Healthy Characteristics of Vitamin E
Food and beverage developers recognize the unique health potentials of all forms of vitamin E
Vitamin E is found in abundance in vegetable oils, as plants are the only species capable of producing this vitamin. In the diet, nuts and whole grains and their oils are the predominant sources. Vitamin E was assumed to be so abundant in the diet, its use in the food and beverage industry (in tocopherol form)was relegated to the status of a common antioxidant preservative. Most of the time, it wasn’t even labeled as a vitamin, but as “tocopherols.”
By the 1980s, however, it was determined that, due to a sharp decline in intake of vitamin E-rich foods, many Americans were coming up deficient. The lipid-soluble vitamin is, however, critical for a number of functions throughout the body, from maintaining cell integrity to involvement in thousands of enzymatic activities that control systemic and neurological functions to gene expression, fertility (for both men and women), eye health, bone health and immunity.
Vitamin E is actually composed of two structurally similar compounds, tocopherols and tocotrienols. Each compound is comprised of four components, each of which has distinct molecular structures. Each component is referred to as an isomer (or vitamer) of vitamin E. Each isomer of vitamin E has unique properties, health benefits, characteristics, and attributes, with important applications when formulating food or beverage products.
The definition for vitamin E has caused decades of misunderstandings. Identifying and recognizing the benefits of various components of what vitamin E truly is can lead to innovative food and beverage product formulations with significant potential to contribute to human health.
There are eight known major isomers of vitamin E: four tocopherols alpha (α), beta (β), gamma (γ), and delta (δ)—and four tocotrienols (α, β, γ, δ). Each designation is determined by the isomer’s position and degree of methylation. But, until relatively recently, vitamin E was synonymous with just its tocopherol form.
The reason for this misconception is that, for many decades, it was erroneously thought that alpha-tocopherol was the most biologically active isomer of vitamin E. This partially explains why the RDA for vitamin E only refers to alpha-tocopherol, and why the IU amount shown on a dietary supplement label for vitamin E also only refers to alpha-tocopherol. For this reason, it has seemingly been accepted that—unless specifically labeled otherwise—vitamin E is alpha-tocopherol.
Tocopherols are differentiated from tocotrienols in that they possess saturated phytyl side chains, whereas tocotrienols, by the degree of unsaturation at the side chains that have three double bonds.
The double bonds are important in terms of cardiovascular health: When tocotrienols are consumed in sufficient amounts, their double bonds have the ability to reduce the activity of HMG-CoA reductase, the enzyme that controls cholesterol synthesis. This enzyme just happens to be the one targeted by statin drugs that lower cholesterol in the blood by reducing its production of cholesterol in the liver.
Mother Knows Best
Due to the clean-label trend, attention has been drawn of late to differences in the composition of “natural” vs. “synthetic” vitamin E, and what isomers they do or do not contain.
Natural vitamin E’s active form is either d-alpha tocopherol or the more stabilized forms, d-alpha tocopheryl acid succinate and d-alpha-tocopheryl acetate.
Synthetic vitamin E, dl-alpha-tocopherol, by comparison, is a mixture of eight unusual isomers of alpha-tocopherol, of which only one is the nature-identical: d-alpha-tocopherol. As such, synthetic dl-alpha-tocopherol contains only 12.5% d-alpha-tocopherol.
The remaining 87.5%, termed “alpha-tocopherol,” is not found in nature. This is one reason food processors and supplement companies have significantly reduced the use of synthetic vitamin E in formulations, despite its lower cost. Today, synthetic vitamin E tocopherols are primarily used in animal feed.
Tocotrienols have been given increased attention, as they have demonstrated significant physiological and biological properties. Some scientists report these properties might mitigate or protect against a wide range of diseases. These properties include antioxidant and anti-inflammatory bioactivity; anti-cancer and anti-tumor activity; lipid and cholesterol-lowering effects; as well as cardioprotection, neuroprotection, and radioprotection.
As the range of health benefits reported for tocotrienols increase in numbers, formulators have given increased attention to identifying sources of tocotrienol ingredients, such as those derived from annatto seed, coconut, barley, or commercially extracted palm oil and rice bran.
The discovery of tocotrienols was first reported in 1964, followed two years later by the isolation of the first of four tocotrienol isomers. It was not until the late 1980s that their prodigious health benefits began to emerge.
Recent studies measuring the bioactivity of different isomers of vitamin E have demonstrated compelling evidence that tocotrienols can play an important role in disease prevention; and over-emphasis on using tocopherols could be interfering with the tocotrienol’s health benefits.
This is not to belittle or disregard the demonstrated benefits of tocopherols, such as inhibiting cell proliferation, platelet aggregation, or monocyte adhesion, that, among many benefits, have been the subject of thousands of studies. Also, it’s important to remember the major isomer found in most consumed foods is gamma-tocopherol —rather than alpha-tocopherol—as the primary vitamin E isomer.
It is now evident that alpha-tocopherol can interfere with the cholesterol-lowering action of delta- and gamma-tocotrienols, the two most bioactive tocotrienols.
This discovery is not insignificant, as none of the other six isomers of vitamin E have been shown able to suppress the production of the key protein that controls cholesterol synthesis in the liver, at the molecular level, as do these two tocotrienols.
This “sibling rivalry” can be explained by the structural differences between the two forms. Tocopherols have longer structural tails, without double bonds. This prevents them from reducing overproduction of cholesterol, as compared to the tocotrienols, owing to their shorter double-bonded tails.
Human and animal studies demonstrate that multiple forms and amounts of tocotrienols are well-tolerated. A number of tocotrienol-based ingredients that have achieved GRAS status for specified intended uses are available to formulators. Three patented tocotrienol ingredients have achieved GRAS status in 2009.
The first of these GRAS ingredients is a tocotrienol-rich fraction derived from palm oil. In 2010 another palm oil-derived tocotrienol was determined to be GRAS. And, in the same year, a source of tocotrienols derived from annatto seed achieved the same status. However, the composition of each of these GRAS ingredients is different, as each contains varying amounts of tocotrienols, some with or without tocopherols.
An annatto-derived tocotrienol ingredient contains a minimum of 70% tocotrienols: approximately 10% fatty acids and 20% annatto oleoresins. It contains no tocopherols. By comparison, the palm tocotrienol-rich fraction consists of a mixture of all four tocotrienol isomers, and an alpha-tocopherol content of 20-30%, with the balance consisting of tocopherols.
Interestingly, when it comes to tocopherols and tocotrienols, there’s evidence that in formulating for health, it can sometimes be a “one or the other proposition.” The discovery that the health benefits of tocotrienols might be hindered by alpha-tocopherol wasn’t reported until the 1990s. One way alpha-tocopherol interferes with tocotrienol bioactivity simply is by inhibiting tocotrienol absorption.
Interference by closely related nutrients is not a new concept.
Beta-carotene, for example, has been shown to interfere with the absorption of lutein, a fellow carotenoid, and vice versa.
In 2012, hundreds of studies were discussed at the Second International Conference on Tocotrienols, co-sponsored by the American Oil Chemists Society (AOCS). [Editor’s note: This conference was a predecessor of the highly anticipated third international meeting planned for 2017. For more information, visit www.aocs.org.]
The conference clarified the order of the potency of the tocotrienol isomers (T3) in terms of their potential beneficial bioactivities, as follows: δ-T3 → γ-T3 → α-T3 → alpha-tocopherol. However, for immune enhancement, alpha-tocotrienol is the most potent, followed by gamma-tocotrienol, with delta- the least. This suggests that increasing consumption of all tocotrienols—especially delta and gamma—is desirable. In formulating a functional food or beverage, knowing the properties of specific tocotrienols is critical to creating a product with real potential benefits.
For example, delta- and gamma–tocotrienols have been shown to improve the heart’s metabolic and vascular integrity by having an inhibiting effect on the production of a key enzyme linked to hypercholesterolemia. The combination of the two tocotrienol isomers do this by accumulating in endothelial cells at a level at least 30 times greater than alpha-tocopherol.
In addition, by modulating at least a 20-fold larger number of genes affecting endothelial cells that contribute to keeping arteries healthy, the two tocotrienol isomers prevent cell adhesion to endothelial cells that can attenuate the progression of atherosclerosis.
Other cardio-protective effects include inhibition of platelet aggregation and monocyte adhesion; and reduced oxidation of low-density atherogenic apolipoprotein B and lipoprotein plasma levels.
Gamma-tocotrienol also has been shown to exhibit potent cardio-protective attributes. Alpha-tocotrienol demonstrates a capacity for preventing stroke-induced injuries in the brain. Collectively, the cardio protective and anti-angiogenic properties of the tocotrienols have the potential to mitigate the progression of cardiovascular disease.
Beginning in 1989, the first in vivo evidence of tocotrienol’s anti-cancer properties was reported using tocotrienols derived from palm oil. Two years later, tocotrienol’s chemo-preventive properties were shown against chemically-induced mammary and hepatic tumors. Over the following two decades, numerous animal studies found evidence of suppression of tumor growth using oral doses of tocotrienols against a wide range of cancers.
How tocotrienols are able to fight against the development of cancer has been the subject of studies worldwide. One mechanism of action is by inducing cancer cell death (apoptosis). Among tocotrienols, delta-tocotrienol has been shown to be the most potent against breast cancer cells, whereas gamma-tocotrienol the most potent against prostate cancer cells.
Another front in tocotrienols’ ability to help counter cancer is through inhibition of angiogenesis—the uncontrolled growth of abnormal blood vessels in the tumor. This is a critical step in tumor growth, without which a tumor cannot expand beyond about a millimeter in diameter.
In vivo animal studies have demonstrated inhibition of tumor growth against breast, prostate, hepatic, and skin cancers.
More recent studies have demonstrated success in significantly diminishing cancerous tissues in animal experiments. This is believed to be due to the ability of tocotrienols to target multiple genes known to trigger cancer growth. Delta-tocotrienol has been shown to be the most potent in inhibiting breast cancer cells, whereas gamma-tocotrienol is the most potent against prostate cancer cells.
Of promising interest is the NIH-funded cancer study led by Mokenge Malafa, MD, and Kazim Husain, PhD, at the Monfitt Cancer Center. In 2012, they reported observing tumor regression in patients with late-stage pancreatic cancer given daily oral doses of annatto seed-derived gamma-tocotrienol and delta-tocotrienol.
How these tocotrienols initiate anti-tumor effects is unknown. Whereas tocopherols lack an isoprenoid side chain in their chemical structure, tocotrienols have this side chain—which some studies report may be a critical attribute that gives them potent anticancer bioactivity.
Most tocopherol food sources are far richer in gamma-tocopherol than in alpha-tocopherol, particularly oils derived from soybean, corn, cottonseed, and sesame seed.
These oils contain between three to five times as much gamma- as alpha-tocopherol, as do nuts (peanuts, pecans, and walnuts). Widespread use of these plant products represents approximately 80% of the gamma-tocopherol vitamin E consumed in the typical US diet.
In contrast, tocotrienols are far less prevalent in the plant world than tocopherols. Oat, rye, and barley cereals contain small amounts of tocotrienols, with alpha-tocotrienol being the predominant form in oat and barley.
Flaking or steaming of dehulled oat groats has been shown to result in moderate losses of the tocotrienols (but not the tocopherols). Beta-tocotrienol is the major isomer in hulled and dehulled wheats.
Effective amounts of tocotrienol vitamin E can be as little as 140mg/day, with an average effective dose considered 200-400mg/day. Test subjects have tolerated well over 3g/day without negative side effects.
When it comes to degree of bioactivity of tocotrienols, there can be significant differences in terms of potency. Alpha- and beta-tocotrienols have been found to be the least active forms overall, while delta- and gamma-tocotrienols are the most active.
The extract from the seed of the annatto tree (Bixa orellana), a tropical plant, contains 70% tocotrienols, of which 90% are delta-tocotrienol and 10% gamma-tocotrienol, and is tocopherol-free.
Lower levels of delta- and gamma-tocotrienols are found in rice oil, palm oil (Elaeis guineensis), and rice bran oil. They contain the whole complement of tocotrienols, as well as between 25-50% of tocopherols.
Since vitamin E is a fat-soluble vitamin, consumers should be encouraged to consume it with other lipid-soluble nutrients, such as omega-3s, carotenoids, or CoQ10. It also helps to include them with meals that include some fat. This allows the digestive system to better solubilize and emulsify the nutrients without the use of non-nutrient chemical emulsifiers.
Although all of the isomers of vitamin E display antioxidant activity, recent studies of tocotrienols have shown that they are significantly more potent than tocopherols in inhibiting tumor viability and cell growth, and demonstrating anti-cancer bioactivity independent of their free-radical scavenging properties. Their cardiovascular disease-preventing properties are particularly noteworthy. The amount of tocotrienols currently consumed in Western diets is, at best, at trace levels.
Since so few plants have appreciable amounts of these vitamin E isomers, it can prove beneficial for food and beverage manufacturers to consider incorporating tocotrienols into a variety of products, including cereals, soup mixes, fat spreads, and sports/protein drinks, as well as in dietary supplements.
Vitamin E Critical During the First 1,000 Days
Condensed from a report by David Stauth, Linus Pauling Institute
Only a tiny fraction of Americans consume enough dietary vitamin E to meet the estimated average requirement; in fact, the diet of most people is insufficient, according to Maret Traber, PhD, professor in the College of Public Health and Human Sciences at Oregon State University, principal investigator with the Linus Pauling Institute and a national expert on vitamin E.
Further, according to an analysis published by the Linus Pauling Institute, adequate levels of this essential micronutrient are especially critical for the very young, the elderly, and women who are or may become pregnant.
“Many people believe that vitamin E deficiency never happens,” Traber said. “That isn’t true. It happens with an alarming frequency, both in the US and around the world. But some of the results of inadequate intake are less obvious, such as its impact on the nervous system and brain development, or general resistance to infection.”
In a review of multiple studies, published in Advances in Nutrition, Traber outlined some of the recent findings about vitamin E. Among the most important are the significance of vitamin E during fetal development and in the first years of life; the correlation between adequate intake and dementia later in life; and the difficulty of evaluating vitamin E adequacy through measurement of blood levels alone. Inadequate vitamin E is associated with: increased infection, anemia, stunting of growth, and poor outcomes during pregnancy for both the infant and mother. Overt deficiency, especially in children, can cause neurological disorders, muscle deterioration, and even cardiomyopathy.
Studies with experimental animals indicate that vitamin E is critically important to the early development of the nervous system in embryos, in part because it protects the function of omega-3 fatty acids, especially DHA, which is important for brain health. The most sensitive organs include the head, eye, and brain. One study showed higher vitamin E concentrations at birth were associated with improved cognitive function in two-year-old children.
Findings about diseases that are increasing in the developed world, such as non-alcoholic fatty liver disease and diabetes, suggest obesity does not necessarily reflect adequate micronutrient intake. A report in elderly humans showed that a lifelong dietary pattern that resulted in higher levels of vitamins B,C, D, and E were associated with a larger brain size and higher cognitive function.
Vitamin E protects critical fatty acids, such as DHA, throughout life. One study showed people in the top quartile of DHA concentrations had a 47% reduction in the risk of developing all-cause dementia.
“It’s important all of your life, but the most compelling evidence about vitamin E is about a 1,000-day window that begins at conception,” Traber said. “Vitamin E is critical to neurologic and brain development that can only happen during that period. It’s not something you can make up for later.”
Traber recommends a supplement for all people with at least the estimated average requirement of vitamin E, but that it’s particularly important for all children through about age two; for women who are pregnant, nursing or may become pregnant; and for the elderly.
The Linus Pauling Institute at OSU is a world leader in the study of micronutrients and their role in promoting optimum health or preventing and treating disease. Find out more at www.lpi.oregonstate.edu.
What’s In a Name?
Major reference works, such as the Merck Index, had erroneously defined tocopherol as being synonymous with vitamin E for years. In 2001, the Index changed how this vitamin was defined. Nevertheless, misappropriation of the term vitamin E continues to this day (particularly by the media) when reporting on the outcome of studies involving alpha-tocopherol.
Unfortunately, even some industry publications misuse or misunderstand the terminology.
Armed with knowledge about the multiple other forms of vitamin E, when referring to a study that administers one isomer, such as alpha-tocopherol, it’s erroneous to refer to it as “vitamin E.” This is because alpha-tocopherol is just one of the eight isomers that constitutes what vitamin E actually is.
By the same token, when considering labeling, food, beverage, and supplemental product manufacturers should also be more specific in presenting vitamin E nomenclature.