Vitamin E

Glenville Jones. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1. Cambridge, UK: Cambridge University Press, 2000.

As any nutritional text dated prior to 1970 will indicate, vitamin E has not received much respect from nutritionists. In such texts it is often placed after vitamin K, in the miscellaneous category. This is because it took a good 40 years from its discovery in 1923 (Evans and Bishop 1923) to demonstrate a clear-cut human deficiency disease for vitamin E. Though numerous studies had shown vitamin E to be an essential component of animal diets, deficiency symptoms varied from one species to the next, from reproductive disorders in rats to vascular abnormalities in chickens. Thus, it was not clear that humans had an obligatory requirement for vitamin E. Recent research, however, has shown that this is indeed the case and that vitamin E is just as important to human nutrition as the other vitamins. It is, therefore, pleasing to see that vitamin E is now placed in its proper place in the alphabet of vitamins.

Vitamin E is the nutritional term used to describe two families of four naturally occurring compounds each, the tocopherols and the tocotrienols (Pennock, Hemming, and Kerr 1964). Tocopherols and tocotrienols both contain a chroman ring, which is essential for biological activity, but differ in the degree of saturation of their fatty side chains. They are otherwise interchangeable in their biological role. Each family comprises alpha, beta, gamma, and delta forms, which differ significantly in their potency. Thus, alpha-tocopherol represents the principal source of vitamin E found in the human diet with a small contribution also coming from gamma-tocopherol (Bieri and Evarts 1973). Many texts, including this one, use the terms alpha-tocopherol and vitamin E interchangeably.

Located in the cellular membranes, alpha-tocopherol helps the cell to resist damage from powerful oxidants known as free radicals. These are generated naturally inside the body as by-products of fuel oxidation, and they can be generated artificially by external factors such as radiation, chemotherapy, or pollutants. B.Ames (1983) believes that aerobic respiration using oxygen is the most important of these external factors in generating free radicals and that antioxidants such as vitamin E help to resist free-radical damage. Because of its stabilized chroman ring structure, vita-min E is able to mop up these free radicals and their immediate products, minimizing the damage to the lipids of the membrane and therefore maintaining cell membrane integrity. Simply put, vitamin E stops the fat of the body from turning rancid.

History of the Discovery of Vitamin E


The decade between 1915 and 1925 was one of the most productive in the history of nutrition. The use of semipurified or semisynthetic diets allowed researchers to demonstrate the essential nature of individual components of the diet and, more specifically, to recognize the existence of the vitamins A, B1, C, and D. Nutritionists (Osbourne and Mendel 1919; Mattill and Conklin 1920) showed that though these diets were able to maintain life, they failed to support reproduction in laboratory animals. Reproductive biologists, thus, realized that the estrous cycle of the female rat or testicular development in the male constituted useful animal models for studying the essential nature of nutritional factors (Long and Evans 1922). Using a basal semipurified diet comprising casein, starch, lard, butter, fats, and brewer's yeast, which would allow rats to grow but not reproduce, groups headed by Herbert M. Evans and L. B. Mendel set about the laborious task of finding a substance that would promote fertility.

Detailed historical accounts of the events surrounding the discovery of vitamin E, its chemistry and biology, have been published by two pioneers in the field, Evans (Evans 1962) and Karl E. Mason, a student of Mendel (Mason 1977). Their recollections are concise, modest accounts of the important milestones in the field, and unlike other accounts of historical events from rival camps, the two actually agree! The reader is referred to the often flowery account of Evans, who describes the identification of a factor in lettuce and wheat germ required for preventing resorption of fetuses in the pregnant rat. He writes:

Good fairies attended every phase of the advent and early history of vitamin E. We turned our attention at once to the prevention rather than alleviation of these strange resorptions—a prevention which might disclose at once what individual natural foodstuffs carried a missing needed substance. Lettuce, relished by these poor sufferers of our rancid lard diet, was spectacularly successful, and we may have entertained the conviction that vitamin C which was not essential for growth was necessary in pregnancy, had we not quickly shown that not the aqueous, but only the fatty, component of these leaves, the chlorophyll-rich green oil, had worked the good result. Then, to our surprise, wheat was equally remedial, and the concept that vitamin C was involved could not, of course, survive. The good fairies accompanied me to the large Sperry flour mill at a neighboring town, Vallejo, where I found three great streams flowing from the milling of the wheat berry: the first constituted the outer cover or chaff; the second the endosperm, the white so-called flour; and the third which came in flattened flakes, stuck into such units by its oil content—the germ. Night had not fallen that day, before all these components were fed to groups of carefully prepared females—animals which had begun gestation on vitamin E–low diets and were fed both the watery and fatty solutions. Single daily drops of the golden yellow wheat germ oil were remedial.That an oil might enrich the embryo's dietary needs for vitamin A and vitamin D, the only fat-soluble vitamins then known, was negated at once when we added the well-known rich source of vitamins A and D, cod liver oil, an addition which did not lessen but increased and made invariable our malady.(Evans 1962: 382)

From the words Evans used to describe his rats, we can clearly discern that he cared about the animals he used in those early studies. The factor initially described as "antisterility factor X" was born (Evans and Bishop 1922). Parallel studies by Mason (1925), working with the male rat, showed that the same factor appeared essential to prevent testicular degeneration in the rat. The name, vitamin E, seems to have been suggested by an opportunist, Barnett Sure, in 1924, based upon the vitamin nomenclature of the time, although the endorsement of this title by Evans helped to gain it widespread use (Evans 1925).

Following the discovery of vitamin E, nutritionists spent the next decade describing symptoms of its deficiency in a variety of animals, except humans. Research also focused on its chemical nature. Finally in 1936, Evans, working with Gladys and Oliver Emerson, published the identity of vitamin E from wheat germ oil as an alcohol with the chemical formula (C29H50O2). Evans named this substance "alpha-tocopherol." The origin of this name is described in his personal account:

I well remember their (the Emersons') plea to me to suggest a proper name for their purified substance when success crowned their efforts. I promptly invited George M. Calhoun, our professor of Greek to luncheon in Berkeley in our small Faculty Club."Most scientists, medical men especially," said Calhoun, "have been guilty of coining Greek-Latin terms, bastards, of course, and we might have to do this.""What does the substance do?" he asked."It permits an animal to bear off-spring," I replied. "Well, childbirth in Greek is tocos," he said, "and if it confers or brings childbirth, we will next employ the Greek verb phero. You have also said that the term must have an ending consonant with its chemical—'ol', it being an alcohol; your substance is 'tocopherol,' and the pleasant task assigned me quickly solved and not worth the delightful four-course dinner you have arranged."(Evans 1962:383)

It is, therefore, evident that vitamin E was renamed alpha-tocopherol for the meager price of a four-course meal.

Erhard Fernholz provided the structural formula for alpha-tocopherol in 1938, and it was first synthesized chemically by the brilliant Swiss chemist Paul Karrer working at Hoffmann-LaRoche laboratories in Basel (Karrer et al. 1938).

Vitamin E Deficiency in Humans


During the period 1925 to 1935 there appeared an ever increasing and confusing series of papers in the nutritional literature showing the importance of vita-min E in the prevention of reproductive defects in rats; prevention of embryonic mortality and encephalomalacia in chicks; and prevention of nutritional muscular dystrophy in guinea pigs and rabbits. How could deficiency of a single nutritional factor cause all these different pathological changes in different laboratory animals but have no apparent parallel condition in humans? Even in avian species like the chick and duck the symptoms were not consistent.

Vitamin E deficiency appeared in different sites: muscular dystrophy in ducklings and vascular changes and encephalopathy in chicks. The common thread tying together all these apparently different defects ascribed to vitamin E deficiency was not immediately evident. Although H. S. Olcott and H. A. Mattill (1931) had pointed out the association of antioxidants and vitamin E in lettuce oil, it was not until 1937 after the discovery of alpha-tocopherol that it became clear that alpha-tocopherol was an antioxidant (Olcott and Emerson 1937). It was still later through the work of researchers such as A. L. Tappel and J. G. Bieri in the late 1950s and early 1960s, that the free-radical theory of lipid peroxidation and the function of vitamin E as an antioxidant developed to the point where the conflicting findings could be rationalized using a single mechanism (Tappel 1962).

According to this free-radical theory, membrane lipids in all membranes of the body should be susceptible to oxidative damage, and the exact location of damage observed in different animal species would depend upon variables such as specific membrane lipid composition, vitamin E content, and cellular metabolic rate. Based upon this theory it became easy to rationalize various patterns of damage due to vita-min E deficiency in different animal species. With this new understanding of the nature of vitamin E action came the realization that vitamin E deficiency in humans might show up in different sites (i.e., different membranes) from those showing vitamin E deficiency in animal tissues. Moreover, the recognition that the common feature of all these deficiency symptoms was damage caused by free radicals began a search for human individuals who might generate or be exposed to higher levels of such destructive factors and who might, therefore, develop vitamin E deficiency. These individuals turned out to be prematurely born infants.

Looking back at the extensive literature on vitamin E in humans, it is clear that clues of vitamin E deficiency in pediatric medicine were emerging even in the late 1940s. The advent of modern neonatal units led to the use of respirators in which newborns were kept in an oxygen-rich environment. Premature infants were particularly favored for this treatment, and two conditions suggesting vitamin E deficiency affecting premature infants came to light: hemolytic anemia, in which erythrocyte membranes have an increased tendency to rupture; and retrolental fibroplasia, in which the blood vessels of the developing retina are damaged, leading to scarring and blindness (Farrell 1980). First observed in the 1940s, these conditions were documented and rationalized for the first time with the advent of the free-radical theory.

Free radicals, generated from the oxygen-rich gaseous mix used in such respirators, attacked cellular membranes, in particular those of red blood cells and the cells of the retina. It should be noted that although premature infants are susceptible to damage resulting from vitamin E deficiency, this is due only in part to an increased "insult" from oxidants; it is also partly the result of reduced vitamin E stores and lower vitamin E levels in their blood. Not surprisingly, the severity of retrolental fibroplasia is markedly decreased by pharmacological doses of vitamin E (Hittner et al. 1981). As the assault on cellular membranes in such fast-growing children is diminished and as vitamin E stores are bolstered in the first weeks of life, the risk of vitamin E deficiency decreases substantially. Consequently, vitamin E deficiency is very difficult to demonstrate in healthy children or in adults eating a standard balanced diet.

Toward the end of the 1950s, the Food and Nutrition Board of the National Research Council of the United States funded a long-term, six-year, dietary study of the relationship between blood vitamin E levels and consumption of polyunsaturated fatty acids (PUFA) in a group of male subjects who were given a diet low in vitamin E. The study became known as the Elgin Project, after the hospital in Illinois where it was carried out (Horwitt 1960). Institutionalized subjects were closely monitored for symptoms of vitamin E deficiency while they underwent the increased stress of a diet with a higher PUFA: vitamin E ratio. Not surprisingly, the subjects failed to develop a clear-cut clinical syndrome except that plasma vitamin E levels dropped and red cells showed an increased tendency to hemolysis, but it took two years for these changes to occur.

If vitamin E deficiency does occur in humans beyond the neonatal period, it is usually secondary to another disease state that results in malabsorption of vitamin E from the diet. Since vitamin E is absorbed with the fat in the diet, conditions that result in fat malabsorption, such as chronic cholestasis (liver disease) or cystic fibrosis where there is pancreatic blockage, will result in vitamin E deficiency. Another rare cause of vitamin E deficiency is the genetic absence of beta-lipoprotein, the transporter of vitamin E in the blood, in a condition known as abetalipoproteinemia (Muller, Lloyd, and Bird 1977).

In such individuals with vitamin E supply or transport problems, there is an increased tendency of red cells to hemolyze and also a shortened red cell survival time. More recently, the medical fraternity has begun to recognize muscle and neurological problems that result from human vitamin E deficiency (Sokol 1988).These abnormalities include loss of reflexes and gait disturbances that are accompanied by pathological changes. Autopsies performed on patients with cystic fibrosis show more advanced axonal degeneration than would be expected of normal age-matched individuals (Sung 1964). It would be surprising if humans were spared all of the neurological and muscular defects observed in animals. However, such human vitamin E deficiency is rarely accompanied by the acute muscle, brain, and blood vessel defects observed in laboratory animals fed semisynthetic diets. We should be thankful that it is not.

Dietary Sources of Vitamin E


The substance alpha-tocopherol is present in the diet in a variety of plant oils, including wheat germ oil and the lettuce oil discovered in pioneering work. Soya bean and other plant oils, which became more common dietary components in the latter half of the twentieth century, contain gamma-tocopherol, a less potent version of vitamin E. It is interesting to note that the unsaturated fatty acids, which are present in plant oils and are so prone to free-radical oxidation in our food, are accompanied by the highest concentrations of vitamin E. It is as if nature realized their sensitivity and put in a natural preservative to protect these oils (Bieri, Corash, and Hubbard 1983). Animal fats contain lower amounts of vitamin E, and fish oils have variable amounts depending upon the diet of the fish and the age of the fish oil. Though cod-liver oil has been shown to contain vitamin E, it also contains a high concentration of polyunsaturated fatty acids that can easily become oxidized by free radicals and, consequently, as noted by Evans (1962), be deleterious rather than protective.

One special food associated with vitamin E is wheat germ bread. Sometimes referred to in Europe as Hovis (from the Latin hominis vis meaning "the strength of man"), this bread is made with flour containing five times as much of the fatty germ as whole-meal bread. The procedure by which the wheat germ is stabilized involves separating it from the flour, lightly cooking it in steam, and returning it to the flour. This process was jointly patented in the United Kingdom in 1887 by Richard "Stoney" Smith of Stone, Staffordshire, and Macclesfield Miller and Thomas Fitton of the firm S. Fitton and Son. This was about 35 years before the experiments of Evans, which led to the discovery of vitamin E. Although the health-promoting properties of Hovis were clearly recognized in early advertising campaigns, there is no evidence that Hovis was aimed at special groups of people (i.e., those with muscular, reproductive, or vascular problems). With such rich sources of vitamin E as Hovis bread in our normal diet, it is difficult to consume a diet that will result in vitamin E deficiency.

Other Uses of Vitamin E


The history of vitamin E is much shorter than that of the other vitamins, but the absence for so long of a clear-cut human deficiency syndrome allowed for the development of a number of bogus or exaggerated claims for vitamin E, or at least claims that have never been properly substantiated. Most of these have been built upon deficiency symptoms observed in laboratory animals and not in humans. One, based upon findings in the rat, is that vitamin E is a fertility vita-min. As a result, some physicians used the vitamin to treat a number of conditions that produced spontaneous abortions. In a series of poorly controlled, anecdotal studies, Evan Shute (1939) claimed that vitamin E was particularly effective in countering habitual abortion, which is defined as spontaneous abortion before the sixteenth week of gestation during three successive pregnancies. When others tried to confirm these findings, they failed to do so and were left to conclude, as did C.T. Javert, W. F. Finn, and H. J. Stander:

There is such a maze of literature the proper cognizance cannot be taken of all the pertinent articles. As the reader reviews them in order to develop his own philosophy let him [all obstetricians were male in those days] be reminded of the following important matters:

  1. The high percentage of success irrespective of which vitamin, hormone or method is employed;

  2. The lack of specific information as to the pathogenesis of human spontaneous abortion. (1949: 887)

This skepticism was found to be well grounded; others who have reviewed three decades of experimentation on abortion have also concluded that vitamin E supplementation is ineffective (Marks 1962).

In addition, there have been numerous claims that large doses of vitamin E are beneficial in cardiovascular conditions such as angina, congestive heart failure, and peripheral vascular disease. Current medical opinion is that these claims are unproven. However, this debate was being revisited in the 1990s with the suggestion that the "oxidized" lipoprotein, LDL, may be the chief villain in atherosclerosis, and that its level in the bloodstream inversely correlates with alpha-tocopherol levels. New clinical studies of vitamin E and the risk of coronary heart disease in both male and female health workers have, again, suggested a protective role for the vitamin (Rim et al. 1993; Stampfer et al. 1993). Consequently, long-term supplementation with vitamin E to prevent heart disease is again being discussed.

The association of vitamin E deficiency with nutritional muscular dystrophy in guinea pigs and rabbits led to trials of its use as a supplement in Duchenne's muscular dystrophy (Berneske et al. 1960). Because this condition is a genetically inherited disease with a different etiology than the nutritional version, it is not surprising that vitamin E was ineffective, but this is not to say that vitamin E supplementation cannot help to alleviate some of the consequences of muscular and neurological disease and, therefore, benefit the patient. The recent elucidation of the molecular defect in Lou Gehrig's disease (ALS) as a lack of the enzyme super-oxide dismutase (Rosen et al. 1993) has already led to a reevaluation of dietary antioxidant supplementation in this disease because the enzyme works in concert with vitamin E to reduce free radicals inside the cell. It is hoped that the results will be more positive than those reported recently in another neurological condition, Parkinsonism, where alpha-tocopherol supplementation was unsuccessful as an adjunct therapy to the drug deprenyl (Shoulson et al. 1993).

The old adage that if a little is good, a lot must be better, pervades nutritional science. The association of vitamin E with muscle health has led to the use of vitamin supplements in sports (Cureton 1954). Consequently, vitamin E can be considered one of the earliest performance-enhancing drugs, in use long before anabolic steroids and growth hormones. However, a controlled study of Scottish track-and-field athletes in the early 1970s by I. M. Sharman, M. G. Down, and R. N. Sen dispelled the notion that vitamin E improved performance. Presumably the athletes agreed because they moved on to other treatments.

In the 1970s, megadose vitamin therapy came into vogue in North America, and Senator William Proxmire from Wisconsin, who advocated such self-treatments for improved health, subsequently led opposition to legislation that might have blocked such potentially dangerous megadose vitamin products. Simultaneously in vogue was the free-radical theory of lipid peroxidation, which resulted in the idea that the natural aging process is an inability of the organism to keep up with oxidation (Harman 1956).

A possible solution to the problem came from Ames (1983), who suggested that a battery of dietary and endogenously produced antioxidants, headed by vitamin E and also including glutathione, vitamin C, beta-carotene, and possibly uric acid, might help to slow down this process. Ames concluded that the natural aging process results from an inability to completely prevent the harmful effects of oxidation. As a consequence, megadoses of vitamin E have been consumed by thousands of North Americans in the hope that augmenting the antioxidant supply might help defeat free radicals and prevent aging. Although it is difficult to believe that supplemental dietary vitamin E will prevent aging if alpha-tocopherol levels are already adequate in the blood of the majority of adults, the toxicity symptoms (gastrointestinal disturbances) of vitamin E are minor. Thus there seems not much reason to prevent a little self-experimentation, although it is worth noting that this self-experimentation is ably assisted by the pharmaceutical industry.

As the antioxidant properties of vitamin E have become more and more evident, the food and cosmetic industry have found wider and wider uses for it. Vitamin E is a poor antioxidant in vitro and is largely replaced by other substances when a preservative is needed in food. However, the vitamin is now added to a broad range of soaps and shampoos and other cosmetic products in the hope of convincing the buyer that it has special properties in skin and hair. The fact that human vitamin E deficiency is not accompanied by skin and hair problems, or that vita-min E might not even enter the hair or skin when applied via this route, does not seem to be a weighty argument for the consumer. Perhaps the most outrageous claim this contributor has come across in recent years is one stating that a cream containing vitamin E might protect against frostbite. It was applied by a Canadian sled-dog racer to the underside of her dogs' testicles to protect them from the harmful effects of the snow and cold (Sokol 1985).

The past two to three decades have, however, also seen some legitimate uses of vitamin E in medical science. The development of total parenteral feeding solutions in the 1970s included a recognition of the essential nature of vitamin E (Bieri et al. 1983). Long-term artificial feeding solutions are, therefore, supplemented with vitamin E.The widespread use of cancer chemotherapeutic agents such as adriamycin, which generates free radicals to kill cancer cells, can be augmented by vitamin E therapy to help protect surviving normal cells. Tissue transplantation normally involves maintenance of donor organs in oxygenated perfusate prior to surgery, a process that leads to free-radical generation. Use of antioxidants and free-radical scavengers helps improve the survival of such organs, presumably by minimizing the damage caused by free radicals. Children with cholestasis and poor vitamin nutriture receiving liver transplants are given water-soluble vitamin E preparations to help the donated organ survive. Vitamin E can also attenuate the damage caused by free radicals released during myocardial infarctions (Massey and Burton 1989). It appears that uses for vitamin E will continue to proliferate well into the new millennium.