In 1936, Evans et al. isolated a substance as crystals from wheat germ oil, which was characterized as the allophanate of an alcohol. They named the substance "tocopherol," which was derived from a combination Greek word phero, "to bring" and the Greek word tocos, meaning "childbirth" (Evans, H. M. The pioneer history of vitamin E. Vitam. Horm. 1962; 20:379–387.). Its characterizations indicated that this material had all chemical and biological properties of vitamin E. (Evans H. M., Emerson, O. H. & Emerson, G. A. The isolation from wheat germ oil of an alcohol, -tocopherol, having the properties of vitamin E. J. Biol. Chem. 1936; 113: 319–332). Back to Top
Discovery and Charaterization of Tocopherol Isoforms
The different iso-forms of vitamin E, α-, ß-, and γ-tocopherols and their allophanates were characterized in 1937 by Olcott (of Mattill’s group) and Emerson (of Evans’ group). Their collaborative investigation concluded that "α-, ß-, and γ-tocopherols and their allophanates are effective antioxidants towards lard." (Olcott, H. S. & Emerson, O. H. Antioxidants and the autoxidation of fats. IX. The antioxidant properties of the tocopherols. J. Am. Chem. Soc. 1937; 59: 1008–1009.).
Tappel was the real pioneer who initiated biochemical studies on the mechanism of antioxidant activity of vitamin E (Tappel, A. C. & Zalkin, H. Inhibition of lipide peroxidation in mitochondria by vitamin E. Arch. Biochem. 1959, 80: 333–336). Back to Top
Discovery and Characterization of Tocotrienol Isoforms
Tocotrienols, among the iso-forms of vitamin E complex family, were first isolated from rubber in 1965 (Dunphy, P. J.; Whittle, K. J.; Pennock, J. F.; Morton, R. A. "Identification and Estimation of Tocotrienols in Hevea Latex". Nature 1965; 207: 521). The biological roles of tocotrienols were not established until 1980 when tocopherols and tocotrienols as the components of vitamin E complex were reported for their ability to lower cholesterol by Qureshi and Elson from University of Wisconsin – Madison). Back to Top
Comparisons of Vitamin C and Vitamin E as antioxidants
Vitamin C and Vitamin E are the same as they both are both vitamins and antioxidants. Vitamin E complex is a milder antioxidant than Vitamin C. Vitamin E and Vitamin C has a contract difference in terms of the lipholicity and the hydrophilicity. They can be described by 2 antonyms – hydrophobic and hydrophilic.
Vitamin C contains 6 carbon atoms and 6 oxygen atoms. Its structure is characterized by 4 hydroxy groups and a 1,4-lactone ring (a 5 member ring ester), making vitamin C very hydrophilic and water-soluble.
In contrast, Vitamin E has a long saturated carbon chain and a bicyclic ring system with a total of 29 carbon atoms and only one hydroxyl group, making it very hydrophobic, and oil-soluble.
Biological Activity of Vitamin E in Cellular Membrane
The cellullar membrane consists of 3 classes of amphipathic lipids: phospholipids, glycolipids, and cholesterols. Phospholipids are the most abundant, and ~ 30% of the plasma membrane is lipid. The phospholipids and glycolipids in cell membrane usually contain fatty carbon chains of an even number of carbon atoms, typically between 16 and 20, either saturated or unsaturated. The length and the degree of unsaturation of fatty acid chains are associated with membrane fluidity. The unsaturated lipids have carbon-carbon double bonds generally in cis-configuration, create a kink, prevent the fatty acids from packing together too tightly, and therefore, decrease the melting temperature by increasing the fluidity of the membrane. The non-covalent interaction of hydrophobic tails plays the essential role for the membrane structure of flexibility, which is crucial for a variety of vital biological events of cells. Back to Top
The unsaturation of fatty acid chains or carbon-carbon double bonds are specially vulnerable to damaging attack by reactive oxygen species (ROS) or free radicals. The lypholicity of vitamin E makes it a unique antioxidant soluble in fat. Vitamin E, a multi-natural product complex, including α-, β-, γ-, and δ- tocopherols and corresponding four tocotrienols can break the propagation of free-radical chains in the very hydrophobic environment, where other hydrophilic antioxidants can hardly reach.
Some isoforms of vitamin E have been well investigated as an antioxidant, while some others are still under investigation. The α-tocopherol (alpha-tocopherol) has been the most studied vitamin E molecule as it has the highest bioavailability. α-Tocopherol is known to be the most effective lipid-soluble antioxidant. α-Tocopherol prevent oxidation of cell membranes by directly reducing and scavenging both original reactive oxygen species and the resulting lipid radicals produced in the lipid peroxidation chain reaction. Some experts argue that the tocotrienols are more potent antioxidants in the vitamin E family, but have been the least studied. Back to Top
Controversies of Vitamin E as Antioxidant
It is irrefutable that Vitamin E has well-established antioxidant properties. However, the significance of the antioxidant properties of vitamin E is not consistently recognized by scientists as Vitamin E molecules have very low concentrations in the body. Vitamin E is required for a variety of properties of their isoforms, not necessarily as antioxidant. Back to Top
Vitamin E Properties Other than Antioxidant
For example, γ-tocopherol (gamma-tocopherol) is an electron-rich nucleophile and can attack electrophilic mutagens. In general, Vitamin E molecules are vital enzyme cofactors and play a variety of roles in signal transduction. Tocotrienols have been investigated for the role of inhibiting HMG-CoA reductase in neuron protection and in prevention of and cholesterol reduction; δ-tocotrienol inhibits processing of sterol regulatory element‐binding proteins (SREBPs).
Alpha-tocopherol has been demonstrated an important role in signal transduction in vascular smooth muscle cells, while other forms of vitamin E have not been found the same, raising interest in the roles of vitamin E beyond its antioxidative function. Back to Top
Vitamin E Deficiency
Etiology of vitamin deficiency is one of the major nutritional subject of World Health Organization (WHO) for the last half century. Dietary vitamin E deficiency is a well-known problem in some developing countries due to the inadequate intake of vitamin E. The symptoms of vitamin E deficiency include hemolytic anemia and neurologic deficits. The ratio of plasma α-tocopherol to total plasma lipids is used to measure vitamin E difficiency. A low ratio is the diagnosis or indication of vitamin E deficiency. Vitamin E deficiency induces fragility of red blood cells (RBCs) and degeneration of neurons, including peripheral axons and posterior column neurons.
Adults in developed countries have very rarely cases of vitamin E deficiency, and Vitamin E deficiency is usually caused by fat malabsorption, including abetalipoproteinemia (Bassen-Kornzweig syndrome, - a genetic defect or absence of apolipoprotein B), pancreatitis, short bowel syndrome, chronic cholestatic hepatobiliary disease and cystic fibrosis. Other than fat malabsorption, genetically defective liver metabolism may also cause a rare genetic form of vitamin E deficiency. Back to Top
Symptoms and Signs: Mild hemolytic anemia and nonspecific neurologic deficits are common and major symptoms caused by vitamin E deficiency. Abetalipoproteinemia is a lipis disorder and vitamin E deficiency, leading progressing neuropathy and retinopathy in the first twenty years of life. Vitamin E deficiency likely causes retinopathy of prematurity or retrolental fibroplasia in infants. Vitamin E deficiency may lead to muscle weakness in some cases of intraventricular and subependymal hemorrhage in neonates.
Chronic cholestatic hepatobiliary disease or cystic fibrosis in children leads to neurologic deficits. One of further possible consequences is spinocerebellar ataxia, associated with losses of deep tendon reflexes, truncal and limb ataxia. The losses also include vibration and position senses, ophthalmoplegia, muscle weakness, ptosis, and dysarthria. These symptoms do not usually show for adults with malabsorption, as adipose tissue in adults can store vitamin E.
Oral supplement of vitamin E in high doses is the common treatment if there are neurologic deficits or if deficiency results from malabsorption. Back to Top
Vitamin E Benefits for Skin
Vitamin E has been largely used for skin health and skin care. Vitamin E benefits for skin are generally accepted. Most skin care products contain vitamin E. Vitamin E is used in lotions, creams, oral supplementation, for its role in the anti-aging of skin. Creams or lotions are the major forms of vitamin E formulations for skin care, as natural vitamin E can be effectively absorbed through skin. It is believed that vitamin E helps skin look younger and reduce the ugly appearance of fine lines and wrinkles. Vitamin E has been demonstrated the antioxidant activity and protects skin cells from ultra violet light, pollution, drugs, and other factors that produce skin cell damaging free radicals. Vitamin E lotions exhibit some benefits in preventing and treating sunburns.
Vitamin topical formulations are claimed to protect the epidermis layer of the skin from ultra violet light damage at the early stages. Vitamin E in sunscreens increases the effectiveness of sunscreens to protect skin under the sun exposure. Vitamin E is believed to have the important benefit in helping prevent skin cancer due to its sun light protection quality from its powerful antioxidant properties.
Vitamin E is used as supplementation in the treatment of various skin diseases or skin conditions. Psoriasis is often treated using topical and oral formulation containing vitamin E. Vitamin E in oral formulation is said to help treat erythema (a skin inflammation-related reddish, painful, and tender lumps). Back to Top
Controlled studies indicated that vitamin E does not exhibit benefits to reduce scarring (acne scars or surgical scars) and to heal skin from various forms of damages such as burns.
Vitamin E (alpha-tocopherol) containing the hydroxyl group (alcohol form) in skin lotions and creams is found more effective than the acetate ester form (alpha-tocopherol acetate). The acetate form is much less absorbable by skin, has weaker antioxidant activity, and provides less benefits of vitamin E.
General Health Benefits of Vitamin E Supplementation
Vitamin E Supplementation in the general population of developed countries has been of controversies and continued debate. There have no well established clinical data to support that vitamin E Supplementation in high doses affords observable and quantifiable health benefits in clinical trials.
For example, alpha-tocopherol was clinically evaluated in 2007 and was not found to have the benefit in reducing the risk of major cardiovascular events in middle aged and older men. See: "Vitamins E and C in the Prevention of Cardiovascular Disease in Men: the Physicians' Health Study II Randomized Controlled Trial". JAMA: the Journal of the American Medical Association 2008; 300 (18): 2123–33.
It should also be noted, however, that the health benefits of dietary supplement are often long-term effects and may not be quantifiable in the clinical studies which last only short period time. Dietary supplement are mostly used not for targeting specific diseases but for optimal health. The health benefits may show in different ways from person to person. Back to Top
But, still, clinical studies using tocotrienols of 42 mg/day have shown to reduce blood cholesterol levels by 5%-35%. (Reference: Effect of a palm-oil-vitamin E concentrate on the serum and lipoprotein lipids in humans". Am J Clin Nutri 53 (4 Suppl): 1027S–1030S.
Tocotrienols as members of natural vitamin E complex have been claimed to protect against brain cell damage, prevent cancer and reduce cholesterol, - biological properties not shown by tocopherols. [Ref: Cardioprotection with palm oil tocotrienols: comparison of different isomer. Am J Physiol. Heart and Circulatory Physiology 2008; 294 (2): H970–8]. Scientists argued that tocotrienols have the unsaturated side-chains, which make penetration of saturated fatty tissues more efficiently. Experts have suggested for the recent decade that tocotrienols be better antioxidants than tocopherols for the nutritional benefits in preventing cardiovascular diseases and cancer. Back to Top
Tocotrienols are proven to be safe supplement with tolerable doses of 240 mg/day for 48 months.[Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids 1995; 30 (12): 1179–83].
Vitamin E discussed in the public is generally related to alpha-tocopherols, which have been claimed for a variety of benefits. Vitamin E supplementation higher than the daily-recommended doses are claimed to help treat or prevent:
•Alzheimer’s disease •Parkinson’s disease •eye inflammation •cataracts •restless leg syndrome and muscle cramping •cardiovascular disease •rheumatoid arthritis •asthma •diabetic complications •prostate cancer and breast cancer •menstrual pain •low sperm count.
It is generally accepted that vitamin E is an immune system booster. Vitamin E helps the body increasing and regulating the levels of vitamin A, which is especially important in older adults. Topical vitamin E is believed to promote good blood circulation and prevent blood clot formation in people with diabetes. Back to Top So far, most studies about vitamin E have been based on supplementation of alpha-tocopherols. The high dosage supplementation causes reduced serum gamma- and delta-tocopherol concentrations. For example, oral consumption of alpha-tocotrienols is thought to protect against stroke-associated brain damage in vivo. There have been on-going investigations and no conclusion has been reached. Other forms of vitamin E have to be investigated to make any meaningful conclusion. Back to Top
Vitamin E Metabolism – Absorption & Excretion
Reference: Vitamin E metabolism. Molecular Aspects of Medicine (2007); 28 (5): 437-452.
Vitamin E is absorbed through intestines and packaged into chylomicrons, which are secreted into the systemic circulation in the lymphatic pathway. Vitamin E is basically transported in plasma lipoproteins - α-tocopherol transfer protein. Lipoprotein lipase (LPL) plays the role in extrahepatic tissues to pick up some the tocopherols transported in chylomicrons. The remaining alpha-tocopherols in the chylomicrons are transported to the liver. The α-tocopherol transfer protein located in the liver specifically picks up alpha-tocopherol from all incoming forms of tocopherols for incorporation into plasma lipoproteins. Alpha-tocopherol is mainly incorporated into nascent very low density lipoproteins (VLDL). Lipoprotein lipase (LPL) converts VLDL into IDL and LDL during the circulation, while other components, including α-tocopherol, are dislocated to HDL.
In additopn to the LPL action, a number of α-tocopherol-lipoprotein receptors have been identified for the uptake of lipoproteins by different tissues. Back to Top
Any excess of α-tocopherol and/or other forms of vitamin E are excreted in bile. Excess alpha-tocopherol is converted into alpha-CEHC [2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman]. Alpha-CEHC is a major water-soluble metabolite of vitamin E and is excreted in the urine. Other tocopherols, such as γ- and δ-tocopherols, are almost quantitatively converted and excreted in the urine as the corresponding CEHCs.
Vitamin E as antioxidant is oxidized in a number of different ways. α-Tocopheryl radicals react with other free radicals to produce non-radical oxidation products, which are conjugated to glucuronic acid and excreted through the bile or urine. Back to Top
Vitamin E Doses
Vitamin E daily intake for adolescents and adults (14 years and older) recommended by the Food and Nutrition Board at the Institute of Medicine is 15 mg/day. One IU of Vitamin E is equivalent to 0.67 mg of d-alpha-tocopherol, or 1 mg of dl-alpha-tocopherol acetate. That is, the recommended dietary intake (RDA) for vitamin E is about 20 International Units (IU) per day.
The most common supplementation dosage of vitamin E for adults is approximately 300 to 800 IU per day. Many nutritional experts argue that 100 to 200 IU per day is more than enough, and it is not necessary to take more. Supplementing with up to 1,600 IU per day is proposed for tardive dyskensia.
A quote from a related source: “Analysis of a variety of clinical trials suggests that doses of Vitamin E that exceed 400 IU per day may actually increase the risk of death slightly in older individuals that have existing medical conditions”. Back to Top
Recycle of Vitamin E by Other Antioxidants
Vitamin E can be oxidized to a variety of different substances after vitamin E molecules react with free radicals, - either original reactive oxygen species (ROS) or the resulting lipid radicals. The oxidized tocopherols and tocotrienols may be reduced back to the original active form and are therefore recycled by a variety of other stronger reducing species such as Vitamin C, OPC, ubiquinol, and antioxidant enzymes inside the body. α-Tocopheroxyl radicals are the best studied in this understanding of the recycling biochemistry (ref to be added).
Vitamin E vs OPC Antioxidant Supplements
Some studies indicate that foods containing a small amount of vitamin E provide better benefits than large doses of vitamin E supplementation. The interaction of vitamin E with other antioxidants plays the key role in its better utilization.
Recycle of vitamin E by super antioxidant OPC is well established. OPC can largely enhance the antioxidant effect of vitamin E. Vitamin E supplementation may not be needed, and may not better than vitamin E rich foods with supplementation of OPC antioxidant.
On the other hand, many nutritional experts don’t recommend supplementation of a single vitamin in large doses in the long-term, which causes the low plasma levels of other vitamins. Balanced multivitamins are much better supplement. The antioxidant activities of vitamins should be enhanced by recycling them with supper antioxidant OPC supplements. Back to Top
Tocopherol Vitamin E Rich Foods
Natural vitamin E includes 4 tocopherols and 4 tocotrienols. RRR-α-tocopherol is the most abundant among the 8 members of vitamin E complex in nature.
Tocopherol- vitamin E is rich in breakfast cereal, nuts, vegetables, vegetable oils, pie and chips, fish, and fruit. Here are some examples of tocopherol vitamin E rich foods and the content of alpha-tocopherol:
Sunflower oil 490mg/kg; Cottonseed oil 430mg/kg; Safflower oils 400mg/kg; Hazelnuts 250mg/kg; Almonds 240mg/kg; Wheat germ 220mg/kg; Rapeseed oil 220mg/kg; Cod liver oil 200mg/kg; Mayonnaise 190mg/kg; corn oil 170mg/kg; Soya bean oil 160mg/kg Peanut oil 150mg/kg.
Natural Sources of Vitamin E - Tocotrienols
Good sources of tocotrienol include rice, palm, annatto, rice bran oil, coconut oil, cocoa butter, barley, and wheat germ. The tocopherol-to-tocotrienol ratio in rice, palm, and annatto is 1:1, 1:3, and 1:999, respectively. Sunflower, peanut, walnut, sesame, and olive oils, however contain only tocopherols, not a good source of tocotrienols – vitamin E.
Natural vitamin E supplement in functional food and anti-ageing cosmetics are often made from tocotrienol rich distillates from rice, palm, or annatto, with the total vitamin E content of 20%, 35%, 50%, and 70%. Both forms of vitamin E - tocopherols and tocotrienols are extremely sensitive towards heat in the presence of air or oxygen. The distillates have to be made under high vacuum to reduce the high temperature and associated thermal decomposition. Vitamin E can be prepared in favor of the high content of tocotrienols, and even in a tocopherol-free form from annatto.
Synthetic Vitamin E
Synthetic vitamin E is synthetic alpha-tocopherol, which contains as many as 8 different isomers. The dl-alpha-tocopherols are the 2 major diatereo isomers. Only d-alpha-tocopherol is bio active while l-alpha-tocopherol is inactive. The vitamin E transporter in human liver recognizes specifically the d-alpha-tocopherol.
Natural vitamin E does not contain the inactive l-alpha-tocopherol. Natural vitamin E
contains not only the active d-alpha-tocopherol as the major component, but a variety of related active forms of vitamin E such as d-alpha-tocopheryl acid succinate, d-alpha-tocopheryl acetate, beta-tocopherol, delta-tocopherol, and gamma-tocopherol. “Mixed tocopherols” is a common term used by vitamin E manufacturers for referring to these different types.
There have been quite many clinical studies showing that natural vitamin E is about 3 folds as effective as synthetic vitamin E. It is not possible and there is no such a mechanism for routinely testing vitamin E supplements on the market. The contents or quality of vitamin E on the market are not guaranteed. Back to Top
1. Colombo ML. An update on vitamin E, tocopherol and tocotrienol-perspectives. Molecules. 2010 Mar 24;15(4):2103-13.
Summary: Vitamin E complex is synthesized by photosynthetic eukaryotes. Other oxygenic photosynthetic organisms such as cyanobacteria also synthesized vitamin E. Tocochromanols deposited in oily seeds and fruits or in young tissues undergoing active cell divisions have the role in preventing lipid oxidation. The natural forms of tocochromanols are reviewed and discussed as promising compounds in maintaining a healthy cardiovascular system and satisfactory blood cholesterol levels.
2. Packer, L. Vitamin E is nature’s master antioxidant. Sci. Am. 1994; 1: 54–63.
3. Kamal-Eldin, A. & Appelqvist, L.-A. The chemistry and antioxidant properties of tocopherol and tocotrienols. Lipids 1996; 31: 671–701.
4. Brigelius-Flohe, R. & Traber, M. C. Vitamin E: function and metabolism. FASEB J. 1999; 13: 1145–1155. 366 WOLF
5. Torricelli P, Ricci P, et al. Synergic effect of α-tocopherol and naringenin in transglutaminase-induced differentiation of human prostate cancer cells. Amino Acids. 2010 Oct 28.
6. Cook-Mills JM, McCary CA. Isoforms of Vitamin E Differentially Regulate Inflammation. Endocr Metab Immune Disord Drug Targets. 2010 Nov 5.
7. Sylvester PW, Kaddoumi A, et al. The value of tocotrienols in the prevention and treatment of cancer. J Am Coll Nutr. 2010 Jun;29(3 Suppl):324S-333S.
8. Yang CS, Lu G, et al. Inhibition of inflammation and carcinogenesis in the lung and colon by tocopherols. Ann N Y Acad Sci. 2010 Aug;1203:29-34.
9. Aggarwal BB, Sundaram C, Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol. 2010 Dec 1;80(11):1613-31.