Vitamin E

Vitamin E
Drug class

The α-tocopherol form of vitamin E
Use Vitamin E deficiency, antioxidant
Biological target Reactive oxygen species
ATC code A11H
External links
MeSH D014810
AHFS/Drugs.com MedFacts Natural Products

Vitamin E refers to a group of compounds that include both tocopherols and tocotrienols.[1] Of the many different forms of vitamin E, γ-tocopherol is the most common in the North American diet.[2] γ-Tocopherol can be found in corn oil, soybean oil, margarine, and dressings.[3][4] α-tocopherol, the most biologically active form of vitamin E, is the second-most common form of vitamin E in the diet. This variant can be found most abundantly in wheat germ oil, sunflower, and safflower oils.[4][5] As a fat-soluble antioxidant, it stops the production of reactive oxygen species formed when fat undergoes oxidation.[6][7][8] Regular consumption of more than 1,000 mg (1,500 IU) of tocopherols per day[9] may be expected to cause hypervitaminosis E, with an associated risk of vitamin K deficiency and consequently of bleeding problems.

Forms

The nutritional content of vitamin E is defined by α-tocopherol activity. The molecules that contribute α-tocopherol activity are four tocopherols and four tocotrienols, identified by the prefixes alpha- (α-), beta- (β-), gamma- (γ-), and delta- (δ-).[10] Natural tocopherols occur in the RRR-configuration only. The synthetic form contains eight different stereoisomers and is called 'all-rac'-α-tocopherol.[11] Water soluble forms such as d-alpha-tocopheryl succinate are used as food additive.

α-Tocopherol

Sample of α-tocopherol, one of the various forms of vitamin E

α-Tocopherol is an important lipid-soluble antioxidant. It performs its functions as antioxidant in the glutathione peroxidase pathway,[12] and it protects cell membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction.[7][13] This would remove the free radical intermediates and prevent the oxidation reaction from continuing. The oxidized α-tocopheroxyl radicals produced in this process may be recycled back to the active reduced form through reduction by other antioxidants, such as ascorbate, retinol or ubiquinol.[14] However, the importance of the antioxidant properties of this molecule at the concentrations present in the body are not clear and the reason vitamin E is required in the diet is possibly unrelated to its ability to act as an antioxidant.[15] Other forms of vitamin E have their own unique properties; for example, γ-tocopherol is a nucleophile that can react with electrophilic mutagens.[16]

Tocotrienols

Compared with tocopherols, tocotrienols are sparsely studied.[17][18][19] Less than 1% of PubMed papers on vitamin E relate to tocotrienols.[20] The current research direction is starting to give more prominence to the tocotrienols, the lesser known but more potent antioxidants in the vitamin E family. Some studies have suggested that tocotrienols have specialized roles in protecting neurons from damage[20] and cholesterol reduction[21] by inhibiting the activity of HMG-CoA reductase; δ-tocotrienol blocks processing of sterol regulatory element‐binding proteins (SREBPs).

Oral consumption of tocotrienols is also thought to protect against stroke-associated brain damage in vivo.[22] Until further research has been carried out on the other forms of vitamin E, conclusions relating to the other forms of vitamin E, based on trials studying only the efficacy of α-tocopherol, may be premature.[23]

Functions

Vitamin E has many biological functions, the antioxidant function being the most important and best known.[24] Other functions include enzymatic activities, gene expression, and neurological function(s). The most important function of vitamin E has been suggested to be in cell signaling (and it may not have a significant role in antioxidant metabolism).[25][26]

So far, most human supplementation studies about vitamin E have used only α-tocopherol. This can affect levels of other forms of vitamin E, e.g. reducing serum γ- and δ-tocopherol concentrations. Moreover, a 2007 clinical study involving α-tocopherol concluded supplementation did not reduce the risk of major cardiovascular events in middle-aged and older men.[38]

Deficiency

Main article: Vitamin E deficiency

Vitamin E deficiency can cause:

Supplementation

While vitamin E supplementation was initially hoped to have a positive effect on health, research has not supported this hope.[41] Vitamin E does not decrease mortality in adults, even at large doses,[42] and high-dosage supplementation may slightly increase it.[43][44] It does not improve blood sugar control in an unselected group of people with diabetes mellitus[42] or decrease the risk of stroke.[45] Daily supplementation of vitamin E does not decrease the risk of prostate cancer and may increase it.[46] Studies on its role in age-related macular degeneration are ongoing as, though it is of a combination of dietary antioxidants used to treat the condition, it may increase the risk.[47]

A 2012 Cochrane Review examined the potential effectiveness of antioxidant vitamin supplementation in preventing and slowing the progression of age-related cataract. The included studies involved supplementation of vitamin E, along with β-carotene and vitamin C, either dosed independently or in combination, and compared to the placebo. The systematic review showed that vitamin E supplementation had no protective effect on reducing the risk of cataract, cataract extraction, progression of cataract, and slowing the loss of visual acuity.[48]

Overdose

Main article: Hypervitaminosis E

Vitamin E can act as an anticoagulant, increasing the risk of bleeding problems. As a result, many agencies have set a tolerable upper intake levels (UL) at 1,000 mg (1,500 IU) per day.[9] In combination with certain other drugs such as aspirin, hypervitaminosis E can be life-threatening. Hypervitaminosis E may also counteract vitamin K, leading to a vitamin K deficiency.

Dietary sources

mg/(100 g)
[note 1] 		Some foods with vitamin E content[6]
lowhigh
150 Wheat germ oil
41 Sunflower oil
95 Almond oil
34 Safflower oil
1526 Nuts and nut oils, such as almonds and hazelnuts[note 2]
15 Palm oil[49]
14 Olive oil
12.2 Common purslane[50]
1.53.4 High-value green, leafy vegetables: spinach, turnip, beet greens, collard greens, and dandelion greens[note 3]
2 Avocados[51]
1.4 Sesame oil[52]
1.11.5 Asparagus[note 4]
1.5 Kiwifruit (green)
0.781.5 Broccoli[note 5]
0.81 Pumpkin[note 6]
0.260.94 Sweet potato[note 7]
0.9 Mangoes
0.540.56 Tomatoes[note 8]
0.360.44 Rockfish[note 9]
0.3 Papayas
0.130.22 Low-value green, leafy vegetables: lettuce[note 10]

Butter and egg yolk are the only food containing vitamin E and free from phytate

Recommended daily intake

The Food and Nutrition Board at the Institute of Medicine (IOM) of the US National Academy of Sciences reported the following dietary reference intakes for vitamin E:[6][53]

mg/dayAge
Infants
40 to 6 months
57 to 12 months
Children
61 to 3 years
74 to 8 years
119 to 13 years
Adolescents and adults
1514 and older

One IU of vitamin E is defined as equivalent to either: 0.67 mg of the natural form, RRR-α-tocopherol, also known as d-α-tocopherol; or 0.45 mg of the synthetic form, all-rac-α-tocopherol, also known as dl-α-tocopherol.[6]

History

Vitamin E was discovered in 1922 by Herbert McLean Evans and Katharine Scott Bishop[54] and first isolated in a pure form by Gladys Anderson Emerson in 1935 at the University of California, Berkeley.[55] Erhard Fernholz elucidated its structure in 1938 and shortly afterwards the same year, Paul Karrer and his team first synthesized it.[56]

The first use for vitamin E as a therapeutic agent was conducted in 1938 by Widenbauer, who used wheat germ oil supplement on 17 premature newborn infants suffering from growth failure. Eleven of the original 17 patients recovered and were able to resume normal growth rates.[24]

In 1945, Drs. Evan V. Shute and Wilfred E. Shute, siblings from Ontario, Canada, published the first monograph arguing that megadoses of vitamin E can slow down and even reverse the development of atherosclerosis.[57] Peer-reviewed publications soon followed.[58][59] The same research team also demonstrated, in 1946, that α-tocopherol improved impaired capillary permeability and low platelet counts in experimental and clinical thrombocytopenic purpura.[60]

Later, in 1948, while conducting experiments on alloxan effects on rats, Gyorge and Rose noted rats receiving tocopherol supplements suffered from less hemolysis than those that did not receive tocopherol.[61] In 1949, Gerloczy administered all-rac-α-tocopheryl acetate to prevent and cure edema.[62][63] Methods of administration used were both oral, that showed positive response, and intramuscular, which did not show a response.[24] This early investigative work on the benefits of vitamin E supplementation was the gateway to curing the vitamin E deficiency-caused hemolytic anemia described during the 1960s. Since then, supplementation of infant formulas with vitamin E has eradicated this vitamin’s deficiency as a cause for hemolytic anemia.[24]

Vitamin E supplementation and cardiovascular disease

Vitamin E and atherosclerosis

Atherosclerosis is a disease condition refer to the build up of plaque, which is a substance containing lipid and cholesterol (mainly the low-density lipoprotein or LDL cholesterol) on the inner layer of the arterial lumen.[64] With the existing plaque, instead of being smooth and elastic, the layers become thickened and irregular and the lumen of the artery become narrower. This vessel-narrowing effect lead to a reduction of blood circulation and can lead to or worsen the condition of hypertension.[65]

There are currently multiple theories explaining factors causing and affecting the cholesterol plaque build up within arteries with the most popular theory indicating that the rate of build up is affected by the oxidation of the LDL cholesterol. LDL cholesterol is one of the five major groups of lipoproteins with one of the physiological roles being lipid transportation. A typical LDL particle contain 2,700 fatty acid molecules and half of them are poly-unsaturated fatty acids, which are very oxidation sensitive.[66] Once the oxidation of LDL occur, it will start a series of undesirable effects starting from the increase production of inflammatory cytokines by stimulating the endothelial cells and monocytes, followed by increased production of tissue factors, production of macrophages and monocytes, which eventually lead to the formation of foam cells and accelerated development of atherosclerosis. With the presence of adequate concentration of vitamin E, which is a very potent fat-soluble antioxidant, it can inhibit the oxidation of LDL, and this inhibition contributes protection against the development of atherosclerosis and can stabilize the existing plaque.[66]

Critical evaluation of current related literature

Many observational and interventional studies have been conducted to clarify the association between vitamin E and CVD and it’s risk factors. The many observational studies supported a protective role for dietary and supplementary vitamin E intake on the risk of CVD. For randomized controlled trials (RCTs), however, the results are more controversial.

According to Asplund (2002)’s [67] meta-analysis, nine cohort studies showed that high intake of tocopherol was associated with a lower risk of CVD events compared with lower intake. The odds ratio (OR) was 0.74 (95% confidential interval (CI): 0.66-0.83). In this study, higher dietary, supplementation and combined vitamin E intake was also associated with lower CHD incidents, as presented in Appendix II. A large cohort study conducted by Rimm et al [68] in 1993 included 39,919 male health professionals aged between 40 to 75 showed that consumption of more than 60IU of vitamin E (any form) per day was associated with a lower incidence of CHD compared with less than 7.5 IU/day intake. This study also showed an inverse association between vitamin E supplementation and the incidence of CHD. The relative risk (RR) of at least 100 IU/day for at least two years was 0.63 (95% CI: 0.74-0.84). A European cohort study was conducted by Knekt et al in 1994. This study also found an inverse relationship between higher vitamin E (any form) intake and lower CHD risk in men and women. In addition, Kushi et al (1996) discovered an inverse relationship between vitamin E intake and CHD mortality among 34,486 postmenopausal women (RR=0.38, 95% CI: 0.18-0.8; trend: P=0.014).

For the result of RCTs, as mentioned previously, it was controversy. A meta-analysis of 6 RCTs showed no significant association between vitamin E supplementation and CVD mortality; the pooled OR (95% CI) was 1.0 (0.94-1.06) (Vivekananthan et al, 2003). Another meta-analysis of 7 RCTs also snowed similar results, with the pooled Ors (95% CI) of cardiovascular events, non-fatal MI, non-fatal stroke, and CVD deaths being 0.98 (0.94-1.03), 1.00 (0.92-1.09), 1.03 (0.93-1.14), and 1.00 (0.94-1.05), respectively [69]

Notes

  1. ↑ "USDA Nutrient Data Laboratory". In notes 2–11, USDA NDL Release 24 numbers are given as mg/(100 g). Low and high values vary some by raw versus cooked and by variety.
  2. ↑ 26 almonds, 15 hazelnuts
  3. ↑ Spinach (2.0 raw, 2.1 cooked), turnip (2.9 raw, 1.9 cooked), beet (1.5 raw, 1.8 cooked), collard (2.3 raw, 0.88 cooked), and dandelion greens (3.4 raw, 2.4 cooked)
  4. ↑ 1.1 raw, 1.5 cooked
  5. ↑ 0.78 raw, 1.5 cooked
  6. ↑ 1. raw, 0.8 cooked
  7. ↑ 0.26 raw, 0.94 boiled
  8. ↑ 0.54 raw, 0.56 cooked
  9. ↑ 0.36 raw, 0.44 cooked
  10. ↑ Lettuce (0.18 iceberg, 0.22 green leaf, 0.13 romaine, 0.15 red leaf, 0.18 butterhead)

References

  1. ↑ Brigelius-Flohé R, Traber MG; Traber (1999). "Vitamin E: function and metabolism". FASEB J. 13 (10): 1145–1155. PMID 10385606.
  2. ↑ Traber, MG (1998). "The biological activity of vitamin E". The Linus Pauling Institute. Retrieved 6 March 2011.
  3. ↑ Bieri JG, Evarts RP; Evarts (1974). "γ-Tocopherol: metabolism, biological activity and significance in human vitamin E nutrition". American Journal of Clinical Nutrition 27 (9): 980–986. PMID 4472121.
  4. ↑ 4.0 4.1 4.2 Brigelius-Flohé R, Traber MG; Traber (1 July 1999). "Vitamin E: function and metabolism". FASEB J. 13 (10): 1145–55. PMID 10385606.
  5. ↑ Reboul E, Richelle M, Perrot E, Desmoulins-Malezet C, Pirisi V, Borel P; Richelle; Perrot; Desmoulins-Malezet; Pirisi; Borel (15 November 2006). "Bioaccessibility of carotenoids and vitamin E from their main dietary sources". Journal of Agricultural and Food Chemistry 54 (23): 8749–8755. doi:10.1021/jf061818s. PMID 17090117.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 National Institute of Health (4 May 2009). "Vitamin E fact sheet".
  7. ↑ 7.0 7.1 Herrera E, Barbas C; Barbas (2001). "Vitamin E: action, metabolism and perspectives". Journal of Physiology and Biochemistry 57 (2): 43–56. doi:10.1007/BF03179812. PMID 11579997.
  8. ↑ Packer L, Weber SU, Rimbach G; Weber; Rimbach (2001). "Molecular aspects of α-tocotrienol antioxidant action and cell signalling". Journal of Nutrition 131 (2): 369S–73S. PMID 11160563.
  9. ↑ 9.0 9.1 "Vitamin E — Health Professional Fact Sheet". dietary-supplements.info.nih.gov. Retrieved 5 February 2015.
  10. ↑ Traber, M.G. "19". In Ross, A. Catherine. Modern Nutrition in Health and Disease (11 ed.). Philadephia, PA: Lippincott Williams & Wilkins. pp. 293–294. ISBN 9781605474618.
  11. ↑ Traber, MG. "Chapter 15: vitamin E". In Bowman BA and Russell RM. Current Knowledge in Nutrition I (9 ed.). Washington DC, USA: ILSI. ISBN 978-1-57881-199-1.
  12. ↑ Wefers H, Sies H; Sies (1988). "The protection of ascorbate and glutathione against microsomal lipid peroxidation is dependent on Vitamin E". European Journal of Biochemistry 174 (2): 353–357. doi:10.1111/j.1432-1033.1988.tb14105.x. PMID 3383850.
  13. ↑ 13.0 13.1 Traber MG, Atkinson J; Atkinson (2007). "Vitamin E, Antioxidant and Nothing More". Free radical biology & medicine 43 (1): 4–15. doi:10.1016/j.freeradbiomed.2007.03.024. PMC 2040110. PMID 17561088.
  14. ↑ Wang X, Quinn PJ; Quinn (1999). "Vitamin E and its function in membranes". Progress in Lipid Research 38 (4): 309–36. doi:10.1016/S0163-7827(99)00008-9. PMID 10793887.
  15. ↑ Brigelius-Flohé R (2009). "Vitamin E: the shrew waiting to be tamed". Free radical biology & medicine 46 (5): 543–54. doi:10.1016/j.freeradbiomed.2008.12.007. PMID 19133328.
  16. ↑ Brigelius-Flohé R, Traber MG; Traber (1999). "Vit amin E: function and metabolism". FASEB J. 13 (10): 1145–55. PMID 10385606.
  17. ↑ Traber MG, Packer L; Packer, L (1995). "Vitamin E: beyond antioxidant function". American Journal of Clinical Nutrition 62 (6): 1501S–1509S. PMID 7495251.
  18. ↑ Traber MG, Sies H; Sies, H (1996). "Vitamin E in humans: demand and delivery". Annual review of nutrition 16: 321–47. doi:10.1146/annurev.nu.16.070196.001541. PMID 8839930.
  19. ↑ Sen CK, Khanna S, Roy S; Khanna; Roy (2004). "Tocotrienol: the natural vitamin E to defend the nervous system?". Annals of the New York Academy of Sciences 1031: 127–42. Bibcode:2004NYASA1031..127S. doi:10.1196/annals.1331.013. PMID 15753140.
  20. ↑ 20.0 20.1 Sen CK, Khanna S, Roy S; Khanna; Roy (2006). "Tocotrienols: Vitamin E Beyond Tocopherols". Life Sciences 78 (18): 2088–98. doi:10.1016/j.lfs.2005.12.001. PMC 1790869. PMID 16458936.
  21. ↑ Das S, Lekli I, Das M, Szabo G, Varadi J, Juhasz B, Bak I, Nesaretam K, Tosaki A, Powell SR, Das DK; Lekli; Das; Szabo; Varadi; Juhasz; Bak; Nesaretam; Tosaki; Powell; Das (2008). "Cardioprotection with palm oil tocotrienols: comparison of different isomers". American journal of physiology. Heart and circulatory physiology 294 (2): H970–8. doi:10.1152/ajpheart.01200.2007. PMID 18083895.
  22. ↑ Khanna S, Roy S, Slivka A, Craft TK, Chaki S, Rink C, Notestine MA, DeVries AC, Parinandi NL, Sen CK; Roy; Slivka; Craft; Chaki; Rink; Notestine; Devries; Parinandi; Sen (2005). "Neuroprotective Properties of The Natural Vitamin E α-Tocotrienol". Stroke 36 (10): 2258–64. doi:10.1161/01.STR.0000181082.70763.22. PMC 1829173. PMID 16166580.
  23. ↑ Sen CK, Khanna S, Roy S; Khanna; Roy (2007). "Tocotrienols in health and disease: the other half of the natural vitamin E family". Molecular Aspects of Medicine 28 (5–6): 692–728. doi:10.1016/j.mam.2007.03.001. PMC 2435257. PMID 17507086.
  24. ↑ 24.0 24.1 24.2 24.3 Bell EF (1987). "History of vitamin E in infant nutrition". American Journal of Clinical Nutrition 46 (1 Suppl): 183–186. PMID 3300257.
  25. ↑ Azzi A (2007). "Molecular mechanism of alpha-tocopherol action". Free radical biology & medicine 43 (1): 16–21. doi:10.1016/j.freeradbiomed.2007.03.013. PMID 17561089.
  26. ↑ Zingg JM, Azzi A; Azzi (2004). "Non-antioxidant activities of vitamin E". Current medicinal chemistry 11 (9): 1113–33. doi:10.2174/0929867043365332. PMID 15134510.
  27. ↑ Traber MG, Stevens JF; Stevens (2011). "Free Radical Biology and Medicine – Vitamins C and E: Beneficial effects from a mechanistic perspective". Free Radical Biology and Medicine 51 (5): 1000–13. doi:10.1016/j.freeradbiomed.2011.05.017. PMC 3156342. PMID 21664268.
  28. ↑ UHMWPE Biomaterials Handbook, 2nd Edition, Kurtz ed. (2009)
  29. ↑ Schneider C (2005). "Chemistry and biology of vitamin E". Mol Nutr Food Res 49 (1): 7–30. doi:10.1002/mnfr.200400049. PMID 15580660.
  30. ↑ 30.0 30.1 Devaraj S, Hugou I, Jialal I; Hugou; Jialal (2001). "-Tocopherol decreases CD36 expression in human monocyte-derived macrophages". J Lipid Res 42 (4): 521–527. PMID 11290823.
  31. ↑ Azzi A, Stocker A; Stocker (2000). "Vitamin E: non-antioxidant roles". Prog Lipid Res 39 (3): 231–255. doi:10.1016/S0163-7827(00)00006-0. PMID 10799717.
  32. ↑ 32.0 32.1 Villacorta L, Graça-Souza AV, Ricciarelli R, Zingg JM, Azzi A; Graça-Souza; Ricciarelli; Zingg; Azzi (2003). "α-Tocopherol induces expression of connective tissue growth factor and antagonizes tumor necrosis factor-α-mediated downregulation in human smooth muscle cells". Circ. Res. 92 (1): 104–110. doi:10.1161/01.RES.0000049103.38175.1B. PMID 12522127.
  33. ↑ Muller DP (2010). "Vitamin E and neurological function. Review". Mol. Nutr. Food Res 54 (5): 710–718. doi:10.1002/mnfr.200900460. PMID 20183831.
  34. ↑ Dowd P, Zheng ZB; Zheng (1995). "On the mechanism of the anticlotting action of vitamin E quinone". Proc Natl Acad Sci U S A. 92 (18): 8171–8175. Bibcode:1995PNAS...92.8171D. doi:10.1073/pnas.92.18.8171. PMC 41118. PMID 7667263.
  35. ↑ Brigelius-Flohé R, Davies KJ; Davies (2007). "Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food? Comments on the two accompanying papers: "Molecular mechanism of alpha-tocopherol action" by A. Azzi and "Vitamin E, antioxidant and nothing more" by M. Traber and J. Atkinson". Free radical biology & medicine 43 (1): 2–3. doi:10.1016/j.freeradbiomed.2007.05.016. PMID 17561087.
  36. ↑ Atkinson J, Epand RF, Epand RM; Epand; Epand (2008). "Tocopherols and tocotrienols in membranes: a critical review". Free radical biology & medicine 44 (5): 739–64. doi:10.1016/j.freeradbiomed.2007.11.010. PMID 18160049.
  37. ↑ 37.0 37.1 Whitney, Ellie; Sharon Rady Rolfes (2011). Peggy Williams, ed. Understanding Nutrition (Twelfth ed.). California: Wadsworth, Cengage Learning. ISBN 0-538-73465-5.
  38. ↑ Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Glynn RJ, Gaziano JM; Buring; Christen; Kurth; Belanger; MacFadyen; Bubes; Manson; Glynn; Gaziano (2008). "Vitamins E and C in the Prevention of Cardiovascular Disease in Men: The Physicians' Health Study II Randomized Trial". JAMA: the Journal of the American Medical Association 300 (18): 2123–33. doi:10.1001/jama.2008.600. PMC 2586922. PMID 18997197.
  39. ↑ 39.0 39.1 39.2 39.3 39.4 Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press, 2000.
  40. ↑ 40.0 40.1 40.2 40.3 40.4 Kowdley KV, Mason JB, Meydani SN, Cornwall S, Grand RJ; Mason; Meydani; Cornwall; Grand (1992). "Vitamin E deficiency and impaired cellular immunity related to intestinal fat malabsorption". Gastroenterology 102 (6): 2139–42. PMID 1587435.
  41. ↑ Haber, David (2006). Health promotion and aging: practical applications for health professionals (4th ed.). New York, NY: Springer Pub. p. 280. ISBN 978-0-8261-8463-4.
  42. ↑ 42.0 42.1 Abner EL, Schmitt FA, Mendiondo MS, Marcum JL, Kryscio RJ; Schmitt; Mendiondo; Marcum; Kryscio (July 2011). "Vitamin E and all-cause mortality: a meta-analysis". Current aging science 4 (2): 158–70. doi:10.2174/1874609811104020158. PMC 4030744. PMID 21235492.
  43. ↑ Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E; Pastor-Barriuso; Dalal; Riemersma; Appel; Guallar (2005). "Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality". Annals of internal medicine 142 (1): 37–46. doi:10.7326/0003-4819-142-1-200501040-00110. PMID 15537682.
  44. ↑ Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C; Nikolova; Gluud; Simonetti; Gluud (16 April 2008). Bjelakovic, Goran, ed. "Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases". Cochrane database of systematic reviews (Online) (2): CD007176. doi:10.1002/14651858.CD007176. PMID 18425980.
  45. ↑ Bin Q, Hu X, Cao Y, Gao F; Hu; Cao; Gao (April 2011). "The role of vitamin E (tocopherol) supplementation in the prevention of stroke. A meta-analysis of 13 randomized controlled trials". Thrombosis and haemostasis 105 (4): 579–85. doi:10.1160/TH10-11-0729. PMID 21264448.
  46. ↑ Haederle, Michael. "Vitamin E Supplements Raise Risk of Prostate Cancer". Health Discovery. AARP. Retrieved 11 November 2011.
  47. ↑ Olson JH, Erie JC, Bakri SJ; Erie; Bakri (May 2011). "Nutritional supplementation and age-related macular degeneration". Seminars in ophthalmology 26 (3): 131–6. doi:10.3109/08820538.2011.577131. PMID 21609225.
  48. ↑ Mathew MC, Ervin AM, Tao J, Davis RM; Ervin; Tao; Davis (2012). "Routine Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract". Cochrane Database Syst Rev 6: CD004567. doi:10.1002/14651858.CD004567.pub2. PMID 22696344.
  49. ↑ "Wolfram Alpha". http://www.wolframalpha.com.
  50. ↑ Simopoulos AP, Norman HA, Gillaspy JE, Duke JA. Common purslane: a source of omega-3 fatty acids and antioxidants. J Am Coll Nutr. 1992;11(4):374-82.
  51. ↑ "09038, Avocados, raw, California". National Nutrient Database for Standard Reference, Release 26. United States Department of Agriculture, Agricultural Research Service. Retrieved 14 August 2014.
  52. ↑ http://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=323&nutrient2=341&nutrient3=342&subset=1&fg=4&sort=c&measureby=g USDA List for Vitamin E in Vegetable Oils
  53. ↑ Institute of Medicine. Food and Nutrition Board. (2000). Dietary Reference Intakes: Applications in Dietary Assessment. Washington, DC: National Academy Press. p. 289. OCLC 45618946.
  54. ↑ Evans HM, Bishop KS; Bishop (1922). "On the existence of a hitherto unrecognized dietary factor essential for reproduction". Science 56 (1458): 650–651. Bibcode:1922Sci....56..650E. doi:10.1126/science.56.1458.650. JSTOR 1647181. PMID 17838496.
  55. ↑ Oakes, Elizabeth H. (2007). "Emerson, Gladys Anderson". Encyclopedia of World Scientists. p. 211. ISBN 1438118821{{inconsistent citations}}
  56. ↑ Subcommittee on Vitamin Tolerance, Committee on Animal Nutrition, National Research Council (1987). "Vitamin E, in Vitamin Tolerance of Animals". National Academy of Sciences. Retrieved 22 December 2013.
  57. ↑ Shute, W. E.; Shute, E. V.; et al., Alpha Tocopherol (Vitamin E) in Cardiovascular Disease. Toronto, Ontario, Canada: Ryerson Press, 1945
  58. ↑ Vogelsang A, Shute EV; Shute (June 1946). "Effect of vitamin E in coronary heart disease". Nature 157 (3997): 772. Bibcode:1946Natur.157..772V. doi:10.1038/157772b0. PMID 21064771.
  59. ↑ Shute EV, Vogelsang AB, Skelton FB, Shute WE; Vogelsang (January 1948). "The influence of vitamin E on vascular disease". Surg Gynecol Obstet 86 (1): 1–8. PMID 18920873.
  60. ↑ Skelton F, Shute E, Skinner HG, Waud RA; Shute; Skinner; Waud (1946). "Antipurpuric Action of A-Tocopherol (Vitamin E)". Science 103 (2687): 762. doi:10.1126/science.103.2687.762-b. PMID 17836459.
  61. ↑ György P, Rose CS; Rose (1948). "Effect of dietary factors on early mortality and hemoglobinuria in rats following administration of alloxan". Science 108 (2817): 716–718. Bibcode:1948Sci...108..716G. doi:10.1126/science.108.2817.716. PMID 17752961.
  62. ↑ Gerloczy F (1949). "Clinical and pathological role of d, 1-alpha tocopherol in premature infants; studies on the treatment of scleroedema". Ann Paediatr 173 (3): 171–86. PMID 18140084.
  63. ↑ Brion LP, Bell EF, Raghuveer TS; Bell; Raghuveer (2003). Brion, Luc P, ed. "Vitamin E supplementation for prevention of morbidity and mortality in preterm infants". Cochrane Database Syst Rev (4): CD003665. doi:10.1002/14651858.CD003665. PMID 14583988. These observations explain why even a small dose of 5 mg of dl-alpha-tocopheryl acetate provided enterally has proven to be more efficient than larger intramuscular doses (30 mg) in treating scleredema (Gerlóczy 1949)
  64. ↑ American Heart Association, 2015
  65. ↑ Maruyama, K; Iso, H (2014). Overview of the Role of Antioxidant Vitamins as Protection Against Cardiovascular Disease: Implications of Aging. Available from: Aging: Oxidative Stress and Dietary Antioxidants (1 ed.). New York: Elsevier Inc. p. Chapter 21.
  66. ↑ 66.0 66.1 Simon, E; Gariepy, J; Cogny, A; Moatti, A; Simon, A (2001). "Erythrocyte, but not plasma, vitamin E concentration is associated with carotid intima–media thickening in asymptomatic men at risk for cardiovascular disease.". Atherosclerosis.
  67. ↑ Asplund, K (2002). "Antioxidant vitamins in the prevention of cardiovascular disease: a systematic review.". Journal of Internal Medicine.
  68. ↑ Rimm, E.B; Stampfer, M.J; Ascherio, A (1993). "Vitamin E consumption and the risk of coronary heart disease in men". New England Journal of Medicine.
  69. ↑ Eidelman, R.S; Hollar, D; Hebert, P.R; Lamas, G.A; Hennekens, C.H (2004). "Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease". . Archives of Internal Medicine,.

Further reading

External links