Daphne A Roe. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1. Cambridge, UK: Cambridge University Press, 2000.
Folic Acid
The history of the discovery of the B vitamins includes both the recognition that particular diseases can result from dietary inadequacies and the subsequent isolation of specific nutrients from foods that have been found to prevent and to cure those diseases. Most of these dietary deficiencies were first recognized in humans, but in certain instances, the deficiency was produced by feeding restricted diets to experimental animals.
After each of the B vitamins was isolated, extensive biochemical and physiological studies were conducted to define their specific functions. States of B vitamin dependency were also discovered in which the need for a particular vitamin exceeded the physiological level. These vitamin dependencies were found either to have a genetic basis or to be drug-induced.
Moreover, recognition that certain synthetic compounds bearing close chemical resemblance to B vita-mins could block the activity of naturally occurring vitamins has led to a better understanding of vitaminic functions and has provided us with certain drugs that are used in cancer chemotherapy and in the treatment of infections and inflammatory diseases.
Vitamin B research, as well as clinical and public health information, is summarized here to emphasize some significant advances in our knowledge of these compounds. But first a note on nomenclature seems appropriate.
B Vitamin Nomenclature
The confusing nomenclature of the B vitamins can only be understood historically. In 1915 E. V. McCollum and M. Davis concluded that young rats needed two unknown “growth factors,” one fat-soluble and the other water-soluble, and for convenience they called them “factors A and B,” respectively. Casimir Funk had already coined the term “vitamine” in the belief that any unknown factors would prove to have the chemical structure of “amines.” J. C. Drummond then suggested that the term be modified to “vitamin,” which had no chemical significance, and he called the antiscurvy factor “vitamin C.”
Further research showed that “factor B” was made up of at least two components, one heat-labile and the other more stable; these were termed vitamins B1 and B2 respectively. Vitamin B1 was later shown to be the anti-beriberi vitamin, known as thiamine. The B2 factor was again found to be complex. Among other things, it included riboflavin, which was first named “vitamin G” in honor of Joseph Goldberger, who had made classical studies of pellagra in the United States. The designation vitamin B3 was given to a compound that seems to have been pantothenic acid but was sometimes incorrectly used to mean niacin. Biotin was first called “vitamin H” by workers in Germany who had shown that its deficiency in rats resulted in abnormalities of the skin (in German Haut), and folic acid, at one time, was termed “vitamin M” because it was first shown to be needed by monkeys. Today, however, these three letters, namely, G, H, and M, are no longer used, and the vitamins are known by the names riboflavin, biotin, and folic acid and classified as parts of the vitamin B complex.
Other workers claimed higher numbers in the B series when they believed that they had discovered new growth factors. But many of these assertions seem to have been erroneous claims and only two “B” numberings are still in use: B6 for pyridoxine and closely related compounds, and B12 for cobalamin and its derivatives. The coding is convenient because in each case it covers more than one precise chemical compound.
In recent years, some entrepreneurs engaged in selling materials that have been claimed to cure cancer and other diseases have named their products as vitamins in attempts to portray them as essentially natural materials, and so to escape the strict regulations applying to drugs. An example is B17, or “laetrile,” which is not recognized by orthodox nutritionists.
Thiamine
Use of polished rice as a dietary staple has long been known to lead to the development of a disease known as beriberi, which was first described as affecting Japanese sailors as well as prisoners in the Dutch East Indies. Signs of beriberi include paralysis due to polyneuritis and congestive heart failure. Christian Eijkman, a medical officer in Java, was the first to show (1890) that a paralytic illness resembling beriberi could be produced in chickens by feeding them polished rice (Jansen 1950). He, and his successor Gerrit Grijns, also demonstrated that the polyneuritis of beriberi could be cured by feeding rice bran.
In 1912, Funk extracted a substance from rice bran that he believed was the anti-beriberi substance and that he characterized chemically as being an amine. He then coined the term “vitamine” as a contraction of “vital amine.” With the discovery of other organic compounds that were “vital” but not amines, the term “vitamin” was used instead. The anti-beriberi vitamin was named thiamine. The biologically active coenzyme form of thiamine is required for the oxidative decarboxylation of pyruvic acid. Thiamine is also required in the metabolism of glucose and many other enzyme-catalyzed reactions.
It has been shown that alcoholics may develop an acute thiamine deficiency if they drink heavily and concurrently go without food. Their condition of acute thiamine deficiency, which is manifested by a confusional state and paralysis of certain eye muscles, is designated as Wernicke’ encephalopathy. It responds to high doses of intravenously administered thiamine. If this confusional state is not recognized and treated with thiamine, a chronic organic brain disorder develops, associated with dementia. Those who have this disorder may require institutionalization. Korsakoff’s psychosis is believed to be a chronic form of Wernicke’s encephalopathy, and the health costs of caring for persons with this disease have led to the fortification of beers with thiamine in an experimental public health intervention in Australia (Yellowlees 1986).
Nicotinic Acid, or Niacin
Pellagra is a disease that we now recognize as being caused by a deficiency in nicotinic acid (niacin). It is characterized by development of a dermatitis, which appears on areas of the body exposed to strong sunlight; by diarrhea, associated with malabsorption of nutrients; and by a severe confusional state. This disease was first described by Gaspar Casal, who wrote of the diet of Spanish peasants with pellagra or mal de la rosa, as it was then called (the book was published posthumously in 1762).
Because the Spanish peasants who had this disease subsisted on cornmeal, and because corn, particularly moldy corn, was also the dietary staple of other poverty-stricken populations in southern Europe that developed pellagra, it was believed that the disease was caused by eating a corn-based diet, particularly when the corn had been improperly stored and became moldy. It was also observed that the diet of those with pellagra was especially lacking in animal protein.
It was not until 1914, when pellagra had become a problem in the southern United States, that Goldberger began his studies, which ultimately demonstrated that the nutritional etiology of pellagra produced a comparable condition in dogs called “black tongue” and identified foods that were pellagra-preventing (Roe 1973). Later investigators extracted some of these foods, including liver, and attempted isolation of nutrients lacking in the diets of those with the disease. During this period, independent studies by Otto Heinrich Warburg and Walter Christian identified nicotinic acid as one of the substances forming “coferment,” which was thought to be important in normal metabolism. Shortly after this discovery, nicotinic acid was found to be an essential factor for the growth of certain bacteria.
Conrad Elvehjem and his co-workers, who carried out extensive studies at the University of Wisconsin in the 1930s, tested various liver-extract fractions for activity as growth factors in experimental animals. One sample was found to contain a substance that was identified by Wayne Woolley as nicotinic acid. Subsequently, others in Elvehjem’s laboratory cured “black tongue” in dogs by feeding them the nicotinic acid obtained from such liver extracts (Kline and Bau-mann 1971).
Once it was known that nicotinic acid could cure this disease in dogs, Tom Spies gave nicotinic acid to several subjects with pellagra and found that the human disease responded to it as well. The nutrient nicotinic acid was subsequently given the alternate name of niacin in order to avoid lay confusion of the term with nicotine.
Later studies of the metabolism of niacin in experimental animals showed that they could synthesize it from a precursor, which proved to be the amino acid tryptophan. Because animal proteins are particularly rich in tryptophan, this finding helped to explain the old observation that diets of pellagrins were invariably low in meat and milk (Goldsmith 1964).
Nicotinic acid is active biochemically in several coenzyme forms, and it is necessary for the synthesis and breakdown of fatty acids, carbohydrates, and amino acids. In human studies conducted soon after the discovery of its activity as a vitamin, it was found that when large doses of niacin were administered, individuals became flushed. Although this observation was an early indication that niacin might be toxic if given in excessive amounts, it also suggested that high doses might relieve conditions associated with constriction of blood vessels. In fact, the vitamin failed to yield the hoped-for therapeutic advantage, but it was found later that niacin in high doses could reduce blood cholesterol levels (Havel and Kane 1982).
Riboflavin
Riboflavin, another of the B-complex vitamins, was first isolated from the greenish yellow pigment in milk. Its deficiency occurs in populations whose diets are lacking in dairy foods and green vegetables and produces a disease characterized by cracks at the corners of the mouth, sore tongue, dermatitis of the folds of the body, and changes in the eyes that make them sensitive to light exposure. It was realized that some pellagra sufferers in the United States were deficient in riboflavin as well as in niacin. The condition was also described in very low-income, rural populations in India (Sebrell and Butler 1938). In more recent years, this same condition has been identified in alcoholics. Flavins, including two major active forms of the vitamin designated riboflavin, have also been isolated from liver. Furthermore, it has been shown that flavins are necessary for energy utilization and that requirements for riboflavin increase during periods of physical activity (Roe 1991).
Vitamin B6
The term “vitamin B6” embraces a group of closely related compounds: pyridoxine, pyridoxal, and pyridoxamine. Laboratory investigations resulting in the identification of vitamin B6 were launched after it became known that a particular form of dermatitis, which developed in rats fed purified diets, could not be cured with any known nutrient but could be prevented by giving the animals a particular yeast extract.
The early clinical studies of vitamin B6 deficiency were based on observations of infants fed an autoclaved formula diet. Then, during the 1950s, when active research was being conducted on the biochemical functions of vitamin B6, further insight into the clinical manifestations of its deficiency was obtained by putting human volunteers on a diet that lacked the vitamin and giving them a vitamin B6 antagonist at the same time.
Following this study, vitamin B6 deficiency was observed in patients who were given the drug isoniazid for the treatment of tuberculosis. It was then realized that the drug was also a vitamin B6 antagonist. In both the experimentally produced vitamin B6 deficiency and the drug-induced disease, dermatitis and neurological symptoms developed, and later an anemia surfaced as well, in which iron was improperly utilized. Biochemical studies showed that there were three physiologically active forms of vitamin B6 and that these forms are interconvertible. They have been found to function in amino acid metabolism, in the synthesis of heme from which hemoglobin is formed, and in neurotransmitter activity (Roe 1985).
Pantothenic Acid
Metabolic pathways that depend on pantothenic acid include those involved with the biosynthesis of cholesterol and steroid hormones. Abnormalities have been described in several different types of experimental animals placed on diets deficient in pantothenic acid. In rats, these changes included slow rate of growth in young animals and graying of the fur in older animals. The fertility of rats has also been shown to decline, and gait disorders have been observed in pigs. In addition, destruction of the adrenal glands, associated with bleeding into these glands, has been found in postmortem examinations of several species in which the deficiency has been induced.
Little is known of human requirements for the vita-min, but because it is widespread in foods, there is little danger of deficiency. Thus, pantothenic acid deficiency has been described only in humans who are very severely malnourished and in volunteers who have been fed both a pantothenic acid-deficient diet and a pantothenic acid antagonist (Fox 1984).
Biotin
Biotin is another B vitamin that is involved in the biosynthesis of fatty acids. Biotin deficiency has been described in infants as a result of an inborn error of metabolism. A biotin deficiency has also been described in infants and in older individuals with intestinal diseases. Both groups were fed formula diets lacking in biotin, and both were concurrently receiving broad-spectrum antibiotics that prevented the intestinal synthesis of this vitamin (Mock et al. 1985).
Folic Acid (Folacin)
In 1929-31, Lucy Wills and her colleagues described a severe anemia among pregnant women living in conditions of purdah (seclusion) in Bombay. Because of cultural taboos, these women ate a monotonous and limited diet in which green vegetables and fruits were lacking (Wills and Mehta 1929-30; Wills and Talpade 1930-1). The anemia was characterized by a severe lowering of the red blood cell count and the appearance of large immature cells in the bone marrow and in the peripheral blood. This so-called macrocytic (large-celled) anemia was cured by giving the women a yeast extract. Subsequent studies showed that certain crude liver extracts could also cure it.
Wills also reported poor pregnancy outcomes for the Indian women who were anemic. She subsequently described the anemia in other populations who lived on diets that lacked fruit and green vegetables. Later investigations led to the isolation of a nutrient, both from liver and from green vegetables, that prevented and cured the same macrocytic anemia. This nutrient was named folic acid, or folacin. Early investigations of folic acid showed that it existed in several different forms that had a number of critical functions in cell maturation.
In other studies, researchers deliberately synthesized chemical analogues of folic acid and demonstrated that these substances not only blocked the normal activity of folic acid but also prevented cell division. Such findings led to the development of specific folic acid antagonists, including aminopterin and methotrexate, which inhibit the division of malignant cells. Methotrexate, which was the less toxic of the two substances, is now employed to control certain forms of cancer and leukemia (Roe 1990). However, it was also found that if aminopterin or methotrexate was taken during the first trimester of pregnancy, birth defects occurred in the offspring. The defects were shown in rat studies to develop if one or another of these drugs was administered during the gestational period of embryogenesis (Nelson 1963).
Another association of folic acid nutriture has been revealed more recently, namely that the risk of women bearing infants with neural tube defects, such as spina bifida, is greatly reduced if they are given supplementary folic acid from the time of conception through the first trimester. Currently, a debate continues about whether or not it would be desirable to fortify cereals with folic acid as a public health measure to prevent neural tube defects (MRC Vitamin Study Research Group 1991).
Vitamin B12 (Cobalamin)
Vitamin B12 was first isolated as the active factor in liver extracts that, given by injection, maintained subjects suffering from pernicious anemia. This disease was first described by Thomas Addison in the nineteenth century, who observed that it occurred primarily in older men and women and is characterized by the presence of a macrocytic anemia. The changes in the blood picture are identical to those seen in folic acid deficiency. In addition, patients with pernicious anemia may develop an irreversible neurological disorder that leads to sensory loss, including loss of balance. A confusional state may also be present.
Studies of pernicious anemia have revealed that it is an autoimmune disease in which cells in the lining of the stomach are destroyed. As a result, the so-called intrinsic factor found in normal gastric secretion is no longer produced in the stomach and there is a loss of capacity to absorb vitamin B12. Vitamin B12 deficiency can also develop when it cannot be absorbed because of surgical loss of the absorption site in the lower part of the small intestine. Aside from these circumstances, a very low intake of vitamin B12 can also cause pernicious anemia, although such a low intake is unlikely to occur except with people who are strict vegans, since the vitamin is present only in animal foods. Deficiency signs may, however, take several years to develop because of body stores of the vita-min built up in earlier periods.
Investigations of the cause of the neurological complications of vitamin B12 deficiency followed recognition that the same complications may develop in those who are exposed to nitrous oxide (Roe 1985). More recently, more such neurological studies have been carried out on the metabolic defect existing in children with genetic disorders of vitamin B12 metabolism (Metz 1993).
Vitamin B12 has essential functions in the synthesis of the amino acid methionine and is also required for the interconversion and cellular uptake of different forms of folic acid (Buchanan 1964)