Introduction

Vitamin E consists of a family of eight different compounds, four tocopherols and four tocotrienols (designated as alpha, beta, gamma and delta). Tocopherols and tocotrienols have similarities and differences in their molecules. The tocopherols consist of a head (chroman ring) and a tail (phytyl). The chroman ring carries the active antioxidant group. Each tocotrienol has an identical chroman ring as the corresponding tocopherol. Tocotrienols differ from tocopherols on their tail; the tocotrienols have three unsaturated sites while tocopherols have none. Our food contains all eight compounds. In many countries, including the United States, the typical diet supplies higher levels of non alpha tocopherols, especially gamma-tocopherol. In the past vitamin E became synonymous with only alpha-tocopherol and, as a result, alpha-tocopherol is the most commonly form used in food fortification, supplements and, most important, in the human clinical trials.

Natural vs. synthetic. alpha-Tocopherol is available commercially in the naturally occurring and the synthetic forms. For most vitamins, the synthetic forms are identical to the natural and have identical function in the body. Not so for alpha-tocopherol. All molecules in the naturally occurring d-alpha-tocopherol are identical. In contrast, the synthetic dl-alpha-tocopherol is a mixture of eight different molecular entities known as stereoisomers. Of these eight, only one is identical to the natural form. The other seven do not exist in nature. The potency advantage of the natural d-alpha-tocopherol is officially recognized by the Food and Drug Administration (FDA), the World Health Organization (WHO) and the United States Pharmacopoeia (USP). The natural form was recognized as 36 percent more potent than the synthetic. Studies in humans using powerful new techniques confirmed that the natural d-alpha-tocopherol is twice as bioavailable than of the synthetic. Based on extensive research, the Food and Nutrition Board of the National Academy of Sciences recommended that the biopotency of the natural d-alpha-tocopherol is twice as that of the synthetic dl form.

The recent controversy. Human blood and tissue contain much more alpha-tocopherol than any of the other tocopherols and tocotrienols as results of a specific transfer mechanism. At the heart of this mechanism is the alpha-tocopherol transfer protein which recognizes the alpha-tocopherol and preferentially puts more of it in the blood. Conclusive evidence showed that supplementation with alpha-tocopherol, especially at high levels, causes depletion of gamma-tocopherol and probably of the other tocopherols in the blood and the tissues. The major significance of this depletion on the efficacy of vitamin E received increased attention following results of major human clinical studies such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the Heart Outcomes Prevention Evaluation (HOPE) Study and several metaanalyses. As a result the efficacy and even the safety of supplemental vitamin E as alpha-tocopherol were questioned. These results, coupled with increasing, research based, understanding of the role of the other tocopherols and the tocotrienols in nutrition and health, contributed to the emerging perspective on vitamin E.

Emerging research

Significant ongoing research shows that tocopherols and tocotrienols and probably their bioactive metabolites, exhibit individually and in combination, responses that are different that those of alpha-tocopherol. These responses, which include inflammation, cell signaling and gene expression, and tumor cell specific toxicity and apoptosis, support the emerging perspective that only the complete family of tocopherols and tocotrienols provides the full potential of vitamin E to produce nutritional and health benefits.

Below is a brief summary of significant findings on the role of gamma-tocopherol and the tocotrienols.

gamma-Tocopherol

The research team of Dr. Bruce Ames at Berkeley University reported that gamma-tocopherol is more effective than alpha in quenching nitrogen radicals which contribute to inflammation and chronic disease. gamma-Tocopherol but not alpha increased cNOS protein expression. gamma-Tocopherol and its major metabolite reduced synthesis of the inflammatory prostaglandin E2 (PGE2) in both lipopolysaccharide-stimulated macrophages and IL-1b-treated human epithelial cells. In contrast, alpha-tocopherol reduced slightly PGE2 formation in macrophages, but had no effect in epithelial cells. The corresponding metabolite of alpha-tocopherol was not active. Our research indicated that gamma-tocopherol, added to a semi-purified diet, was more effective than alpha-tocopherol in reducing ras-p21 oncogenes in the colonocyte of rats. Phase I clinical studies are evaluating the role of gamma-tocopherol on colon and prostate cancer.

The anti-inflammatory properties of gamma-tocopherol were evaluated further in a collaborative research by the University of North Carolina, Michigan State, Berkeley and Purdue Universities and funded by the National Institutes of Heath. They conducted studies with mice and humans and evaluated a number of inflammatory markers associates. The results showed that gamma-tocopherol reduced systemic oxidative stress and inhibited important inflammatory pathways associated with allergic rhinitis and asthma. These included eosinophil infiltration, pulmonary production of PGE2, leukotriene B4 receptor (LTB4) and cysteinyl leukotrienes, and nasal expression of interleukins IL-4, -5, -13 and Interferon-gamma (IFN-γ). The researchers suggested that their results support therapeutic efficacy of gamma-tocopherol to inhibit ozone exacerbation of allergic airway responses.

Tocotrienols

Radioprotection. Dr. Sree Kumar of the Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences and Martin Hauer-Jensen MD of the Winthrop P Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences reported that gamma-tocotrienol exhibits major protection to radiation exposure. It functions as an inhibitor of HMG-CoA reductase (the key enzyme in LDL cholesterol synthesis), which prevents the depletion of the nitric oxide synthase (NOS) cofactor BH4. Impaired function of NOS produces excessive free radicals which damage the tissue. Additional research showed that both gamma and delta tocotrienols reduce injury to bone marrow and hematopoietic system and stimulate hematopoiesis. These findings have major implications not only in protection to major radiation exposure to nuclear accident or attack but also in radiation therapy and wound healing.

Cancer. Several researcher groups reported effects of tocotrienols on mechanisms carcinogenesis. Significant effects, primarily of gamma and delta tocotrienols on breast, prostate, colon and pancreatic cancers included caspase dependent and independent apoptosis, angiogenesis, inflammation and signal transduction mechanisms. A human clinical study is evaluating the role of delta-tocotrienol in pancreatic cancer.

Neuroprotection. The research team of Dr. Chandan Sen of the Ohio State University Medical Center reported that alpha-tocotrienol inhibits glutamate-induced activation of phospholipase A2 which results in neuroprotection with major implications for neurodegenetative diseases and stroke. Dr. Sen is conducting a Phase I clinical trial on the human tissue distribution of orally supplemented natural vitamin e tocotrienol, which will provide data for additional clinical studies.

Cardiovascular. The function of gamma-tocopherol as an inhibitor of HMG-CoA reductase (the key enzyme in LDL cholesterol synthesis) and its relationship to the nitric oxide synthase (NOS) cofactor BH4 and inflammation support observations on cardiovascular benefits of tocotrienols. A Phase II Double Blind Placebo Controlled Study is currently evaluating the neuroprotective and anti-atherogenic effects of palm tocotrienol rich fraction

Wound healing, burn injury and surgical scars. The protective effects of tocotrienols on radiation injury and other mechanisms of action suggest benefits in wound healing, burn injury and surgical scars. A clinical study at Ohio State University is evaluating the efficacy of tocotrienols on the treatment of surgical scars.

Summary and Conclusions

The emerging research on the unique individual effects of tocopherols and tocotrienols, coupled with the strong evidence of synergistic effects and epidemiological and other data suggesting health benefits of vitamin E especially from diet indicate that:

1. The use of alpha-tocopherol and often the synthetic dl-form contributed to the absence of clinical benefit in major clinical studies by:
   1. Providing the form that may not be the most beneficial for the specific application.
   2. Causing the depletion of the other tocopherols and tocotrienols from the blood and the tissue thus causing an adverse imbalance and eliminating their benefits and synergies.
2. The proven synergistic effects of tocopherols and tocotrienols and their unique individual effects indicate that vitamin E supplements should contain the complete family of tocopherols plus tocotrienols. Additional tocotrienols and/or non-alpha tocopherols may be appropriate for people with special needs and at high risk for certain disease conditions.
3. The development of nutritional and health guidelines and products such as dietary supplements and health products specific for specific diseases or health conditions must consider all vitamin E homologs and bioactive metabolites, and their individual and combined effects in relation to their absorption, metabolism and tissue uptake.

Recommendations

The emerging scientific consensus and perspective on vitamin E indicates that only products that contain the complete vitamin E family – of tocopherols plus tocotrienols in their natural form provide the full spectrum of benefits.

Specially formulated products rich on the specific active homologs can play a significant role in health programs for major disease conditions such as neurodegenerative, immune / inflammatory, some cancers and cardiovascular.

The protection of gamma and delta-tocotrienols against radiation injury and associated mechanisms of actions and research, support benefits in skin heath, wound healing, burn injury and surgical cars. The antioxidant properties of tocopherols and tocotrienols, couples with the unique functions reviewed above suggest a major role in anti-aging programs.

A. C. Grace Company has 50+ years of history providing pure vitamin E products to the market and was the first company to introduce a high gamma-tocopherol mixed tocopherols (in 1962) when most companies were offering alpha-tocopherols only products. For more information visit the A. C. Grace Company website.