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By Herbert M. Evans
Summary: In 1922 biologists Herbert Evans and Katharine Bishop discovered that rats deprived of a certain fat-soluble substance in their diet failed to reproduce. Thanks to this research, the substance—later named vitamin E—was known initially as “the antisterility vitamin.” In subsequent years, however, researchers would discover that vitamin E is responsible for much more than fertility, its deficiency leading to muscular and neural dystrophies in various species of animals, particularly in the young. In this lecture from 1939, Dr. Evans discusses both his own research and that of others into vitamin E’s critical role in the health of muscle and nerves, adding that while a certain minimal amount of the vitamin may ward of full-blown degeneration, there are likely effects of partial inadequacy as well, such as slowed growth. While today medicine has nebulously reduced the function of vitamin E to that of an antioxidant, Dr. Evans’s discussion speaks to a role much more immediately involved in the physiology of the body. Indeed, he notes, when scientists fed rabbits a diet deficient in vitamin E but supplemented with a known antioxidant, the animals “developed the [same] dystrophy and succumbed in the usual way.” From Journal of the Mount Sinai Hospital, 1939. Lee Foundation for Nutritional Research reprint 56.
New Light on the Biological Role of Vitamin E
Delivered at the Blumenthal Auditorium, Mount Sinai Hospital, New York City, October 20, 1939, as part of the William Henry Welch Lectures series.
Over a decade go, at the conclusion of our long program of studies on the role of vitamin E in the physiology of reproduction in higher animals, Burr and I1 permitted vitamin-E–low mother rats to attempt to suckle and, if possible, rear their young. Although they had been given but little more vitamin E than had proved necessary to ensure the birth of living young, if vitamin B was high, lactation was not seriously interfered with and the young grew normally and to all appearances throve. Suddenly, towards the end of the lactation period, a calamity intervened, for we were surprised to find that the majority of these well-nourished young developed a mysterious malady characterized mainly by muscular paralyses. Half of the affected sucklings died from the malady—often so suddenly that there were no signs of wasting from undernutrition.
The disorder was not due to constitutional inferiority of the young through germinal impairment or any inadequacy in their intrauterine life, because the disease, though diminished, also occurred when we allowed the young from normal, natural-food mothers to suckle from these vitamin-E–low mothers. The disease was therefore unquestionably due to defect in the E-low mother’s milk, and the final proof of this was secured by shifting her and her own litter to natural foods, in which cases the paralysis never occurred.
We then began the addition of single nutritive elements to the diet of other vitamin-E–low mothers; these efforts were without effect until vitamin E was given them—in the least contaminated form then available: wheat germ oil or concentrates from its nonsaponifiable fraction. To put the cap on the proof, the direct administration of these substances to the young was similarly completely effective in preventing the disease.
This previously unknown need for vitamin E in the economy of the developing young was remarkably limited in time; the paralyses were prevented if the substance was given as late as the fifteenth day of life. The disease otherwise developed by the twenty-fifth day of life—so this ten-day period is a critical one as regards need for vitamin E.
While we were absorbed in other studies, primarily those concerning the nature of vitamin E itself, Olcott2 examined the muscular system in these young rats and discovered a remarkable, widespread degeneration quite exactly resembling that reported by Goettsch3 and by Goettsch and Pappenheimer4 almost ten years ago, in their low-E guinea pigs and rabbits, to which I shall revert presently. Lipshutz5 had reported definite cerebrospinal lesions in these young but had neglected a simple examination of the musculature.
Olcott’s finding was spectacular. It showed that the Goettsch-Pappenheimer discoveries could be extended to other mammals and, above all, to the form in which the paralysis had been first noted. Now, it is highly important to note that in all our work it has been demonstrated that a certain number of young never develop the paralyses, a certain number completely recover, spontaneously, without any form of treatment, and a certain number recover with permanent paralyses. In our 1928 paper, we reported that the last-mentioned animals, except for the paralyses, may exhibit every evidence of normality and health. We reared large numbers of them and retained them for a significant part of their life span. Many were bred, and when vitamin E was administered early in gestation and in lactation, the young were normal in every way. These older animals then suffered grave localized disability but only this, and as Ringsted6 has emphasized, they never die from this cause but from some intercurrent infection.
Ringsted was the first to recognize that animals that escape the early paralysis because they are taken from natural-food mothers and placed on the E-free diet only after weaning nevertheless after some months gradually develop well-localized disabilities—paralyses. These were then reported by Burr, Brown, and Moseley,7 by Knowlton and Hines,8,9 and by us.10 Finally, Einarson and Ringsted11 have given us a careful exploration of the spinal cord as well as muscles of these older animals and have described stages in the cord lesions that begin with the dorsal roots and the proprioceptive tracts of the fasciculi cuneatus and gracilis, then involve the anterior horn cells and ventral roots, and finally, in some cases, the pyramidal tracts. They state that the cord lesions therefore “resemble closely a combination of two of the most important systemic degenerations occurring in man—namely tabes dorsalis and spinal progressive muscular atrophy.”
As to the muscles, their opinion is that the lesions remind one of a muscular atrophy of spinal origin, i.e., a neurogenous muscular atrophy—especially the marked proliferation of the marginal nuclei and the absence of hypertrophic fibers—though they admit that in the early stage, resemblances to a pure myogenous atrophy are found. They emphasize the possibility that injury to the autonomic innervation of the musculature is primary and that a secondary involvement of the cerebrospinal system occurs, giving at first the picture of tabes and then of amyotrophic lateral sclerosis.
The cause of the death of vitamin-E–low paralyzed sucklings is at present a mystery, but it could conceivably be ascribed to paralysis of the muscles of respiration. An elaborate electrocardiographic study has not shown us cardiac impairment, and the myocardium is histologically normal. I have already mentioned the occasional spontaneous and complete recovery of young sucklings so badly paralyzed that they could not right themselves when placed on their backs. Some of these spontaneous recoveries have been sacrificed when forty-five days of age, and their striated musculature is histologically normal and normal in creatine content, whereas this is never the case at the time of paralysis.
Barrie12 of England in 1938 demonstrated that alpha-tocopherol prevents the paralysis and death of these suckling young, followed promptly by a similar demonstration independently undertaken by Goettsch and Ritzmann13 of New York. We in Berkeley had under way a similar long series of experiments and have had no trouble in verifying these results. Goettsch and Ritzmann gave a total of 5 mg of alpha-tocopherol to each suckling young between the tenth and twenty-fifth day of life. We have given 1 mg daily in the same interval and have found it protective. But it is easier and just as reliable to treat the young by way of the mother so that her milk contains the substance, for the disease is invariably prevented when the mother is given a single dose of 6 mg of alpha-tocopherol on the day of littering.
Now, as previously mentioned, the lesions of the striated musculature were not first produced in rats but in rabbits and guinea pigs deprived of vitamin E, and we can now say that when care is taken to ensure that adequate amounts of the vitamin B complex are coincidentally present, alpha-tocopherol acts in the case of these animal forms also to cure or prevent paralysis and death (Mackenzie and McCollum,14 1939; Shimotori,15 1939).
It is to Goettsch and Pappenheimer, who were interested in the production of vitamin E deficiency in a species other than the rat, that we must ascribe the discovery that rabbits and guinea pigs reared on a diet in which the vitamin E had been destroyed by treatment with ferric chloride develop a deficiency disease characterized by dystrophy of the voluntary muscles. In their earliest experiments, it was unfortunate that the addition of wheat germ to the diet appeared only to delay the onset of the dystrophy but not prevent it, although Mattill16 subsequently found that the inclusion of 2 percent wheat germ oil was at least adequate to prevent the development of dystrophy in rabbits for many months, during which time the animals grew normally, and Mackenzie and McCollum14 have lately shown the effectiveness of alpha-tocopherol if vitamin B is high.
Morgulis and coworkers17,18 felt that at least two factors, both present in whole wheat germ, were required for the prevention or cure of the disease in rabbits. One factor was soluble in 70 percent ethanol and the other in typical fat solvents. The latter factor was present in the unnsaponifiable fraction of wheat germ oil and was in all probability vitamin E. The most recent development here seems decisive, for it was with the Goettsch and Pappenheimer diet—supplemented with 10 percent ether-extracted wheat germ—that Mackenzie and McCollum, employing rabbits, have been able to note the curative effect of alpha-tocopherol in connection with this experimental muscular dystrophy. A decrease in muscle creatine is invariable in dystrophic animals, and there is always a corresponding increase in urinary creatine. This led Mackenzie and McCollum to devise an ingenious method for predicting the onset of the dystrophy. Vitamin E therapy in this way could be initiated a few hours before obvious paralysis would otherwise appear.
Madsen, McCay, and Maynard,19,20 at Ithaca, have for some years been interested in devising purified diets for guinea pigs and rabbits; in the course of these studies, they found that when cod-liver oil was included in the ration, these animals succumbed from a muscular dystrophy. When the unsaponified fraction of cod-liver oil was given in place of the oil itself, the dystrophy was not prevented, although its onset was delayed. Likewise the omission of cod-liver oil and the use of irradiated yeast and carotene as sources of vitamins A and D did not prevent the eventual development of muscular lesions, although the onset was delayed. Madsen, McCay, and Maynard believed that cod-liver oil, particularly its saponifiable fraction, contained some toxic factor that hastens the degeneration of the skeletal musculature but also that a second factor must be admitted to be involved in the trouble.
The complicity of cod-liver oil in their results was at first confusing, for we knew from the studies of Agduhr and Stenstriim21 that this substance is toxic in many ways—for instance, to the cardiac musculature. Moreover, to make matters worse, the Cornell investigators were able to show that the addition of cod-liver oil or concentrates to a natural food diet resulted in muscular dystrophies. Mattill22,23 has made the ingenious suggestion that in herbivores with a large cecum, food could remain long enough for autoxidative changes to progress farther and more rapidly than in omnivorous animals such as rats.
“From this point of view,” he said, “the long search for a toxic factor in cod-liver oil and for cures of the disorders produced thereby may have been following a wrong trail.” That it is not merely to the antioxidative properties of a curative substance that we must ascribe effects was also shown by Mattill when he reared rabbits on a synthetic diet devoid of vitamin E but with an antioxidant; they developed the dystrophy and succumbed in the usual way. Finally, even using cod-liver oil, Miss Shimotori in our laboratory has been able to prevent the dystrophy by administering alpha-tocopherol to guinea pigs reared on the Madsen, McCay, and Maynard diet, the alpha-tocopherol and cod-liver being administered on alternate days.
It is highly interesting that characteristic disturbances and death occur in birds when the attempt is made to rear them without vitamin E. We owe our knowledge of these conditions almost exclusively to the Pappenheimer and Goettsch group. They have shown that chicks deprived of vitamin E develop a nervous disorder, called by them encephalomalacia; goslings develop a degeneration of the skeletal musculature; and turkeys develop an ideopathic degeneration of the smooth musculature of the gizzard. Here again, delay in ascribing the disorders solely to the lack of vitamin E was occasioned by the annoying finding that they were not prevented by the addition of certain natural foods known to contain E—grain products including wheat germ and greens. Furthermore, when natural foods were treated with FeCl3, the paralysis disease was prevented although vitamin E was effectively destroyed; yet Dam of Copenhagen24 and Pappenheimer, Goettsch, and Jungherr25 have here also in the last few months shown that alpha-tocopherol will prevent chick encephalomalacia.
No more remarkable example of species specificity in reactions to vitamin need could be furnished than that found in the Columbia studies on domestic birds, for the gosling has the muscular paralyses of young mammals and dies just as suddenly and mysteriously, while in the chick disorder we have an equally good example of pure involvement of the nervous system, albeit a secondary involvement, for the Columbia studies showed clearly that involvement of the chick’s nervous system was secondary to a peculiar impermeability of the blood vessels supplying the nervous tissue.
“We have not been able,” they say, “to bring proof that the capillary thrombosis is a primary cause of the ensuing necrosis. Indeed, it may well follow upon a prolonged vasoconstriction or vasomotor paralysis or the first followed by the second.” May not, therefore, a primary injury to the sympathetic nervous system be involved here, as Einarson11 supposes to be the case in the myopathy of adult rats where cerebrospinal lesions are absent? We could thus harmonize the two astonishingly different pictures produced by lack of the same substance, vitamin E—the massive necrosis of cerebellar tissue in the chick and the muscle fibers in duck and mammal.
I think we may regard it as settled that a characteristic muscular atrophy and obscure fatality occur in divergent mammalian forms when vitamin E is withdrawn and that normality is assured with the same diets provided the pure substance alpha-tocopherol is administered prophylactically. There are probably manifold slighter deficiencies of the body when inadequate amounts of the vitamin are given but nevertheless are sufficient to prevent muscular atrophy. A good example is furnished by the decline in the growth of vitamin-E–low rats after the fourth month of life—a condition promptly relieved by the administration of vitamin E.
With the isolation of alpha- and beta-tocopherol and the synthetic production of these two pure substances, our concept of their chemical nature is complete. They are the chromane substances represented by the formulae on the following page.
John of Goettingen26 and we, independently at Berkeley, in conjunction with L.I. Smith of Minnesota,27,28 have found a certain degree of vitamin E activity in an astonishing range of substances. Von Werder et al.,29 in Germany, and Todd and his associates,30 in England, have also extended the list and range of these substances. If in fact one feeds very high levels of the aromatic nucleus of tocopherol in the form of tetramethylhydroquinone, then the fertility of sterile females can be reinvoked with single doses of 100 mg. This high-melting and relatively insoluble substance is probably poorly absorbed; otherwise it might be even more effective than we have found it to be. Karrer31 has shown that the presence of the methyl groups in the benzene ring plays a very important role because the dimethyltocopherols—the beta and gamma forms—are distinctly less active than alpha-tocopherol. Karrer synthesized the monomethyltocopherols and found them inactive. The nature of the aliphatic part of the tocopherol molecule is also important, but here it is very hard to make any simple generalization of the relation of structure to vitamin activity, since, as already mentioned, durohydroquinone, which has no long side chain whatsoever, nevertheless shows considerable activity, and many substances having side chains that approximate that of the tocopherols have no activity.
It is hardly necessary to remind you of the analogous situation furnished by vitamin D. Calciferol—in the rat at least—possesses enormous vitamin D activity, yet the replacement of a hydrogen by a methyl group in the side chain gives a compound that Windaus found completely inactive. On the other hand, vitamin D3, which is a natural substance occurring in fish liver oils and can be produced by irradiating dehydrocholesterol, is extremely active even though its side chain differs in several respects from that of calciferol. Bills and Hickman32-35 have brought forth evidence to show that there is a potent vitamin D in fish liver oils with a very much shorter side chain than any of the before-mentioned compounds.
[Figure showing chemical structures of alpha-tocopherol and beta-tocopherol, with title:] Figure 1. (See original for image.)Alpha-tocopherol can be oxidized to varying degrees by various procedures. The mildest oxidation—that accomplished by controlled action of FeCl3—opens the ring, giving the para-quinone (alpha-tocoquinone), as shown by John.36,37 We have found that tocoquinone is active in the cure of sterility at 3 mg (Figure 2). (J. Biol. Chem, in press.)
[Figure showing chemical structures of alpha-tocopherol, alpha-tocoquinone, orthoquinone, and C21 lactone, with title:] Figure 2. (See original for image.)A somewhat more drastic oxidizing agent, dilute nitric acid in alcohol, oxidizes tocopherol and all 6-hydroxychromanes in an unusual and interesting manner that has been recently cleared up by Smith, Irwin, and Ungnade.38,39 A methyl group is eliminated, with the formation of an orthoquinone. The reaction with alpha-tocopherol gives a red orthoquinone that forms a phenazine with orthophenylenediamine, but neither quinone nor phenazine crystallizes. More drastic oxidation with permanganate or chromic acid shatters the aromatic ring, giving a lactone that includes merely the aliphatic part of the molecule.
Windhaus40 has stated that the biological role of vitamin E might conceivably be explained by its action as an oxidizing-reducing system, of which a number of analogous examples exist among biologically important substances, such as ascorbic acid and glutathione. He pictured the tocopherol being oxidized to the quinone and then reduced back to the tocopherol. Whether this concept is true or not remains for future work to show. Several investigators have shown that the quinone can readily be reduced to a hydroquinone, which can lose water to give tocopherol itself. This loss of water can be effected very rapidly by the catalytic action of strong acids, but this is unfortunately not a physiological condition. Without the presence of acids, the hydroquinone can be distilled in high vacuum unchanged. According to our experiences, the tocoquinone is about as active as alpha-tocopherol.
Now is perhaps the time to pose the basic question of whether or not that particular part of the molecule of alpha-tocopherol responsible for the cure of female sterility is the same chemical configuration responsible for the prevention or cure of the pathological conditions in the nervous and muscular systems already described.
Waddell and Steenbock41 some years ago introduced an ingenious method for the destruction of vitamin E in natural foods. An ethereal solution of ferric chloride was sprayed on and thoroughly mixed with the food, sterility resulting in male rats from such a diet. The action of FeCl3 in the destruction of vitamin E has been interpreted as a catalytic hastening of atmospheric oxidation. It is in fact possible in this way to decrease or destroy vitamin E in the highest known natural source of it, that is, in wheat germ, for the oil subsequently extracted from such germ does not invoke fertility at 20 g doses, whereas otherwise a gram is invariably efficacious. Such wheat germ oil, thus enormously reduced in its fertility-conferring power, is nevertheless effective in the prevention of the muscular dystrophy of suckling young rats when fed from the tenth day on (Goettsch and Ritzmann13).
We had a somewhat parallel experience in the restoration of normal growth to E-low females characteristically slowed at the fifth month. We had permitted ferric chloride to act on wheat germ oil and had destroyed at least nine-tenths of its fertility-conferring power but not its power to promote growth. The above experiments bring up the question of whether the same chemical configuration in alpha-tocopherol is needed for the normality of both growing embryos and the postnatal development of the muscular and nervous systems—very considerably lower levels sufficing for the last-mentioned requirements—or whether while tocopherol will invariably prevent neuromuscular abnormality, portions of the tocopherol molecule that are not curative of sterility will do so equally well.
A settlement of this question has not yet been effected but may be reached by comparing the kinds of biological efficacy unfolded by various oxidative degradation products of tocopherol. The paraquinone still retains most of its fertility-conferring power, although it may be emphasized that its absorption spectrum in the ultraviolet differs considerably from that of alpha-tocopherol typical for the unaltered tocopherol molecule.
We are now in process of testing the lactone.
[Figure showing absorption spectra of alpha-tocopherol and tocoquinone, with title:] Figure 3. (See original for image.)As will also be the case in the second lecture of this series, you will observe, perhaps with disappointment, that unsolved rather than solved problems have been brought to the fore. The latter have not been neglected—the triumphs of research in this field have been emphasized wherever they have been secured, but the delineation of known and unknown, as light and darkness, gives desirably sharp boundaries to our knowledge and is preferable to envisioning a field as all twilight or the light before dawn. I have not felt it necessary to take the time to deprecate premature claims for the widespread need of vitamin E on the part of domestic animals or human beings, though this may well turn out to be the case. The myopathies in man will soon be investigated empirically with tocopherol, but it is necessary to emphasize that this has been shown to be primarily, if not entirely, a prophylactic rather than a curative agent. Beginning deficiencies and especially those of purely myogenous origin may conceivably be helped by it, but this domain constitutes territory that I have characterized as not yet with light. Nothing would be more welcome could it occur, for it has been well said that medical practice has remained “awestruck and bewildered in the presence of diseases ravaging the muscles, the physician only too often being no more than a helpless onlooker, watching the progressive course of deterioration.”
I would return to characterize the outstanding enigmas in the field I have sought to bring before you—enigmas that I do not doubt may be resolved by physicians and investigators in this audience. They are:
- What is the “specificity” of chemical structure in vitamin E responses, and are different chemical portions of the tocopherol molecule necessary for reproductive and neuromuscular normality?
- What is the actual mode of action of the vitamin in the physiology of embryos, seminiferous epithelium, and neuromuscular apparatus?
- What is the cause of the death of vitamin-E–free sucklings, and how does spontaneous recovery ensue?
- What analogous human clinical conditions exist either of myogenic or neurogenic origin?
By Herbert M. Evans, Director of the Institute of Experimental Biology, University of California. Reprinted from Journal of the Mount Sinai Hospital, Vol. VI, No. 5, 1939, by the Lee Foundation for Nutritional Research.
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