An Interview with Maret G. Traber, Ph.D.
Once upon a time, in this vast land of ours, it was not known that people needed a vital compound in food that would later be called “vitamin E.” Then, scientists discovered this life-enabling compound, determined it was dietary essential for humans and learned everything that needed to be known about it. And, everyone lived happily and healthily ever after. Wait a minute. That’s a fairy tale. That’s not what has happened at all.
The true story, unfortunately, reads quite differently. So, I have called upon vitamin E expert, Maret Traber, Ph.D., to review some important parts of the updated vitamin story in the next several columns. New research suggests that “vitamin E” can be both a vitamin and, at supranutritional levels, have other possible health effects beyond its role as a vitamin.
An expanded understanding of vitamin E and how it functions in the body requires a few adjustments to what was once believed by many before 2000. For use in planning nutritionally adequate diets, only one compound is now considered to be vitamin E and, according to the official 2000 DRI for Vitamin E by the Food and Nutrition Board of the Institute of Medicine, it is no longer correct to say vitamin E is a “family” of compounds (1). The science behind this change had been building for years, but it still was an adjustment for me, after 40-some years of research with vitamin E considering it to be a family of eight structurally similar compounds. Yes, there are similar compounds that can be classified as a “family,“ but only one of these compounds is now considered to be vitamin E in humans. However, some of the family of compounds formerly said to have vitamin E activity—such as tocotrienols—have definitive health benefits and they should be considered on their own merits independent of vitamin E.
We will also report on some disconcerting preliminary studies that suggest one tocopherol compound once thought to be a form of vitamin E may possibly, at high dietary levels, interfere with actual vitamin E and could be detrimental to health.
The ethical guideline for healthcare has long been Primum non nocere (first do no harm). Even the ancient Hippocratic Oath for physicians includes the promise “to abstain from doing harm.” Caution is prudent until adequate clinical research determines what is fact and what is just an irrelevant finding. Some readers probably won’t like the real story. Sorry, but please don’t kill the messengers. Just as people once had to adjust to the concept that the Earth is round and revolves around the sun and not vice versa, some old beliefs about vitamin E may need updating.
We don’t claim that all of the answers are known yet and we are only reporting the current consensus of the scientific community. The coming years will shed more light on the roles of vitamin E and vitamin E-like compounds. We not only want to keep you informed, but we also want to help keep you in the best of health. Oh, if we could only start the story over again with what is now known, it would be straightforward, noncontroversial and not confusing at all. In real life, however, we learn things bit by bit in an incomplete fashion.
The vitamin E story has twists and turns galore, but Dr. Traber and I will try to draw you a roadmap to help you traverse the current body of science.
Fortunately, several exciting developments will help clarify the health benefits of vitamin E. It was only 50 years ago (1966–1968) that vitamin E became accepted as essential for human life. Yet, we continue to have a dearth of knowledge about how vitamin E functions in the body and that has led to much confusion. A confounding factor is that the life-essential role of vitamin E as a nutrient is often confused with its clinical roles at supranutritional levels. A compound may have both nutritional functions and clinical functions. Studies suggest that vitamin E may have at least one essential nutritional role and several nonessential, but health-promoting, actions including gene interactions, cell signaling, inflammation control and nonspecific antioxidant redox interactions.
Many have learned the basics of vitamin E thanks to vitamin E expert, Dr. Traber. Among her many educational articles was our three-part conversation from November 1997 through January 1998 that discussed what vitamin E is and how it works (2–4). The publication of the 2000 Dietary Reference Intake (DRI) affected much of what was previously accepted about vitamin E, but the public seemed not to notice. A lot of material accepted as fact pre-2000 was discarded or changed by the 2000 DRI, but these incorrect concepts are often still being repeated. For those not familiar with the DRI publications, the DRIs refer to a set of at least four nutrient-based reference values. The development of DRIs expands on the periodic reports called Recommended Dietary Allowances, which have been published since 1941 by the National Academy of Sciences. The DRIs are determined by committees of experts in the field of each nutrient as part of a comprehensive effort undertaken by the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes (DRI Committee) of the Food and Nutrition Board, the Institute of Medicine, the National Academies, with the active involvement of Health Canada. Its authority can be traced back to a charter granted to the National Academy of Sciences in 1863. In other words, they are the consensus of experts and they are “official.” They are used by the U.S. Food and Drug Administration (FDA) for their guidance.
Dr. Traber and others have continued researching vitamin E and its modes of action and we now have a much better understanding of the vitamin that was once jokingly called “a vitamin in search for a disease” by its skeptics. Since the classical definition of a vitamin includes organic substances that cannot be made in the body, must be obtained in the diet and in their absence result in disease followed by death, skeptics naturally wanted to know which human disease resulted from a vitamin E deficiency.
The disease or health condition in animals that led to the discovery of vitamin E at the University of California, Berkeley, in 1922 by Herbert McLean Evans, M.D., and Katherine Scott Bishop, M.D., was sterility in laboratory rats. At first, they called this “anti-sterility factor” in the fat portion of laboratory rat diets, “vitamin X.” They soon changed the name to vitamin E. Over the years, we have learned that vitamin E is involved in several important, but non-essential, health functions beyond sterility.
When I was conducting research on the antioxidant roles of vitamin E and health in the 1960s, FDA was still issuing periodic statements that there was no need for vitamin E in humans. Vitamin E was not included in the Institute of Medicine’s Recommended Dietary Allowances until 1968. It has been interesting to see two nutrients used in my early research—selenium and vitamin E—become recognized as essential nutrients years later. My original interest in these two nutrients was piqued by the 1958 research of Klaus Schwarz, M.D., Ph.D., who thought the two nutrients might be working together as “Factor 3” in chickens. However, it was not for several decades that scientists, primarily Dr. Traber, began to uncover the specific roles of vitamin E in deadly human diseases.
Today, vitamin E research is ongoing regarding cardiovascular health and diabetes (5,826 publications), Alzheimer’s disease (413 publications), cancer (543 publications), age-related macular degeneration (AMD) (181 publications), asthma (162 publications), liver disease (247 publications) and more.
Before we discuss the exciting new research on vitamin E by Dr. Traber and others on brain health and neurological damage and metabolic conditions that impair vitamin E absorption and transport, it’s a good idea to review some of the basics. U.S. national surveys show that about 90% of Americans are not getting the officially recommended amount of vitamin E in their diets. However, before we can consider how much vitamin E we need nutritionally, we must know just what it does in the body. In this column, we will focus on the basic nutritional functions of vitamin E. In following columns, we will discuss how the Recommended Dietary Intake was determined and the exciting new research on vitamin E including Dr. Traber’s scientific “game-changing” discoveries. Those findings should help to clarify some of the confusion about its health benefits.
|Maret G. Traber, PhD.|
Maret G. Traber, Ph.D., is the Helen P. Rumbel Professor for micronutrient research in the Linus Pauling Institute and a professor in the nutrition program at the College of Public Health and Human Sciences, at Oregon State University. She received her Ph.D. in nutrition from the University of California, Berkeley, CA. She currently serves on the editorial boards of Free Radical Biology & Medicine and the Journal of Nutrition. Dr. Traber served on the National Academy of Sciences, Institute of Medicine, Panel on Dietary Antioxidants to develop the 2000 Dietary Requirements for vitamins C and E, selenium and carotenoids. She is considered to be one of the world’s leading experts on vitamin E. She pioneered the use of deuterium-labeled vitamin E for studies evaluating vitamin E status in humans. Her studies caused a paradigm shift in our understanding of the mechanisms regulating vitamin E availability in humans. Her work has provided the scientific basis for understanding the complex role of vitamin E in human health.
She has published over 190 peer-reviewed and 110 invited papers in highly regarded journals. She pioneered the methodologies for evaluating vitamin E status in humans and through this work, she identified key mechanisms for regulating vitamin E bioavailability in humans. In 2013, she received the Pfizer Consumer Healthcare Nutrition Sciences Award, presented by American Society for Nutrition and the DSM Nutritional Science Award 2013 on Fundamental Research in Human Nutrition. Current research projects include: vitamin E bioavailability and requirements in humans using advanced pharmacokinetic methodologies; assessment of the interactions of vitamin E and K; and the determination of the mechanisms of vitamin E function during embryogenesis using zebrafish.
Passwater: Dr. Traber, what is the general function of vitamin E?
Traber: Vitamin E does not have a known role as a cofactor, a nuclear receptor ligand or an essential component of any enzymatic system. Rather, vitamin E protects long-chain polyunsaturated fatty acids (PUFA) from lipid peroxidation. In other words, it keeps fat from going rancid. Vitamin E’s major function appears to be a fat-soluble, chain-breaking antioxidant that protects polyunsaturated fatty acids within membranes and lipoproteins. This means that vitamin E protects cell membranes and lipoproteins from oxidative damage due to oxygen radicals and other reactive oxygen species attack. Virtually all of the variation and scope of vitamin E’s biological activity can be seen and understood in light of the protection of polyunsaturated fatty acids and the membrane qualities (fluidity, phase separation and lipid domains) that polyunsaturated fatty acids bring about.
Passwater: Well, this means that vitamin E is important to every cell, tissue and system in the body! Healthy cell membranes are required for healthy cells, which are required for healthy tissues, which are required for good health. Cell membranes are more than just a “skin” for cells. Cell membranes contain receptors for various biochemicals, and they help transport nutrients into cells and transport waste products out of cells. If the PUFA that are part of the phospholipids (which form the bilayer cell membranes) are damaged, the cells won’t function. Benjamin Franklin once pointed out, “For the want of a nail, the shoe was lost. For the want of a shoe, the horse was lost. For the want of a horse, the rider was lost. For the want of a rider, the battle was lost. For the want of a battle, the kingdom was lost.”
Similarly, for the want of adequate vitamin E, many health functions can be lost.
Hundreds of compounds can break free-radical chains and could serve as membrane antioxidants, however it seems that the tocopherols best fit next to the PUFA in the bilayered cellular membranes. Yet, it would be rare to find a tocopherol other than alpha-tocopherol in the membranes.
Traber: Yes, there are plenty of dietary antioxidants, but only alpha-tocopherol is a vitamin. Despite the fact that many compounds, including the other members of the tocopherol family, are peroxyl radical scavengers, the fact remains that the human body prefers alpha-tocopherol and works to maintain it and actively remove the other tocopherols. Essentially, nature has found that alpha-tocopherol works best and strives not to let inferior compounds impede.
A key point is alpha-tocopherol is efficient. Alpha-tocopherol is delivered to the same sites where PUFA are stored by virtually every lipoprotein (such as LDL or HDL), lipid delivery and transport system and, as you mentioned, alpha-tocopherol stereochemically is in close contact with these PUFA.
Another key point is that I believe alpha-tocopherol is the safest of the tocopherols. The alpha-tocopheroxyl radical formed when alpha-tocopherol reacts with a free radical or other reactive oxygen species is relatively long lived and so can be recycled back to alpha-tocopherol by water-soluble antioxidants such as ascorbic acid. Other tocopherols are more reactive after they react with radicals and can readily form compounds that are potentially dangerous to cells.
Passwater: Protecting cell membranes is not as simple biochemically as it sounds. Not that the average person should care, but to illustrate that vitamin E research is more active than ever, let me point out that recent studies have shed light on how it works biochemically. The older but now obsolete concept was that vitamin E was simply stored within the membranes to protect them. It was thought that there was a regulatory mechanism that stored just the right amount of vitamin E unless there was a dietary deficiency. It’s a little more complex than that, as shown by the recent studies. A more correct view is that vitamin E “resides” in close proximity to the PUFA in membranes in such a way that it can donate electrons to terminate free-radicals or reduce oxidizing compounds (5, 6).
Dr. Traber, your identification of Tocopherol Transfer Protein (TTP)’s function shed a lot of light on the body’s need for alpha-tocopherol over other tocopherol family members. We would not be genetically programmed to produce this protein, which is taken up by binding to essentially the only the alpha-tocopherol form of vitamin E, unless there was a reason. We discussed TTP in detail in Part Three of our January 1998 interview (4). When we first met in 1993, it was at a dinner honoring you for your research on the discrimination between forms of vitamin E. You received the Vitamin E Research and Information Service (VERIS) Award that night.
Would you be so kind as to summarize for us the significant findings about TTP?
Traber: TTP is found primarily in the liver where it appears to facilitate the movement of alpha-tocopherol back into circulation where it can be delivered to tissues. Figure 1 illustrates how the vitamin E that circulates through the liver is packaged for redistribution in circulation whereas other tocopherols and tocotrienols are discarded into the bile to be excreted. Thus, TTP can be thought of as sort of a filter that preferentially guides alpha-tocopherol into the bloodstream while allowing the other tocopherols and tocotrienols to be excreted.
The exact mechanism of how TTP works is not known because it moves vitamin E very fast. TTP is also found in the brain and in the placenta. There are reports that it is present in the lungs and the skin. Other than in the liver, the tissue concentrations of TTP are very low and not much work has been done to examine its functions in these tissues. The most progress has come from Danny Manor, Ph.D.’s laboratory at Case Western Reserve University, which examined TTP in the brain.
|Figure 1: Regulation of circulating vitamin E by TTP. Vitamin E and other tocopherols and tocotrienols are delivered to the liver and then re-packaged by TTP for recirculation. Tocotrienols and tocopherols other than alpha-tocopherol are broken down and discarded into the bile to be excreted. Figure adapted from Kayden and Traber (7), provided courtesy of Maret Traber, Ph.D.|
Passwater: Hmmm. There must be a reason that the body wants alpha-tocopherol, but does not want the other tocopherols. Does TTP transport alpha-tocopherol to a regulated storage depot such as the liver?
Traber: As far as we know, there are no mechanisms for storing vitamin E in any form and releasing it on demand. Vitamin E can “reside” in places such as cell membranes, lipoproteins and adipose tissue, but this is not a true “controlled storage.” The data suggest vitamin E gets distributed throughout the body during first-pass chylomicron metabolism following a meal. Then, vitamin E gets to the liver, where alpha-tocopherol is preferentially returned to the plasma in lipoproteins, again for delivery to the tissues.
The amount of any tocopherol appears to be more of a function of how much fat is in the tissue. It is not being actively stored in the tissue. It is just that more is deposited in fat cells because fat likes fat, not water. Just as oil and vinegar in salad dressing quickly separate while oils readily mix, fat-soluble vitamin E dissolves in the fat stores and in membranes, which are also mostly “fat-like.”
Passwater: So, although eight compounds have historically (pre-2000) been said to have vitamin E activity because they were believed to prevent fetus resorption in pregnant laboratory rats, the discovery of TTP has established that only one compound—alpha-tocopherol—is absolutely required by humans. The discovery of TTP was a scientific “game changer.” The scientific community had to alter or discard many thoughts and beliefs about vitamin E.
Traber: Based on the research carried out in the past several decades, it has become clear to me that only alpha-tocopherol is required by humans. People with a defect in the gene for the hepatic alpha-TTP become vitamin E deficient because they are incapable of maintaining normal alpha-tocopherol concentrations in the body when they eat a normal diet. They must consume 1,000 mg of alpha-tocopherol to get the same protection that an unaffected person can obtain with 15 mg.
Passwater: What do the studies indicate about the relationship between TTP and other so-called vitamin E forms? Is TTP a protein structure that transports only alpha-tocopherol or are other vitamers also transported but at a lesser degree? Would alpha-tocotrienol also be transported?
Traber: The TTP pocket that holds alpha-tocopherol has specific alignments with various components of the molecule. It is kind of like a glove where each finger has a specific place in the glove. The non-alpha-tocopherols and tocotrienols don’t stay in the “glove” as well because they are lacking “fingers” to stick in the compartments of the glove. It seems that the TTP really manages to discriminate between the various vitamin E forms and especially between tocopherols and tocotrienols.
Passwater: We now know that vitamin E is much more involved in human health than just fertility, but that’s where the research started. The discovery of dietary factors required to prevent sterility in laboratory animals led to identifying a family of chemically related substances that are said to have vitamin E activity. You described this family of nutrients very nicely in our 1997 discussion (3).
Compounds having similar vitamin functions are called “vitamers.” The eight compounds historically (pre-2000) said to be vitamin E vitamers are four tocopherol isomers and four tocotrienol isomers. (Please see Figure 2).
It is helpful—but not absolutely necessary—to understand the nomenclature of the different forms of compounds that are said to have some degree of vitamin E activity. The information in Sidebar, “Vitamin E Vitamers and Hydroxyl Groups,” will be helpful, but if it is more technical than you care about, skip it. However, if you are willing to put up with a little technical nomenclature, you may find it especially enlightening of vitamin E.
Plants produce four forms of tocopherol and four forms of tocotrienols. Plants make these compounds for their own purposes and not human needs. Tocotrienols are essentially identical to tocopherols except their “tails” are “unsaturated.”
Were the other tocopherols ever shown to actually prevent fetal resorption in pregnant rats when individually tested or were they just part of impure mixtures of the structurally related compounds and assumed to have activity based on their structural similarity to alpha-tocopherol?
|Figure 2: Historical vitamin E vitamers. Prior to 2000, eight compounds (four tocopherols and four tocotrienols) were considered to have some vitamin E activity. Today, in the scientific community it is thought that only the alpha-tocopherol form is essential for humans (2).|
Traber: This is an interesting question and I can only speculate because these studies are fairly old and I did not carry them out. What I think is that there were alpha-tocopherol contaminants in the various “pure” vitamins used for treatment. As recently as 10 years ago, I could not purchase “100% gamma-tocopherol.” It was only sold as 97% with 3% contamination of alpha-tocopherol. When we made diets with 500 mg of gamma-tocopherol/kg, then we ended up with sufficient alpha-tocopherol to ruin tests of gamma-tocopherol function (8)!
Passwater: The primary form of vitamin E found in the healthy Mediterranean diet and most European diets is alpha-tocopherol. In contrast, the primary form of vitamin E in the American diet is gamma-tocopherol. The major source of gamma-tocopherol in the American diet is soybean oil. A major source of alpha-tocopherol in the Mediterranean diet is olive oil. It appears that the American diet rich in gamma-tocopherol from soybean oil is the exception rather than the norm.
It would be fallacious to assume that just because one tocopherol or another was the major tocopherol in any diet that tocopherol was an essential nutrient. That would be like recognizing that refined sugar (sucrose) is the most abundant carbohydrate in a junk-food diet and then concluding that refined sugar was the best carbohydrate for humans. What we eat does not determine the essentiality of a nutrient. However, the essentiality of a nutrient should determine what we eat. The tail should not wag the dog.
It’s possible that various tocopherol molecules may have additional effects than the recognized vitamin E function of protecting membranes and lipoproteins. The gamma-tocopherol molecule differs from the alpha-tocopherol molecule in that the ring (head) is not saturated. Alpha-tocopherol has three methyl groups in the ring whereas gamma-tocopherol has only two methyl groups. As a result, the chemistry can be surprisingly different even though the molecules are so similar. Even though the differences in antioxidant activities of the various tocopherol forms are relatively minor, the differences in biologic activities are quite striking. Are you aware of any human studies showing a health effect of gamma-tocopherol?
Traber: Studies by Francesco Galli, Ph.D., have shown that gamma-tocopherol is rapidly metabolized; a 100-mg dose of labeled gamma-tocopherol had virtually no effect on circulating gamma-tocopherol concentrations in his research (9).
Although no true storage depots for any tocopherols are known, the non-alpha-tocopherols can have minor effects as they circulate in the blood before the liver dumps them into the bile to be excreted. TTP effectively keeps alpha-tocopherol in the circulating blood.
Keeping in mind that gamma-tocopherol is not vitamin E as we have been discussing, both positive and negative effects other than vitamin E activity have been reported for gamma-tocopherol. My group has carried out some collaborative studies with Richard Bruno, Ph.D., R.D., of The Ohio State University showing that gamma-tocopherol may have some anti-inflammatory benefits in smokers. If so, this would not necessarily be a vitamin E function but could be an independent function.
On the other hand, gamma-tocopherol can form “Michael adducts,” yielding covalent bonds with nucleophiles such as cysteinyl thiols (10).
Vitamin E Vitamers and Hydroxyl Groups
Tocopherols and tocotrienols are a “family” of compounds that contain a “hydroxyl” (OH) group. Hundreds of families of compounds and thousands of compounds contain OH groups. What is special about tocopherols and tocotrienols is that they fit nicely into biological membranes and thus can protect them.
An OH group is a chemical functional group containing one oxygen atom connected by a covalent bond to one hydrogen atom. The importance of this is that the hydrogen of the OH group is rather easily replaced. It can be removed as a hydrogen ion (which is a proton) and added to reactive compounds so as to reduce them (decrease their oxygen state).
In chemistry, compounds have their atoms joined circularly rather than linearly. These are called rings. The tocopherols consist of a head called a chromane ring (also called chromanol) and a tail called a phytyl group. The hydroxyl group in the chromane head can “donate” its loosely held hydrogen to free radicals or reactive oxygen compounds so as to reduce them, making them inactive. The long phytyl tail is hydrophobic (not attracted to water), which allows the vitamin E molecule to penetrate into biological membranes. Tocotrienols are similar except that they have three double bonds on the third, seventh and eleventh carbons in their farnesyl isoprenoid tails.
The chromane head has two component rings that are essentially naphthalene wherein one carbon atom is substituted with an oxygen atom. The phytyl tail is a saturated 16-carbon isoprenoid.
Isomers are molecules that have identical chemical formulas (same kinds and numbers of atoms), but different atom arrangements. The four tocopherols that have vitamin E activity are the isomers alpha-tocopherol, beta-tocopherol, gamma-tocopherol and delta-tocopherol, which vary by the number and location of methyl groups in the chromane ring. Alpha-tocopherol has three methyl groups in the chromane ring and thus the ring is saturated.
All of the vitamin E vitamers have an OH group located on carbon number 6 in the chromane head. What distinguishes the various vitamin E vitamers is that they have different numbers and/or placements of methyl groups in the chromane head.
Alpha-tocopherol has three methyl groups, one each on carbon numbers 5, 7 and 8. Thus, the chromane ring is fully saturated.
Delta-tocopherol has only one methyl group added to the chromane head at carbon number 8.
Figure 3 shows the four naturally occurring tocopherols. The differences in antioxidant activities of the various tocopherol isomers forms are relatively minor, while the differences in biologic activities are quite striking. The lack of one of the electron-donating methyl groups on the chromanol ring makes gamma-tocopherol less potent in donating electrons than alpha-tocopherol and is, thus, a slightly less powerful antioxidant. However, this lack of a methyl group at carbon 5 position of gamma-tocopherol makes it better able to trap lipophilic electrophiles such as reactive nitrogen oxide species (RNOS).
This has caused scientists at The Ohio State University led by David G. Cornwell, Ph.D., to suggest that the selectivity due to TTP confers an evolutionary advantage by limiting tissue gamma-tocopherol, a putative precursor of the mutagen gamma-tocopheryl quinone. The researchers have conducted in vitro mutagenicity studies and have reviewed the scientific literature.
They suggest that decreased cancer occurs with decreased gamma-tocopherol intakes, and that the converse is also true: increased gamma-tocopherol intakes are associated with increased cancer rates (11). Some investigators are exploring gamma-tocopherol for its potential anti-inflammatory effects and its ability to trap nitrogen-based free-radicals. While beneficial, none of these properties are vitamin E functions. More than cell culture and association studies are needed. Long-term intervention studies should be performed before making recommendations to supplement or not with relatively large quantities of gamma-tocopherol.
Gamma-tocopherol is relatively high in the American diet because Americans eat processed foods that are high in soybean, corn and cottonseed oils, all of which are high in gamma-tocopherol. Europeans have higher alpha intake because they eat more olive oil.
Gamma-tocopherol is potentially dangerous because when it becomes a radical after donating an electron to a free radical, it itself can form compounds (adducts) with other molecules. The problem is that the body does not know how to remove these toxic adducts that are formed. Therefore, it attempts to metabolize and excrete gamma-tocopherol before it can form these adducts (12, 13)!
Other concerns that have been raised are the possible effects of gamma-tocopherol on the lungs of asthma patients and on pregnancy. Regarding lung health, previous in vitro and animal studies indicated that alpha-tocopherol protects, but that large amounts of gamma-tocopherol promote lung inflammation and airway hyper-responsiveness. Gamma-tocopherol increases the activity of a protein that allows white blood cells to leave the bloodstream and enter tissues, while alpha-tocopherol decreases such activity.
A recent study expands the association to humans (14). Joan Cook-Mills, Ph.D., and her colleagues found a higher incidence of asthma associated with higher blood levels of gamma-tocopherol. But higher levels of alpha-tocopherol—particularly in people with low levels of gamma-tocopherol—were tied to better lung function. The researchers found that a 10-micromolar concentration of gamma-tocopherol in blood plasma yielded a 10–17% reduction in lung function. A 10% reduction in lung function is similar to an asthma attack. The senior researcher in the study, Dr. Cook-Mills, noted, “considering the rate of affected people we found in this study, there could be 4.5 million individuals in the U.S. with reduced lung function as a result of their high gamma-tocopherol consumption.” More research is needed before this finding can be confirmed.
Regarding pregnancy, where vitamin E research began, a new study is disconcerting. Pregnancy is a time for caution. In pregnant women, low plasma alpha-tocopherol was associated with increased risk of miscarriage, and low gamma-tocopherol was associated with decreased risk of miscarriage (15). Conversely, higher levels of gamma-tocopherol were associated with increased risk of miscarriage. The researchers concluded that maternal tocopherol status in the first trimester may influence risk of early pregnancy loss. Again, more research is needed.
Passwater: Dietary gamma-tocopherol and the low amounts of the tocopherols other than alpha that are in mixed-tocopherol supplements are one thing, but dramatically increasing the amount of gamma-tocopherol before it’s safety at high dosage has been adequately tested is another. Can the human body convert gamma-tocopherol into alpha-tocopherol?
Traber: No, only plants can convert the tocopherol isomers.
Passwater: As we have mentioned, gamma-tocopherol is the most prevalent tocopherol isomer in the American diet, but not in healthier diets such as the Mediterranean diet. The most prevalent tocopherol isomer in dietary supplements is alpha-tocopherol. Alpha-tocopherol with mixed-tocopherols is also widely used. Is there any scientific basis for manufacturers to switch their vitamin E source from predominately alpha-tocopherol to predominately gamma-tocopherol in standard multivitamins?
Traber: Well, as we have been discussing, the official 2000 DRI explains why gamma-tocopherol does not fulfill the human vitamin E requirement and does not count toward the vitamin E content. The 2000 DRI results from a committee of experts, is peer reviewed and has withstood the test of time for 15 years now. Gamma-tocopherol is not vitamin E. Also, according to my estimates of the gamma-tocopherol intakes of Americans, they already are consuming nearly 100 mg of gamma-tocopherol daily. Alpha-tocopherol intakes usually don’t even reach 10 mg, so I think there is no need for gamma-tocopherol to replace alpha-tocopherol in multivitamins nor is there a need for high-potency “standalone” gamma-tocopherol based on the current scientific literature. High-potency gamma-tocopherol supplements may have seemed like a good idea based on 1985 state-of-knowledge, but the body of knowledge has changed during the past 25 years. As I mentioned earlier, Dr. Galli’s study suggested that gamma-tocopherol is actively metabolized and excreted by the body (9).
Passwater: In summary of our discussion with Dr. Traber, vitamin E is defined as a fat-soluble compound that protects long-chain polyunsaturated fatty acids in membranes and lipoproteins from lipid peroxidation. According to the 2000 DRI, which the government uses to set dietary requirements, only one compound, not a family of compounds, meets the vitamin E requirement for humans. Only alpha-tocopherol is under genetic control in humans and is actively transported and circulated.
Other tocopherols and tocotrienols formerly considered to be vitamin E “family members” are actively and rapidly excreted by the body. The tocopherols other than alpha may be dietary nutrients in their own rights, but they should be considered as unique compounds, not as another form of vitamin E. As an example, published research suggests that tocotrienols have beneficial health effects that are not vitamin E-related. Similarly, in vitro (test tube) studies and a few laboratory animal studies suggest gamma-tocopherol may also have potential benefit, whereas some epidemiological (correlation) and mechanistic studies have suggested adverse health effects.
The amounts of non-alpha tocopherols and tocotrienols in the diet, as well as in mixed-tocopherol supplements are not considered problematic and may have health benefits other than vitamin E related. Supplementation with high amounts of gamma-tocopherol (200 mg or more) on top of a typical American diet already averaging about 100 mg of gamma-tocopherol but less than 10 mg of alpha-tocopherol, has been reported to have risk as well as possible, as yet clinically unproven, benefit. Clinical intervention trials would help clarify the safety and health benefits of these other (non-vitamin E but similar in chemical structure compounds) but much more study is needed (16).
We also discussed how the liver controls the amount of alpha-tocopherol that circulates in the blood via TTP. We’re off to a good beginning, but what our readers really want to know is what are your new findings.
Why is vitamin E needed for brain health? Is there as link between vitamin E deficiency and neurological damage? Will supranutritional amounts of vitamin E help Alzheimer’s disease patients? Does metabolic syndrome impair vitamin E absorption? Do obese people need more vitamin E, but actually get less? Do pregnant or lactating women need more vitamin E? Can high blood cholesterol or triglycerides interfere with vitamin E reaching body tissues? What about possible interactions between vitamins E and K?
We also need to examine the differences between natural-source vitamin E and synthetic vitamin E and discuss any possible differences in human health.
Dr. Traber, your recent research continues to draw wide interest in the scientific community and we thank you for sharing this information with us. WF
1. Food and Nutrition Board, Institute of Medicine, Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids, (National Academy Press, Washington, D.C., 2000), www.ncbi.nlm.nih.gov/books/NBK225483.
2. R.A. Passwater, “How Vitamin E Works: An Interview with Dr. Maret G. Traber. Part I: Vitamin E Basics,” Whole Foods Magazine 20 (12), 46–60 (1997).
3. R.A. Passwater, How Vitamin E Works: An Interview with Dr. Maret G. Traber. Part II: Various Forms of Vitamin E,” Whole Foods Magazine 20 (13), 56–65 (1997).
4. R.A. Passwater, “How Vitamin E Works: An interview with Dr. Maret G. Traber. Part III: The Function of the Tocopherol Transfer Protein,” Whole Foods Magazine 21 (1), 62–74 (1998).
5. D. Marquardt et al., ”Tocopherol Activity Correlates with its Location in a Membrane: A New Perspective on the Antioxidant Vitamin E,” J. Am. Chem. Soc. 135 (20), 7523−7533 (2013).
6. X Wang X and P.J. Quinn, “Vitamin E and its Function in Membranes,” Pro Lipid Res. 38 (4), 309–336 (1999).
7. H.J. Kayden and M.G. Traber, “Absorption, Lipoprotein Transport, and Regulation of Plasma Concentration of Vitamin E in Humans,” J. Lipid Res. 34 (3), 343–358 (1993).
8. M.G. Traber et al., “Alpha-Tocopherol Modulates Cyp3a Expression, Increases Gamma-CEHC Production, and Limits Tissue Gamma-Tocopherol Accumulation in Mice Fed High Gamma-Tocopherol Diets,” Free Radic. Biol. Med. 38 (6), 773–785 (2005).
9. F. Galli, et al., “Gamma-Tocopherol Biokinetics And Transformation in Humans,” Free Radical Res. 37 (11), 1225–1233 (2003).
10. X. Wang, et al., “Mechanism of Arylating Quinone Toxicity Involving Michael Adduct Formation And Induction Of Endoplasmic Reticulum Stress,” PNAS 103 (10), 3604–3609 (2006).
11. D.G. Cornwell, et al., “Mutagenicity of Tocopheryl Quinones: Evolutionary Advantage Of Selective Accumulation of Dietary Alpha-Tocopherol,” Nutr. Cancer 43 (1), 111–118 (2002).
12. D.G. Cornwell, et al., “Electrophile Tocopheryl Quinones in Apoptosis and Mutagenesis: Thermochemolysis of Thiol Adducts With Proteins and in Cells,” Lipids 38 (9), 973–979 (2003).
13. D.G. Cornwell and J. Ma, “Studies in Vitamin E: Biochemistry and Molecular Biology of Tocopherol Quinines,” Vitam. Horm. 76, 99–134 (2007).
14. M.E. Marchese et al., “The Vitamin E Isoforms Alpha-Tocopherol And Gamma=Tocopherol Have Opposite Associations With Spirometric Parameters: The CARDIA Study,” Respir. Res. 15:31 (2014).
15. A.A. Shamim et al., “First-Trimester Plasma Tocopherols Are Associated with Risk of Miscarriage in Rural Bangladesh,”Am. J. Clin. Nutr. 101 (2), 294–301 (2015).
16. S. Devaraj and M.G. Traber, “Gamma-Tocopherol, The New Vitamin E?” Am. J. Clin. Nutr. 77 (3), 530–531 (2003).
Dr. Richard Passwater is the author of more than 45 books and 500 articles on nutrition. Dr. Passwater has been WholeFoods Magazine’s science editor and author of this column since 1984. More information is available on his website, www.drpasswater.com.
Published in WholeFoods Magazine April 2016