Duane E. Ullrey
contents
Abstract ... 104 Vitamin Beginnings... 104 Vitamin A and Provitamin A Carotenoids ... 106 Vitamin D ... 107 Vitamin E ... 108 Vitamin K ... 109 Thiamin ... 109 Riboflavin ... 109 Niacin ... 110 Pantothenic Acid ... 111 Vitamin B6 ... 111 Biotin ... 112 Folacin ... 112 Vitamin B12 (Cobalamin)... 113 Vitamin C ... 114 Minerals Are Not Just Rocks ... 114 Calcium ... 115 Phosphorus ... 116 Magnesium ... 117 Sodium ... 118 Potassium ... 118 Chloride ... 119 Iron ... 119 Copper ... 120 Zinc ... 121 Manganese ... 122 Iodine... 122 Fluoride ... 123 Molybdenum ... 123 Selenium ... 123 Chromium ...124 Conclusions and Study Topics ...124 Note ... 125 Bibliography ... 125
AbstRAct
The history of the discovery of vitamins and essential minerals has been reviewed, including particularly significant findings from the seventeenth to the late twenti-eth century. Current knowledge of functions, absorption, metabolism, and dietary sources of 4 fat-soluble vitamins, 9 water-soluble vitamins, and 15 mineral elements required by humans and many animals is included. Quantitative requirements for these nutrients at various ages, physiological states, levels of physical activity, and environmental circumstances are regularly revised based on new data. Ranges of cur-rently recommended allowances for these nutrients in human diets are presented.
vItAmIn begInnIngs
Identification of biologically vital elements in the late 1700s, during the “chemi-cal revolution” in France, provided a foundation for subsequent discoveries of the essential nutrients. In 1842, Justus von Liebig, a German organic chemist, stated that protein was the only true nutrient, providing both the structure of muscle and the energy for its contraction. However, an 1847 account of scurvy in Scottish prisoners consuming ample protein (but no potatoes) and its prevention by lemon juice (con-taining negligible nitrogen) belied Liebig’s conclusion. In fact, James Lind showed in 1746, in a controlled experiment, that citrus fruit, but not sulfuric acid or vinegar, cured scurvy. Thus, the effectiveness of oranges, lemons, and limes was known for almost 200 years before the active agent was finally identified in 1932 as ascorbic acid, 4 years after its isolation from adrenal glands by Albert Szent-Györgi.
Rickets was common in young children in large industrialized cities in Western Europe during the late 1800s, even when calcium intakes appeared adequate. Those affected were often fed breast milk substitutes (which tended to be low in fat) and had limited sun exposure due to airborne pollution. Walter Cheadle in 1888 con-cluded that rickets could be prevented by cod liver oil, and Theobald Palm noted in 1890 that rickets was rare in regions with lots of sunlight. In 1924, it was established that ultraviolet (UV) irradiation of rats or of their diet would prevent the disease.
The activated dietary factor was found to be lipid soluble, was named vitamin D (because ascorbic acid had previously been designated vitamin C), and was crystal-lized in 1931.
Other observations relevant to the vitamin story were made by the microbiolo-gist Pekelharing in 1888 concerning beriberi in the army of the Dutch East India colony. Although he thought an unusual bacterial infection might be responsible for this condition, an infectious origin could not be confirmed. Knapp in 1909 observed eye lesions (xerophthalmia and keratomalacia) that were responsive to cod liver oil in rats fed a purified diet. Ultimately, the curative factor was identified and named vitamin A.
Despite this early history and studies from 1900 to 1911 by Gerritt Grijns, who concluded that a polyneuritis in chickens fed white rice was caused by a deficiency of an unstable, water-soluble, organic compound, the vitamin era is commonly stated to have begun in 1912 with the studies of beriberi in humans by Casimir Funk. He isolated a water-soluble organic compound containing an amine group from rice
polishings that was effective in preventing or curing this disease. Funk believed this was a vital amine and coined the term “vitamines” to include this and other, yet-to-be-identified, vital factors. The “e” was dropped when it was established that not all vitamins contained amine groups. E. V. McCollum and associates concluded in 1916 from their studies with purified diets (begun at least 3 years before) and from studies of others that there was an unidentified fat-soluble A (needed for growth and preven-tion of xerophthalmia) and an unidentified water-soluble B, which eventually proved to be the antiberiberi factor found by Funk. Thiamin (B1) was isolated in 1926 and its structure established in 1936.
Pellagra, a disease characterized by dermatitis, gastrointestinal problems, and mental disturbances, was commonly observed in the early 1900s, particularly in the southern United States where corn was a dietary staple, and meat and milk intakes were limited. Although some proposed that it was infectious or caused by a patho-genic mold, Joseph Goldberger and associates, using a dog model, showed in 1928 that pellagra could be cured by yeast. Following isolation of a known chemical, nicotinic acid, from yeast, it was established in 1937 that either nicotinic acid or nicotinamide (jointly designated niacin) were effective antipellagrins. Later, it was found that corn is low in tryptophan, an amino acid that can serve as a precursor for niacin synthesis in animal tissues (if the tryptophan supply is adequate). In addition, an appreciable amount of the niacin in corn is bound and unavailable for absorption unless treated with alkali, as in production of tortillas.
Some patients with pellagra still showed lesions about the mouth (cheilosis) even after treatment with niacin. Yeast that had been autoclaved lost its thiamin activity but still was effective against these lesions. The effective agent was termed B2 but was soon found to be a complex of factors. The agent effective against cheilosis was identical with a greenish-yellow fluorescent pigment isolated from whey in 1935 and was subsequently named riboflavin.
Again, yeast proved useful when in 1931 it was found to cure a macrocytic anemia of pregnancy commonly seen in Mohammedan women in Bombay, India. Lucy Wills induced this anemia, and a leukopenia, in rhesus monkeys fed a poor Bombay diet.
These conditions responded to extracts from yeast or from liver but did not respond to any of the then-known vitamins. The effective factor was temporarily designated vitamin M for monkey. By 1944, it was established that a compound isolated from spinach supported growth in bacteria and in chicks and prevented macrocytic ane-mia in the latter. It was named folic acid from its origin in foliage.
The 1930s and 1940s were a particularly active period in vitamin research, and additions to the water-soluble list by 1937 included pantothenic acid, pyridoxine (B6), and biotin. A fat-soluble dietary factor shown in 1922 to be required for reproduction by rats, and eventually to prevent certain muscular dystrophies, was named vitamin E and was isolated in 1935. Another fat-soluble vitamin, found by Henrik Dam in 1935 to prevent hemorrhages in chicks, was named vitamin K (for “koagulation” in Danish). The last on the list of generally accepted vitamins, isolated in 1948, was water soluble, contained cobalt, and was named vitamin B12. It was found in ani-mal tissues, soil, and certain bacteria but not in higher plants. If the diet contained adequate cobalt, microorganisms in the rumen of cattle or sheep, or in the cecum and
colon of horses, were found to synthesize sufficient vitamin B12 to meet their needs.
The structure of vitamin B12 was established in 1955.
vitamin a anD Provitamin a CarotenoiDs
The term vitamin A refers to a group of compounds possessing the biological activ-ity of all-trans-retinol. They are important for vision, cell growth, communication between cells, and differentiation of cells into specific functional types. They are vari-ably soluble in lipids and organic solvents but insoluble in water. Following digestion and release from the dietary matrix, their absorption is enhanced by bile salts and pancreatic lipase, which promote formation of small lipid droplets (micelles) in the intestinal lumen, within which retinyl esters, such as retinyl palmitate (a combination of retinol and palmitic acid), are dissolved and hydrolyzed. Retinol is taken up by the mucosal cells lining the intestine (enterocytes) and incorporated into chylomicrons (lipoprotein particles) that are transported into the lymph and then into the general blood circulation. The chylomicrons deliver retinyl esters, some unesterified retinol, and carotenoids to the liver and other (extrahepatic) tissues. Retinyl esters that have been stored in the liver are hydrolyzed before transport to the peripheral tissues in association with a complex of retinol-binding protein and transthyretin.
Over 600 carotenoids have been identified, but fewer than 60 have provitamin A activity. Those that do undergo conversion in the body to retinol. One of the most abundant and most active is β-carotene, which can be split into two retinol molecules;
other common dietary carotenoids, α-carotene and β-cryptoxanthin, potentially yield one. This bioconversion may occur during digestion, followed by absorption of retinol as described. In some species, including humans, provitamin A carotenoids also may be absorbed intact and are subject to postabsorption bioconversion. If not converted to retinol, some carotenoids may function as antioxidants.
Historically, vitamin A activity has been expressed in international units (IU), with 1 IU equivalent to 0.3 µg of retinol. IUs are still used in the literature, but the Food and Agriculture Organization of the United Nations/World Health Organization (FAO/WHO) has adopted retinol equivalents (REs), and the U.S. Institute of Medicine (IOM) has adopted retinol activity equivalents (RAEs), with 1 RE or 1 RAE equiv-alent to 1 µg of retinol. Although these two systems are equivequiv-alent in expressing vitamin A activity of preformed vitamin A compounds, they differ in their assign-ment of activity to carotenoids. Furthermore, the vitamin A activity of provitamin A carotenoids varies with the species fed, its vitamin A status, and the nature of the diet. Thus, it is often preferable to use mass as the basis for estimating contributions of provitamin A carotenoids to the requirement for vitamin A. The IOM has set 1 RAE equal to 12 µg of β-carotene or 24 µg of α-carotene or β-cryptoxanthin in food matrices consumed by humans.
WHO/FAO and IOM estimates of requirements and recommended intakes of vita-min A for humans are not identical but tend to be similar for comparable age classes.
Recommended daily dietary allowances range from 300 RAE for 1- to 3-year-old children to 1300 RAE for lactating females. Whole milk, cheese, butter, eggs, organ meats (particularly liver), and fish are important sources of vitamin A in U.S. diets.
The main natural form of vitamin A in these foods is esters (e.g., retinyl palmitate).
Carrots, spinach, broccoli, peas, sweet potatoes, and squash are good sources of provitamin A carotenoids. Ready-to-eat cereals may be fortified with vitamin A.
Carotenoids may be added to margarine and to diets for poultry or salmon—usually to contribute desired color to edible products. Other foods have been fortified, and in the Philippines, additions of vitamin A to coconut oil significantly improved human retinol status. In addition, it has been shown that provitamin A concentrations in sev-eral vegetables (e.g., carrots, cauliflower, yams, cassava, and rice) can be increased by genetic selection or biotechnical amplification. Termed biofortification, it may be a useful public health measure for control of vitamin A deficiency in economically poor cultures when applied to staple food crops. Pharmaceutical vitamin prepara-tions commonly contain retinyl acetate or retinyl palmitate, and those consumed orally may contain carotenoids as well.
vitamin D
Ultraviolet (UV) irradiation of ergosterol in plants or yeast produces ergocalciferol (vitamin D2), whereas UV irradiation of 7-dehydrocholesterol in skin produces pre-vitamin D3, followed by thermal (body heat) conversion to cholecalciferol (vitamin D3). Effective UV wavelengths are in the UVB range, 280 to 315 nm, although solar wavelengths below 290 seldom reach the skin because they are usually screened out by atmospheric ozone and molecular oxygen. Both vitamin D compounds are mod-erately soluble in lipids and insoluble in water. They are best known for the ability of their metabolically active forms to promote intestinal absorption of calcium and its incorporation into bone, thus preventing rickets in growing young and osteomalacia in adults. However, these active forms appear to have broader metabolic functions and may inhibit the proliferation and growth of certain types of cancer, particularly breast, colon, and prostate. In company with the hormones parathormone and cal-citonin (as well as others), vitamin D maintains normal plasma Ca2+ and phosphate concentrations and thus has an impact on a variety of soft tissue events such as neu-romuscular activity, reproduction, and immune function. Vitamin D2 appears to be only about one third as effective as vitamin D3 in elevating human serum 25-hydroxy vitamin D levels (used to assess vitamin D status).
Vitamin D2 or D3 from the diet is absorbed by dissolution in micelles within the intestinal lumen, passive diffusion into enterocytes, and incorporation into chylomi-crons, which enter the general circulation via the lymph. Chylomicrons may deliver vitamin D to the liver and extrahepatic tissues, or some may be transferred to and transported by D-binding protein (DBP). Vitamin D3, formed following irradiation of the skin, slowly diffuses into the blood and is bound to DBP for transport. To become metabolically active, ergocalciferol and cholecalciferol undergo conver-sion in the liver to 25-hydroxy ergocaliferol and 25-hydroxy cholecalciferol, respec-tively, followed by conversion in the kidneys to 1,25-dihydroxy ergocalciferol and 1,25-dihydroxy cholecalciferol (calcitriol). This last renal conversion also results in a 24,25-dihydroxy cholecalciferol, which appears to have metabolic functions alone or in combination with calcitriol.
Vitamin D activity is expressed in IU, with 1 IU equivalent to 0.025 µg cholecal-ciferol. Dietary vitamin D comes primarily from animal products, such as liver, fish,
beef, eggs, and fortified milk (400 IU/quart) in the United States. Some other foods, such as cereals, bread, and margarine, also may be fortified. Estimated adequate dietary intakes range from 200 IU per day for children to 600 IU per day for adults over the age of 70. It has been estimated that 10 minutes of summer sun exposure of the hands and face will supply about 400 IU, but latitude and time of day (as well as season) may greatly affect this estimate.
vitamin e
The term vitamin E may be applied to eight related natural compounds: α-, β-, γ-, and δ-tocopherol and α-, β-, γ-, and δ-tocotrienol. Unlike most vitamins that have specific metabolic roles or that function as cofactors, vitamin E serves as a chain-breaking antioxidant to protect unsaturated fatty acids in cell membrane phospholipids from oxidative damage by scavenging peroxyl radicals that originate from metabolic reac-tions. Most effective in humans is RRR-α-tocopherol (the natural form, also known as d-α-tocopherol), which has a stereoisomeric R-configuration at 2, 4′, and 8′ posi-tions in the tocopherol molecule. Synthetic α-tocopherol (all racemic or dl) has eight potential stereoisomers, with less biological activity than the natural form and with activity dependent on the R-configuration in position 2. Interaction of α-tocopherol with peroxyl radicals results in its oxidation, but it can be restored to its reduced, and functional, form by vitamin C or glutathione. Selenium-dependent glutathione peroxidase also has antioxidant functions in the body, so the quantitative supply of selenium influences the quantitative need for vitamin E and vice versa.
Steps in the digestion and absorption of vitamin E compounds differ somewhat, depending on chemical form. Tocopherols are found as free alcohols in food, but tocotrienols are commonly esterified. Thus, ester bonds must be hydrolyzed by pancreatic esterase or duodenal mucosal esterase before absorption can take place.
This is also true for synthetic ester forms of tocopherols, such as all rac- or dl- α-tocopheryl acetate.
Absorption of vitamin E alcohols from micelles in the intestinal lumen occurs primarily in the jejunum by passive diffusion. Absorbed vitamin E alcohols are incorporated into chylomicrons within the enterocyte and reach the liver via the lymph and general circulation. Equilibration with or transfer to plasma lipoproteins may occur during transport. Delivery of vitamin E to extrahepatic tissues appears restricted to RRR-α-tocopherol, which is incorporated into very low density lipo-proteins (VLDLs) and bound to a very specific protein made in the liver called α-tocopherol transfer protein (αTPP). Other vitamin E forms are poorly recognized by this transfer protein. A genetic defect in the ability of the liver to synthesize αTPP may result in vitamin E deficiency.
Plants, particularly green leaves and seed oils, are good sources of vitamin E, with α-tocopherol predominating in green leaves and in canola, cottonseed, olive, safflower, and sunflower oils. Corn and soybean oils contain some α-tocopherol, but γ-tocopherol predominates. Vitamin E levels in animal products tend to be low and are concentrated in fatty tissues, with most as α-tocopherol. Recommended dietary allowances range from 6 mg per day for 1- to 3-year-old children to 19 mg per day for lactating women.
vitamin k
Naturally occurring forms of vitamin K include phylloquinone, produced by green plants, and at least eight menaquinones, produced by anaerobic bacteria in the lower digestive tract. Menadione is a synthetic form of vitamin K that must be alkylated in the liver to become active. Dietary phylloquinone is absorbed from the small intestine via dissolution in micelles and passive diffusion into the enterocyte. Menaquinones synthesized by bacteria in the lower tract are absorbed by passive diffusion from the ileum and colon. In the enterocyte, vitamin K is incorporated into chylomicrons and carried via lymph into the general circulation. Vitamin K is involved in blood clotting and in bone mineralization by promoting carboxylation of glutamyl residues in specific proteins required for these processes. There also is evidence of activity of vitamin K in promoting nerve growth and neuronal survival. Phylloquinone con-centrations are particularly high (>200 µg/100 g) in broccoli, collards, kale, spinach, Swiss chard, and watercress. Recommended adequate intakes range from 30 µg per day for 1- to 3-year-old children to 120 µg per day for adult men.
thiamin
Thiamin (vitamin B1), when phosphorylated to thiamin diphosphate (TDP, also known as thiamin pyrophosphate, TPP), plays an essential role as a coenzyme in energy metabolism. It promotes conversion of pyruvate (a three-carbon acid) to acetate (a two-carbon acid), which then enters the citric acid cycle, a key cycle in interconversions of energy metabolites in the body. TDP/TPP is also involved in synthesis of five-carbon sugars (pentoses) and nicotinamide adenine dinucleotide phosphate (NADP), in metabolism of branched-chain amino acids, and in oxida-tion of certain branched-chain fatty acids. Thiamin, as thiamin triphosphate (TTP), appears to activate ion transport in nerve membranes and may be involved in nerve impulse transmission. Thiamin is absorbed from the intestine by an energy- and sodium-dependent transport mechanism at low dietary concentrations, but when intakes are high, absorption is mostly by passive transport (diffusion). Thiamin in the blood occurs either in the free form, bound to the protein albumin, or as thiamin monophosphate (TMP). However, most of blood thiamin is in the red cells, not the plasma. Free thiamin is taken up by the liver and phosphorylated. Most of the thia-min in the liver and other (extrahepatic) tissues is in the form of TDP/TPP. Thiathia-min is widely distributed in foods of animal and plant origin, including liver, muscle meats, legumes, whole grains, and fortified breads and cereals. Thiamin supplements are usually in the form of thiamin hydrochloride or thiamin mononitrate. Recommended dietary allowances range from 0.5 mg per day for 1- to 3-year-old children to 1.4 mg per day for pregnant and lactating women.
ribofLavin
Riboflavin (vitamin B2) exists in free form or as part of two coenzymes, flavin mono-nucleotide (FMN) or flavin adenine dimono-nucleotide (FAD). These coenzymes function as prosthetic groups (nonprotein constituents) for flavoprotein enzymes involved in
oxidation-reduction reactions within intermediary metabolic cycles that are central to energy production. They function in these reactions as oxidizing agents through their ability to accept a pair of hydrogen atoms. Absorption of riboflavin requires that it be freed from any bound forms (protein bound or phosphorylated) before transport into the intestinal mucosa via a saturable, energy-dependent carrier. If food riboflavin concentrations are high, some may be absorbed by diffusion. In the enterocyte, riboflavin is phosphorylated to FMN and then dephosphorylated at the basolateral membrane before entering the blood. Free riboflavin or riboflavin bound
oxidation-reduction reactions within intermediary metabolic cycles that are central to energy production. They function in these reactions as oxidizing agents through their ability to accept a pair of hydrogen atoms. Absorption of riboflavin requires that it be freed from any bound forms (protein bound or phosphorylated) before transport into the intestinal mucosa via a saturable, energy-dependent carrier. If food riboflavin concentrations are high, some may be absorbed by diffusion. In the enterocyte, riboflavin is phosphorylated to FMN and then dephosphorylated at the basolateral membrane before entering the blood. Free riboflavin or riboflavin bound