A fresh look at Vitamin E -What you need to know about Isomers and Synergists

A fresh look at Vitamin E -What you need to know about Isomers and Synergists

InterClinical eNews November 2019, Issue 98

Vitamin E is an essential fat-soluble vitamin first discovered in 1922. It is an important antioxidant involved in cellular protection from free radical damage, immune regulation, endothelial cellular integrity, blood viscosity maintenance and wound healing.

 In this issue we take a look at the eight isoforms discovered so far, how vitamin E needs selenium and glutathione to provide antioxidant support, its gene interactions, its properties and why some studies yield equivocal results.

Vitamin E Isoforms
Vitamin E includes eight isoforms comprising alpha, beta, gamma and delta tocopherols and alpha, beta, gamma and delta tocotrienols. All forms of vitamin E are absorbed equally in humans via the duodenum however, alpha tocopherol is taken up preferentially by the liver via the α tocopherol transferase protein, hence it becomes the major isoform in the blood stream. The reason for this preferential treatment is because alpha tocopherol (but not other forms of vitamin E) is essential and a severe deficiency causes the life-threatening condition, Ataxia with Vitamin E Deficiency (AVED). (1)

Several of the tocotrienols have been shown to possess unique biological properties, such as being potent antioxidants. The known properties of the eight vitamin E isoforms are outlined in Table 1. below.

Vitamin E and Immune Modulation
Vitamin E has many immune modulating properties. Cumulative experimental evidence has demonstrated that it can increase natural killer cell activity, improve humoral and cell-mediated immunity and increase interleukin IL-2 and IL-4 production. Further it increases phagocytosis and chemotaxis within neutrophils whilst down regulating TNFα, super oxide formation and neutrophil adherence. (4)

Specific Vitamin E Needs – Gene Variants
Gene studies are beginning to highlight subgroups of the population with specific vitamin E needs. Notably the serum protein haptoglobin gene variant Hp 2-2 in diabetics, is associated with a lowered risk of developing cardiovascular disease when supplementing with vitamin E, and those with the ApoE polymorphism may also benefit from taking extra vitamin E to reduce inflammation in late stage AD. (3)

As more and more gene variant data become available higher doses may become more commonly prescribed for those who require extra of vitamin E due to their particular gene polymorphism(s). (4)

Dosage of Vitamin E
Longitudinal studies show vitamin E supplementation works best over the longer term (i.e. months and years rather than shorter periods of supplementation) and at doses of no more than 400 IU per day.  Best results appear to be achieved by supplementing with a mixture of all eight isoforms i.e. both tocopherols and tocotrienols rather than just alpha tocopherol. (4)

Selenium and Glutathione Antioxidant Activity
Among its many functions, selenium is required for the formation of the glutathione peroxidase family of antioxidants which facilitate the reduction of fatty acid hydroperoxides; rendering them harmless. Selenium is also needed by glutathione for the formation of phospholipid hydroperoxide glutathione peroxidase (PHGPH). PHGPH reduces all hydroperoxides derived from phospholipids, cholesterol and cholesterol esters, thereby protecting precious biological membranes from peroxidative damage and detoxifying cholesterol hydroperoxides within cells. (5)

In experimental evidence a significant correlation has been found between selenium intake and increases in glutathione peroxidase levels in participants with lowered levels, thus indicating improved free radical scavenging status. (6,7) Selenium is also directly involved in cell membrane and DNA integrity as well as playing an important role in thyroid health. Additionally, a recent systematic review found selenium has significant triglyceride and total cholesterol-lowering properties. (5,6)

Selenium and Vitamin E Work Cooperatively
The importance of vitamin E and selenium for quenching peroxide oxidants is demonstrated in an animal study where animals fed a diet low in both vitamin E and selenium showed the lowest levels of reduced glutathione and glutathione peroxidase compared to animals fed a diet deficient in either vitamin E or selenium only. This finding suggests that dual deficiencies of vitamin E and selenium cause a failure to quench and degrade hydrogen peroxide free radicals, resulting in oxidative damage and antioxidant system impairment. In another preclinical trial selenium was found to work synergistically with vitamin E to provide significant antioxidant support in iron-overload by reducing iron levels. (8,9,10)Glutathione and Vitamin E Work Synergistically

The interplay of glutathione and vitamin E is demonstrated in liver cells where together they provided hepatocellular protection from oxidative damage and have also been shown in other studies to:

  • Provide protection against oxidation    
  • Provide a structural function in sperm maturity    
  • Regulate ferroptosis  (programmed cell death dependent on iron) 
  • Induce apoptosis in malignant cells    
  • Play a role in viral immunity    
  • Help prevent motor neuron degeneration
  • Modify the toxicity of silver and mercury in tissues via free radical quenching
  • Enhance antibody formation.

(Ref: 10 – 12)

Interstudy Variability in Vitamin E Experiments
Reviewers are often frustrated with inconsistent study outcomes in vitamin E trials. A number of probable reasons for interstudy variability are outlined in Table Two below.

 Vitamin E, selenium and glutathione work together in a coordinated and concerted manner to provide significant cellular protection from free radical oxidative damage. Individually, these nutrients also provide a range of important health benefits affording this combination of nutrients a diverse range of uses.

InterClinical Comment
For best results the dosage of vitamin E should be considered carefully giving due regard to biochemical individuality, immune status and the type of condition being treated. Research shows that it is preferable to use a natural, mixed isoform supplement and noting that benefits tend to accrue over the longer term.


  1. Azzi A. Tocopherols, tocotrienols and tocomonoenols: Many similar molecules but only one vitamin E. Redox biology. 2019:101259.
  2. Chan JM, Darke AK, Penney KL, Tangen CM, Goodman PJ, Lee GS, Sun T, Peisch S, Tinianow AM, Rae JM, Klein EA. Selenium-or Vitamin E–Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT. Cancer Epidemiology and Prevention Biomarkers. 2016;25(7):1050-8.
  3. Shahar S, Lee LK, Rajab N, Lim CL, Harun NA, Noh MF, Mian-Then S, Jamal R. Association between vitamin A, vitamin E and apolipoprotein E status with mild cognitive impairment among elderly people in low-cost residential areas. Nutritional neuroscience. 2013;16(1):6-12.
  4. Mocchegiani E, Costarelli L, Giacconi R, Malavolta M, Basso A, Piacenza F, Ostan R, Cevenini E, Gonos ES, Franceschi C, Monti D. Vitamin E–gene interactions in aging and inflammatory age-related diseases: Implications for treatment. A systematic review. Ageing research reviews. 2014; 14:81-101.
  5. Maiorino M, Thomas JP, Girotti AW, Ursini F. Reactivity of phospholipid hydroperoxide glutathione peroxidase with membrane and lipoprotein lipid hydroperoxides. Free radical research communications. 1991;12(1):131-5.
  6. Sochi K, Kochanowicz J, Karpińska E, Soroczyńska J, Jakoniuk M, Mariak Z, Borawska MH. Dietary habits and selenium, glutathione peroxidase and total antioxidant status in the serum of patients with relapsing-remitting multiple sclerosis. Nutrition journal. 2014;13(1):62.
  7. Sedighi O, Zargari M, Varshi G. Effect of selenium supplementation on glutathione peroxidase enzyme activity in patients with chronic kidney disease: A randomized clinical trial. Nephro-urology monthly. 2014;6(3).
  8. Avanzo JL, de Mendonça Jr CX, Pugine SM, de Cerqueira Cesar M. Effect of vitamin E and selenium on resistance to oxidative stress in chicken superficial pectoralis muscle. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 2001 Jun 1;129(2):163-73.
  9. Bartfay WJ, Hou D, Brittenham GM, Bartfay E, Sole MJ, Lehotay D, Liu PP. The synergistic effects of vitamin E and selenium in iron-overloaded mouse hearts. The Canadian journal of cardiology. 1998 Jul;14(7):937-41.
  10. Carlson BA, Tobe R, Yefremova E, Tsuji PA, Hoffmann VJ, Schweizer U, Gladyshev VN, Hatfield DL, Conrad M. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox biology. 2016; 9:22-31
  11. Ganther HE. Interactions of vitamin E and selenium with Mercury and silver. Annals of the New York Academy of Sciences. 198;355(1):212-26.
  12. Watts, DL. The nutritional relationships of selenium. JOM. 1994;9;111-17
  13. Qureshi AA, Khan DA, Silswal N, Saleem S, Qureshi N. Evaluation of pharmacokinetics, and bioavailability of higher doses of tocotrienols in healthy fed humans. Journal of clinical & experimental cardiology. 2016;7(4).

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