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Term Paper on Lipid-Soluble Vitamin # 1. Vitamins A:
In his experiments on young rats that were fed defined diets, Hopkins demonstrated that the animals did not grow if lard was the sole dietary lipid. When a small quantity of milk was added to this diet, the animals thrived. The “accessory food factor” in the milk was isolated shortly thereafter in the laboratories of T. B. Osborne and L. B. Mendel, and McCollum and Davis.
The fat- soluble factor later to be designated vitamin A could be distinguished from vitamin D. Its structure was determined by P. Karrer in 1931. In the early 1920s the laboratories of O. Rosenheim and J. Drummond had shown that vitamin A activity could also be attributed to carotenoid pigments of plants. Subsequent dietary studies demonstrated that these substances contain inactive precursors, or pro-vitamins, of A, which are convertible to the active vitamin in the intestinal mucosa of mammals.
Our only natural sources of preformed vitamin A are animal products. As used in modern nutritional science, “vitamin A” is a collective term and refers to all biologically active species of the vitamin. Thus, the alcohol, aldehyde, and acid forms of A are designated as retinol, retinal, and retinoic acid, respectively.
In mammalian tissues the most common form of vitamin A is retinol (or A1) –
Vitamin A2 (3-dehydroretinol), which has another double bond between C-3 and C-4 in the ring, occurs in freshwater fishes. The structure of β-carotene (provitamin A) is as follows –
The isoprene units, which are the intermediates in the biosynthesis of the carotene, are outlined in the structures. The conversion of β-carotene to A1 occurs in the intestinal mucosa and begins with an attack by O2 at C-15. The enzyme is an iron-dependent dioxygenase –
As it is formed, the retinol (trans form) is esterified with long- chain fatty acids, primarily palmitic. The esters are incorporated into chylomicra and enter the blood via the lymphatics for transport to the liver, where they are stored in the Kupffer cells.
Vitamin A is released from the liver as retinol and is carried in the blood bound to a specific α-globulin (retinol-binding protein). This complex combines with plasma prealbumin in a ratio of 1: 1 and is the vehicle for transporting the retinol to a specific receptor in the choroidal surface of the retinal epithelium.
Vitamin A deficiency affects all human tissues and several metabolic roles of the vitamin have been identified. However, the only physiologic activity for which the molecular events can be described is that of the visual cycle.
The critical chemical event on this process is light-induced isomerization of the aldehyde form of the vitamin, 11-cis-retinal –
This change in configuration results in the dissociation of the all-trans-retinal from a specific protein (opsin) and the triggering of a nerve impulse to be transmitted to the brain. These reactions are a part of the cyclic sequence of energy transductions that permit light, to be perceived by the brain.
The function and metabolism of retinoic acid in humans is not defined. For rats this form of the vitamin can partially replace retinol in the diet, and it can enhance growth of bone and soft tissue. Unlike retinol, retinoic acid is not stored in the liver and is excreted in the urine as a glucuronide. Neither retinol nor carotene is excreted in the urine; any portion that is not absorbed in the intestinal tract may appear in the feces but is usually degraded by intestinal bacteria.
One of the most overt signs of vitamin A deficiency is the degeneration of epithelial tissue. Epithelial cells undergo continuous replacement and differentiation. The essentiality of vitamin A for maintaining these processes is underscored by the morphological changes that occur in the epithelial surfaces throughout the body in a vitamin A deficiency.
Epithelial cells undergo squamous metaplasia, a keratinization process in which the cells become flattened and heaped upon one another. These changes are particularly manifest in the eyes and are characteristic of xerophthalmia and keratomalacia. The early signs of these progressive diseases are night blindness, or nyctalopia. A depleted reserve of vitamin A results in a slower rate of regeneration of rhodopsin. As a deficiency becomes more severe, there is a drying of the conjunctiva.
When the cornea has been affected, the condition can be labeled as Xerophthalmia. If unchecked, the cornea softens (keratomalacia) and permanent blindness can follow. Young children, 1½ to 4 years of age, are more susceptible than adults to vitamin A deficiency. Xerophthalmia is tragically common in tropical countries where children have protein-poor diets.
In a severe deficiency, generalized cornification of epithelial cells is also observed in the sweat glands, the lining of the bronchial tree, the kidney medulla, and the skin immediately surrounding the hair follicles. There is evidence that retinal may enhance mucopolysaccharide synthesis. When this process is impaired in a deficiency, it is reasonable that mucus-secreting epithelial cells could be damaged.
Although it is not yet possible to relate many of the symptoms of vitamin A deficiency to a specific biochemical defect, except for the malfunction in the visual cycle, it appears that the vitamin plays a general role in maintenance of stability of membranes, including those of cellular organelles. It is reasonable that morphologic abnormalities associated with a deficiency could affect functions such as ion transport. In particular, it has been suggested that Ca2+ transport in certain membranes is altered.
For purposes of standardizing measurements of the dietary requirement for vitamin A, an international unit has been defined as the activity equivalent of 0.344 µg of synthetic retinal acetate. Rich sources of retinal are cod-liver oil, liver, butter, eggs, and cheese. Carrots and other yellow vegetables also contain high levels of β-carotene.
As is true for all of the lipid-soluble vitamins, retinal is toxic when ingested in excess. Extended intakes exceeding 15 times the RDA are considered dangerous.
Term Paper on Lipid-Soluble Vitamin # 2. Vitamins D:
“Vitamin D” is a collective term used to describe a group of steroid compounds with anthracitic activity. One of these, chalecalciferal (D3), is synthesized in humans. Its precursor is an ultraviolet-sensitive cholesterol derivative, 7-dehydrachalesteral, present in the skin –
It will be recalled that 7-dehydrachalesteral is also a precursor of cholesterol. When the skin is exposed to sunlight, this compound is converted to chalecalciferal –
Since mast natural foods comprising normal diets contain little or no D vitamins, this ultraviolet light-dependent reaction is the principal route whereby humans are provided chalecalciferal. If exposure to sunlight is inadequate or if the preformed vitamin is not supplied, in the diet, rickets will result. Rickets can be considered, therefore, as a sunlight-deficiency disease rather than a dietary-deficiency disease.
The antirachitic action of chalecalciferal requires that it be converted into two other active compounds, 25-hydraxychalecalciferal and 1, 25-dihydraxychalecalciferal. Following its formation in the stratum granulosum of the skin, the chalecalciferal is transported to the liver, complexed with an α- globulin. Here the molecule is hydraxylated at C-25 by a mitochandrial enzyme system requiring NADH and O2.
The second hydroxylation (at C – 1) occurs in the kidney. This reaction is stimulated by parathyroid hormone and a low-plasma phosphate. The 1, 25-dihydraxychalecalciferal is secreted for transport to two major target tissues, the small intestine and bane. Its primary effects of D3 are to increase the absorption of calcium ions by the mucosal cells and to enhance mobilization of calcium in bane.
1, 25-Dihydraxychalecalciferal can be considered to be a hormone. It is synthesized endogenously at one site, the skin, and exerts regulatory functions at distant sites, the small intestines and bane. Unlike the other hormones essential for humans, however, this compound or an appropriate precursor must be provided in the diet if its synthesis from 7-dehydrocholesterol is impaired. This would be the case for a child, for example, who is not exposed to sufficient sunlight.
Very few natural foods contain cholecalciferol. The richest sources are liver oils of fish, which presumably obtain the vitamin from the plankton exposed to sunlight near the surface of the ocean. One of the most common dietary supplements of the D vitamins is that obtained by irradiating yeast ergosterol to yield calciferol (D2).
Another product of this reaction is tachysterol. It is not active but can be reduced catalytically to the dihydroform, which is antirachitic. A component of earlier commercial vitamin D preparations, obtained by irradiation of ergosterol, was designated as D1. This label is no longer used.
The antirachitic efficiency of the D vitamins must be attributed in large measure to their transformation to 1, 25-dihydroxycholecalciferol. This sterol promotes the synthesis of a calcium-binding protein from an intestinal protein, which participates with a Na+-dependent ATPase in transporting calcium at the microvilli of the intestinal absorption cells. In addition, the dihydroxycholecalciferol is involved in inducing bone mineral mobilization.
Less D than A is stored in the body and adipose tissue is the major storage site. The catabolic pathways for the D vitamins are not well defined. The principal excretory route is in the bile, in which some breakdown products are found as glucuronides.
An international unit of the D vitamins is equivalent to the biologic activity of 0.05 µg of calciferol or 0.025 µg of cholecalciferol (D3). A daily dietary intake of 400 IU for normal individuals of all ages does not impose any danger of toxicity.
Term Paper on Lipid-Soluble Vitamin # 3. Vitamins E:
Vitamin E is sometimes referred to as “the vitamin in search of a disease.” Forms of the vitamin are found in human tissues and there is circumstantial evidence that it is needed for normal metabolism. However, many of the manifestations of vitamin E deficiency observed in rats, dogs, rabbits, and guinea pigs are not applicable to humans.
There is no satisfactory evidence to date, for example, to support the widespread popular claims that vitamin E can help ailments such as aging, arthritis, acne, muscular dystrophy, sterility, impotence, or habitual abortion. Fortunately, the vitamin does not appear to be toxic. Some enthusiasts have been reported to eat as much alga day without deleterious effects.
Shortly after the growth-promoting and antirachitic activities of “fat-soluble A” had been distinguished) another lipid-soluble factor, later designated as E, was found in vegetable oils. The laboratories of H. A. Mattill and R. E. Conklin, and H. M. Evans and K. S. Bishop, had shown that rats fed cow’s milk exclusively, or a diet of casein, cornstarch, lard, butter, and yeast did not reproduce.
Although females became pregnant, the fetuses were either aborted or resorbed. In males given the deficient diet there was atrophy of spermatogenic tissue, resulting in permanent sterility. The fat-soluble factor that corrected these conditions was found to be present in significant levels in lettuce, wheat germ, and dried alfalfa. Referred to now as the “fertility vitamin,” E was crystallized from the unsaponifable portion of wheat germ oil and was named Tocopherol (Greek for “an alcohol which helps in the bearing of young”).
As in the case of A and D, there are multiple forms of vitamin E. Eight species have been isolated from plant sources. All are derivatives of 2-methyl-6-hydroxychroman –
A distinctive structural feature of all eight compounds is a 16-carbon side chain on C-2. The chain, which consists of isoprenoid units, is saturated in the four E vitamins designated as the tocopherols and is unsaturated in the tocotrienol series.
The E vitamins also differ from each other in the number of methyl groups substituted at positions 5, 7, and 8. The most potent of the eight compounds is a-tocopherol. Of the remaining derivatives, the most active are β-tocopherol, -tocotrienol, and g-tocopherol.
Although the biochemical roles of the tocopherols and tocotrienols are not as yet clearly defined, one possible function that continues to receive attention is their ability to impair auto-oxidation of highly unsaturated fatty acids. Polyunsaturated fatty acids are vulnerable to oxidative attack by oxygen. The process occurs spontaneously by an autocatalytic mechanism that can be triggered by light or the presence of transition metal ions.
The intermediates in the reaction are free radicals and the products are keto and hydroxyketo acids, as illustrated in the following sequence –
A chain reaction of this type can be interrupted by electron donors that serve as scavengers of the free radical intermediates. As a reductant, glutathione functions in this manner (2 GSH + — C—OO—H → GSSG + HOH + —C—O—H). Analogously, as one-electron donors, the tocopherols are also able to react with free radical (and peroxide) intermediates.
Although the mechanisms of these oxidation-reduction reactions are as yet obscure, it has been demonstrated that an oxidation product is di-α-tocopheroquinone–
It should be noted that an intermediate in the formation of the di-α-tocopheroquinone is a-tocopherolquinone–
However, the α-tocopherol → α-tocopherolquinone conversion is not reversible. It remains doubtful, therefore, whether this particular reaction is important in biologic electron-transfer systems. The oxidative degradation of α-tocopherol in man results in the removal of the isoprenoid side chain and oxidation of the chromane ring. The product is excreted as a diglucosiduronate in the bile –
It should be noted that in experimental animals administration of members of the coenzyme Q group can relieve symptoms of a vitamin E deficiency. In addition, a member of structurally unrelated and unnatural oxidants and reductants, including N, N-diphenyl p-phenylenediamine, methylene blue, and thiodiphenylamine, can mimic some of the biologic activities of the vitamin in experimental animals.
Although it is agreed that humans require vitamin E, known cases of deficiency are rare and symptoms are not well established. There is a plethora of reports showing that red cell hemolysis by hydrogen peroxide in vitro is prevented by administration of the vitamin and that the requirement of the vitamin is related to the level of polyunsaturated fat in the diet.
Some premature infants have an inadequate store of E and develop a macrocytic anemia that can be corrected with diet supplements of the vitamin, together with iron and folic acid. In conditions of prolonged steatorrhea, in which absorption of the vitamin and other fat-soluble essentials are poor, there is impairment of muscle development and a creatinuria occurs.
As underscored earlier, the physiologic abnormalities observed in experimental animals made deficient in vitamin E are diverse and include infertility and reproductive failure, muscle degeneration, encephalomalacia and exudative diathesis, hepatic necrosis, and steatitis.
Because of the importance of unsaturated fatty acids to the integrity of membrane structure, it has been suggested that the varied pathology resulting from a deficiency of the vitamin is related to uncontrolled auto-oxidative reactions in the tissues.
The E vitamins are widely distributed but the vegetable oils are particularly rich sources. One international unit of E is defined as the biologic activity of 0.67 mg of D-α-tocopheroI.
Term Paper on Lipid-Soluble Vitamin # 4. Vitamins K:
In the late 1920s two Danish investigators, H. Dam and H. Schonheyder, described a hemorrhagic condition in chicks fed a fat-free diet. Similar observations were made by W. D. McFarlane in England. Shortly thereafter the Danish laboratories demonstrated that the bleeding could be prevented when the chicks were given either extracts of alfalfa or decayed fish meal.
The active factors from the two sources were designated as K1 and K2, respectively (K for koagulation vitamin), and in nutritional analyses could be distinguished from vitamins A, D, and E. Later in the decade the vitamins were identified by P. Karrer and were synthesized in the United States. K1 (phytomenadione) is the only form of the vitamin that occurs in plants.
Its structure is as follows –
Comparable with the tocopherol, K contains a long side chain consisting of isoprenoid units. K2 was found to be of bacterial origin and exists as a number of analogs that differ only in the length of the side chain. The entire side chain is comprised of farnesyl units in all members of the K2 group and n can range from 4 to 13 –
The only known biologic role of vitamin K in human metabolism is its promotion of the hepatic synthesis of four of the zymogens in the blood-clotting cascade. Specifically, K is required for the synthesis of the g-carboxylglutamate residues needed for Ca2+ binding by these proteins.
In view of the ubiquity of K in all living forms, there is the possibility that the vitamin may have a generalized function in enhancing –g-carboxylation of glutamate residues in proteins other than those required for blood clotting. Because the naphthoquinone moiety is reversibly oxidized and reduced, it has also been suggested that vitamin K may play a role in certain electron transfer systems of animal tissues.
An analog of K is dicumarol, which is a potent antagonist of the vitamin. This compound was found to be the hemorrhagic factor in “sweet clover disease,” the serious syndrome that develops in cattle and hogs that eat spoiled sweet clover hay. This compound now has wide application in clinical medicine as an anticoagulant.
Because of its widespread occurrence in foods and because of its production by intestinal bacteria, available vitamin K is seldom limiting in human adults. Deficiencies can be associated with faulty secretion of bile salts, intestinal obstruction, diarrheal disease, or prolonged administration of sulfa drugs or other intestinal antiseptic drugs.
Not infrequently, newborn infants may present a hemorrhagic condition during the period before the normal bacterial flora are established. Although no RDA for vitamin K has been established, it has been estimated that neonates require 0.15 to 0.25 µg kg-1 daily; it is recommended that the intake for adults be 2 to 10 times this level.