in humans has not been evaluated as yet.

Both vitamin E and zinc act as a stabilizer of cellular membranes. Red blood cells from zinc - or vitamin E-deficient animals are easily broken by free radicals. Supplementation of diets with either vitamin E or zinc makes these membranes more resistant to free radical attack. Zinc-deficient diets cause skin and joint damage in the chicken. Dietary supplementation with high vitamin E doses prevents the above harmful effects of zinc deficiency. These studies suggest that some effects of vitamin E and zinc on cells are similar.

The exposure of vitamin E to iron and copper enhances the destruction of vitamin E. It has been reported that in low birth weight infants, administration of iron may cause the development of vitamin E deficiency anemia, particularly in those infants who were fed formula containing higher levels of polyunsaturated fatty acids.

Vitamin C protects vitamin E from the harmful effects of iron and copper as well as helps to regenerate vitamin E immediately after it has been destroyed by free radicals. During vitamin E deficiency, the levels of vitamin A (retinol and retinyl esters) in liver and retinol in plasma decrease. These levels are increased during alpha tocopherol supplementation. The consumption of higher levels of dietary vitamin A increase the need for vitamin E in the body. Most human studies suggest that the consumption of vitamin E is essential for efficient vitamin A utilization and liver storage. Vitamin E deficiency may also cause deficiency of vitamin B-12. Thus the alterations in the level of vitamin E may effect the levels of other vitamins such as vitamins A, C and B-12.

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Vitamin E has been shown to interact with some pollutants which are present in the environment and diet. The primary atmospheric pollutants are ozone and nitric oxide which are capable of generating free radicals in the body. Vitamin E has been shown to protect against the harmful effect of ozone and nitric oxide. The major food pollutants are nitrites which are present in fresh fruits and vegetables as well as in bacon, sausage and cured meat. Nitrites by themselves are not harmful to adults, but they can combine with amines in the stomach to form nitrosamine. Nitrosamines are among the most potent cancer causing agents for both animals and human beings. The presence of vitamin C or vitamin E in the stomach may prevent the formation of or reduce the levels of nitrosamines. Taking vitamin C or E before eating fresh fruits and vegetables that contain high levels of nitrites is not needed, because they contain another group of chemicals called phenolics, which, like vitamin E, act as an antioxidant and can prevent the formation of nitrosamines. However, it is important to take vitamin E just before eating bacon, sausage, or cured meat in order to prevent the formation of nitrosamines.

In addition to nitrosamines, many other mutagenic substances (agents which cause genetic changes) are formed in the digestive tract. All mutations do not cause cancer, but all cancers are preceded by mutations. It has been shown that the levels of mutagenic substances in the feces are higher for persons who are meat eaters than for those who are vegetarians. The presence of higher levels of fecal mutagenic substances may increase the risk of some cancers. It has been reported that taking vitamin E or vitamin C reduces the mutagenic substances in the feces. Furthermore, reports indicate that taking both vitamin E and C is more effective than taking either individually.

Many chemicals are not carcinogenic until they are converted to an active form in the body. In some cases vitamin E can prevent the conversion of inactive forms of such cancer causing substances to active forms. Vitamin E also prevents the action of tumor promoting and tumor initiating agents which are present in the environment and diet.

Vitamin E influences the effectiveness of many drugs which are currently used in cancer treatment. The above concept has been demonstrated on cancer cells in vitro. For example, vitamin E acetate in combination with vincristine, 5-fluorouracil, adriamycin, or cholorozotocin produced a synergistic effect, whereas vitamin E in combination with bleomycin, 1-2-cholrethyl)-3-cyclohexyl-1-triazeno-imidazole-4-carboxamide (DIIC), mutamycin or cis-diamine) dichloro-platiumn 11 (cis-platiumn 11) produces an additive effect on the inhibition of growth of neuroblastoma cells in vitro. In glioma cell cultures, vitamin E acetate in combination with vincristine or CCNU produced a synergistic effect whereas vitamin E in combination with bleomycin, 5-fluoracil, adriamycin, DTIC, mutamycin and cis-platinum produced an additive effect on the inhibition of growth. These studies suggest that the effectiveness of the interaction of vitamin E with cancer chemotherapeutic drugs depends upon tumor form and type of drug. Vitamin E succinate also enhances the effect of some naturally occurring substance such as prostaglandins and sodium butyrate on neuroblastoma cells in vitro. The relevance of the above results in humans is not known at this time.

Several experimental studies have been reported that vitamin E protects normal tissue against radiation damage; however, higher doses of vitamin E succinate enhance the effect of radiation on cancer cells in vitro. In addition, vitamin E succinate markedly reduces the occurrence of radiation induced cancer in vitro. High doses of vitamin E succinate also enhance the effect of heat on cancer cells in vitro. The above effects of vitamins have not been tested on humans as yet.

Vitamin E protects cells from the toxicity of certain heavy metals. For example, organic mercury is known to cause neurological diseases because of damage to the brain cells. The administration of vitamin E immediately before treatment of animals with organic mercury markedly reduces the symptoms of brain damage in rats, mice and quail. Vitamin E succinate also protects glia cells, one of the cell types present in brain, in vitro against organic mercury-induced toxicity.

Only selenium appears to enhance the effect of vitamin E on the prevention of chemical-induced cancer in vitro.

Vitamin E administration has been useful in the treatment of those disease in humans which are due to vitamin E deficiency. Vitamin E acetate (400 IU) has been shown to be useful in the treatment of cystic mastitis, the most common cancerous growth of the breast in females. Vitamin E acetate (1600 IU/day) before the administration of adriamycin reduces its toxic effect in patients with cancer. This is consistent with the animal studies in which vitamin E has been shown to reduce the toxic effects of adriamycin on heart and skin. Vitamin E also protects against lung damage in animals produced by bleomycin, a commonly used drug in the treatment of cancer. One study reports that vitamin E therapy reduces some of the symptoms of premenstrual syndrome.

Several animal and a few human studies have suggested that vitamin E may be useful in the prevention of some human cancer. Currently, the effect of oral intake of vitamin E (400 to 800 IU/day) in the form of alpha tocopherol, alpha tocopheryl acetate or alpha tocopheryl succinate on the risk of developing some forms of cancer among the high risk human populations is being studies.

Vitamin E may reduce lung damage produced by cigarette smoke. There is increasing evidence that free radicals are generated in the lung by the substances which are present in the cigarette smoke. These free radicals are responsible for increasing the risk of lung cancer well as of emphysema (a chronic lung disease in which breathing becomes difficult). The level of vitamin E in the fluid surrounding lung tissue is six times less among smokers in comparison to those who do not smoke. The presence of higher levels of vitamin E in these fluids or in lung tissue may protect lungs from the attack of free radicals.

Vitamin E may have a role in the management of some neurological diseases. A group of neurologists are initiating a new clinical study using vitamin E in combination with deprenyl in order to slow down the progression of disease in patients with Parkinsonism. It is believed that free radicals are generated by degradation products of dopamine (a chemical which is essential for brain function) and by drugs used in the treatment of Parkinson's Disease.

There are very limited animal studies regarding the use of vitamin E in the management of cancer. One clinical study has utilized high intravenous doses (up to 2 grams per day) of alpha tocopherol in the treatment of 1V Stage metastic neuroblastomas. The objective regression was observed in 50% of treated patients. Preliminary data suggest that vitamin E can help in the management of cancer in more than one way. It can kill tumor cells, enhance the effect of tumor therapeutic agents (drug, radiation and heat), reduce their toxic effect and enhance the immune functions. Numerous animal and one human study suggest that high doses of vitamin may enhance the body's immune defense system. More human studies are needed to evaluate the rate of vitamin E in the treatment of cancer.

Free radicals have been implicated in accelerating the aging processes of organisms as well as individual organs in the body. Therefore, the supplemental use of vitamins on a regular basis should slow down aging processes. This hypothesis has not been adequately tested in humans or animals. In vitro data show that the addition of vitamin E increases the survival of nerve cells.

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Consequences of Deficiency

Vitamin E deficiency can result from a low intake of fresh fruit and vegetables and other foods rich in vitamin E Deficiency can also occur in those individuals who cannot absorb fat. In addition, damage to the pancreas, bile duct, liver, and surgical removal of the major portion of the digestive tract can cause vitamin E deficiency. The plasma level of vitamin E in normal adults is about 10 mcg/ml; a plasma level of 5 mcg/ml or less is considered and indication of vitamin E deficiency. Several human diseases are associated with vitamin E deficiency. Premature infants are born with a deficiency of vitamin E. The smaller the infant, the greater the degree of deficiency. The lack of adequate tissue storage and poor absorption due to immature digestive systems are responsible for this deficiency. Premature infants can suffer lung and brain damage.

The above symptoms appear to be related to vitamin E deficiency because when vitamin E is injected into the muscle these symptoms do not develop.

Children with the disease of poor absorption from the intestine develop brain damage as well as muscle damage When vitamin E is injected into the muscle, the symptoms resulting from brain damage improve. In children with cystic fibrosis symptoms of nerve damage are commonly seen and are considered due to vitamin E deficiency due to poor absorption from the digestive tract.

Hemolytic anemia results from the deficiency of the enzyme glucose-6-phosphate dehydrogenase or of glutathione synthetase. Red blood cells become more sensitive to attack by free radicals, because they cannot form lipids in which vitamins can be stored. Increasing the blood level of vitamin E has been found to be useful in this disease.

In animals, vitamin E deficiency leads to severe damage to muscles. In addition, vitamin E deficiency has been associated with aggregation of platelets. This chemical change in the blood increases the risk of heart disease. Lower blood levels of vitamin E appear to be related to higher risks of subsequent development of breast cancer. Animal studies suggest that vitamin E deficiency may decrease the immune competency of the host.

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Toxicity Levels

In a large human trial involving 9,000 adults, a daily oral intake of 3,000 IU per day of vitamin E acetate for 11 years did not produce any detectable major side effects; however, isolated cases of fatigue, skin reactions and upset stomach have been reported after ingestion of high doses (above 1,000 IU) of vitamin E for a prolonged period of time. Local complications such as soft tissue calcification at the site of injection were reported in two cases of infants who received vitamin E acetate through muscle. It should be emphasized that some of the solvents used in vitamin E preparations have been found to be extremely toxic in vitro. Therefore, any clinical report on humans which does not use solvent as a control cannot be considered conclusive.

Animal studies on toxicity of vitamin E appear contradictory. For example, a high dose of vitamin E acetate (500 mg/kg of body weight) was not toxic in mice; whereas in another study a dose of 400 mg/kg of body weight of dl-alpha tocopheryl acetate was lethal to mice. Unfortunately, the effect of the solvent in which vitamin E was dissolved, was not studied. This may, in part, explain the above opposing results. On study reports that the chronic intake of supplemental vitamin E with food causes an increased deposit of fat in the rat liver. A very high dose of vitamin E (4% of the diet) enhances the incidence of chemically-induced tumor. If one considers that the average adult human consumes about 1 kg of food daily, the above dose of vitamin E would be the equivalent of 40 grams/day. Such high doses of vitamin E are not consumed by humans and are not relevant to human health or to disease prevention.

Based on many studies, it can be estimated that doses up to 400 IU of vitamin taken orally, divided into two doses per day, are unlikely to produce any major toxic effects in an average normal adult.

Vitamin E is sold commercially as the esterified form (alpha tocopheryl acetate, alpha tocopheryl succinate and alpha tocopheryl nicotinate) or as the non-esterified form (alpha tocopherol). They are sold in tablets, capsules, gelatin or in liquid. It should be emphasized that the solutions in which vitamin E is dissolved markedly vary from one preparation to another, and many of them have been found to very toxic in vitro.

The efficacy of various forms of vitamin E appears to be different. Recent experimental studies suggest that alpha tocopheryl succinate is more effective than the other forms of vitamin E; however, this has not been tested in humans as yet. The unesterified form of vitamin E is absorbed from the digestive tract, whereas the esterified form sare first converted to alpha tocopherol by an enzyme and then they are absorbed. The juices from the pancreas and bile help to solubilize vitamin E and thus aid in its absorption. A small protein in the blood acts as a carrier for vitamin E and takes it to all the organs in the body. Since the maximum level of alpha tocopherol in the blood appears 4 to 6 hours after vitamin E is ingested and drops to a basal level in about 12 hours, the maintenance of higher blood levels of vitamin E requires taking it twice a day (morning and evening).

Vitamin E should be consumed both as alpha tocopherol and in the form of an ester (alpha tocopheryl acetate or alpha tocopheryl succinate). The ester form of vitamin E is not degraded in the presence of light and oxygen as rapidly as alpha tocopherol; therefore, its potency in the bottle can be maintained for a longer time. However, they cannot act as antioxidants until they are converted to alpha tocopherol. The presence of alpha tocopherol in the stomach is necessary in order to block carcinogenic events such as the formation of nitrosamines.

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Recommended Dietary Allowances

RDA values (IU/day) for various age groups are listed below:
  • RDA for adult male: 10 mg alpha TE
  • RDA for adult female: 8 mg alpha TE
  • Children 7 to 10 years: 7 mg apha TE
  • Infants: 4 mg apha TE
  • Pregnant and lactating women: 12 mg apha TE

Summary of Vitamin E Deficiency Symptoms

  • Premature Hemolysis of Red Blood Cells
  • Muscle Weakness
  • Increased Lung Tissue Due To Smog, Cigarette Smoking, Air Pollution, etc.
  • Shortened Life of Red Blood Cells
  • Anemia
  • Decreased Resistance to Bacterial Infection
  • Increased Susceptibility to Fibrocystic Breast Disease
  • Increased Tendency to Retrolental Fibroplasia In Babies
  • Increased Tendency to Hemolytic Anemia In Premature Babies
  • Increased Susceptibility to Thrombosis

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Food Sources

While present in small amounts in many foods, NO specific food is a dependable source of vitamin E. The best sources of dietary vitamin E:

Green Leafy Vegetables Cod Liver Oil
Coconut Corn Oil
Mayonnaise Olive Oil
Peanut Butter Palm Oil
Peanuts Pecans
Soybeans Walnuts
Wheat Germ

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