Functions of vitamin A
Constituents of visual pigments
The best-defined function of vitamin A is its role in the visual process. Vitamin A aldehyde, ii-Gis-retinal, combines with the protein opsin, to form rhodopsin, or visual purple, in the rods ofthe retina of the eye, which are responsible for vision in dim light (scotopic vision). When light strikes the eye, the rhodopsin is bleached to yield the original protein opsin and retinal. The retinal is converted to retinol and, although most of it is reconverted to retinal to combine again with opsin, some is lost and must be replaced. Adaptation to dim light depends on the completion of the cycle. When bright light causes excessive bleaching of the visual purple, the eyes' ability to regenerate it appears to be directly related to the amount of vitamin A available. The "dark adaptation" test, which measures the eyes' ability to recover visual acuity in dim light, has been used as a means of determining vitamin A status. Insufficient vitamin A for the synthesis ofrhodopsin results in night blindness, or nyctalopia.
The cones of the retina, which are responsible for vision in bright light (photopic vision), also contain a light-sensitive vitamin A-protein complex, iodopsin (a photo-sensitive violet pigment).
Maintenance of epithelial tissue
Vitamin A has long been associated with the maintenance of normal epithelial tissue, but it is only recently that some metabolic explanations have been found for this function of vitamin A. Animal studies indicate that during cell differentiation the basal cells of the epithelia have two alternative pathways open to them, depending on the availability of vitamin A. If adequate amounts of the vitamin are present they form columnar, mucussecreting goblet cells, whereas, if vitamin A is lacking, they keratinize. the effect of vitamin A on other types of epithelial tissue can be explained further by proposing that different tissues have varying threshold levels for vitamin A.
There are four suggested types of epithelial tissue with different threshold levels for each. The lowest threshold is indicated for the simple columnar epithelium lining the gastrointestinal tract. During differentiation in the presence of vitamin A these basal cells form mucussecreting goblet cells. Squamous cells are formed in vitamin A deficiency. Next in order of threshold levels are the epithelial cells lining the trachea; these also normally consist of simple columnar cells, but in the absence of vitamin A they differentiate into stratified squamous tissue. The corneal epithelium is an example of stratified squamous tissue, which has a still higher threshold for the vitamin, but in a state of vitamin A deficiency produces keratin. Finally, the highest threshold level of vitamin A is proposed for the cells of the epidermis; normally they produce some keratin, but lacking vitamin A, they produce increased amounts.
When the same level of circulating vitamin A is available to these tissues, it must either possess different "potencies" in different cells, or its entry to the cells must be regulated. The second possibility is supported by the recent demonstration that the plasma retinol carrier, RBP, attaches to a specific cell-surface receptor ofthe target cell and releases retinol inside the cell. It remains to be established whether the cell-surface receptors actually regulate the entry of retinol to the cells. Another specific protein, cellular retinol-binding protein (CRBP), binds the vitamin inside the cell and, presumably, delivers it to its cellular site of action. The existence of a 'cellular retinoic acid-binding protein (CRABP) distinct from CRBP has also been demonstrated.
Although the mechanism for the role of vitamin A in modifying cell differentiation has not been identified, evidence indicates that ''vitamin A is capable of in flu encing protein synthesis directly or indirectly, an effect that results in observable fine structural differences in many of the affected cells.
A mechanism similar to that of steroid hormone action has been postulated for vitamin A function in cell differentiation and is increasingly supported by experimental evidence. It now has been demonstrated that both retinol and retinoic acid, attached to their respective cellular carriers (CRBP and CRABP), bind to specific receptorproteins of cell nuclei. I t is proposed that this binding is a step comparable to the delivery of the vitamin to the cell and that it results in release of the vitamin inside the nucleus, where its interaction with the genome influences its expression, leading to differentiation.
In vitamin A deficiency, it has been observed that the membranes lining the nose, throat, trachea and other air passages, the gastrointestinal tract, and the genitourinar) tract show changes in the epithelial cells. A decrease in taste and smell thresholds has also been noted. Rough, dry, and scaly skin, especially on the arms and thighs due to increased keratinization, may also occur with vitamin A deficiency.
whenever these tissue changes occur, the natural mechanism for protection against bacterial invasion is impaired, and the tissue may easily become infected. 8inical observations show that normal mucous membranes lining nose, throat, sinuses, and ear passages are the best defense against infections and that adequate -itamin A is an important factor in maintaining the nor:nal functions of these membranes. Renal calculi may also related to the keratinization of the urinary tract.
Damage to the epithelial layer of the eye is one of the important signs of vitamin A deficiency in humans, particularly children. There is a drying and thickening of the conjunctiva, the tear ducts fail to secrete, and keratinization results, with the epithelial cells ofthe cornea becoming opaque and sloughing off. Infection and permanent blindness may follow if vitamin A is not administered. It should be noted that this action of vitamin A in the eye is distinct from its function in the visual process.
Maintenance of bone growth
Bones also depend on vitamin A for normal growth d development, and this function of the vitamin is ought by several investigators to relate to cell changes t occur during differentiation. When vitamin A is deficient, periosteal progenitor cells in nes and the fibroblasts in collagen have priority in synthesizing collagen fibers and ground substances at the ense of the remodeling osteoclasts and fibroclasts. Evidence ofthis defect is seen in the crippling that occurs in young rats fed a vitamin A deficient diet.
The nerve damage that frequently appears in vitamin in vitaminn deficiency may be traced to the compression of growing tissue in a skeleton that ceases to grow rather than as a direct result of vitamin A deficiency.
Gowth and reproduction
Failure to grow is noted in vitamin A deficiency, as it in many other nutrient deficiencies, before any other symptoms appear. The need for vitamin A for normal growth appears associated with protein utilization, weight gain, and perhaps cell mitosis, although simple ganisms, which grow by cell division, do not require vitamin A.
Vitamin A is essential to normal reproduction in rats, pigs, and other animals. Studies have shown that for successful reproduction and lactation the diet must furnish more vitamin A than is needed for good growth. Female rats on a minimal supply of vitamin A intake may show no outward signs ofvitamin A deficiency yet are not e to bear or rear vigorous young. With an outright lciency there is interference with the normal estrus Ie in the female and a testicular degeneration in the male rat. These symptoms appear related to cell changes, which occur during differentiation. Sows deprived of ade.!late vitamin A may give birth to litters of pigs with defective eyes or without eyeballs. This finding was one of the first evidences that prenatal malnutrition may cause abnormalities in the fetus.
Other roles
Vitamin A is believed to be essential for the maintenance of normal cellular membrane structure and function. Both vitamin A deficiency and excess appear to cause membrane instability. The synthesis of a number of specific glycoproteins in different tissues appears to be influenced by the availability of vitamin A.Transfer of mannose to glycoproteins of the intestinal mucosa and other tissues is believed to involve formation of mannosylretinylphosphate as an intermediate from which the mannose residue is transferred to a protein acceptor.
Mild anemia has been associated ,with vitamin A deficiency, both in human population surveys and in experimentally-produced human and animal deficiencies. On the basis of animal studies, impaired mobilization of iron stores from the liver has been proposed as the cause of the anemia.
The role of vitamin A and its derivatives (retinoids) in the prevention of certain types of cancers of epithelial origin has been under investigation for several years. 20 A number of synthetic derivatives of vitamin A and its two naturally occurring metabolites, retinoic acid and 5,6-epoxyretinoic acid, appear to have anti-tumor activity in experimental animals by inhibiting tumor promotion, a phase following tumor initiation by a carcinogen. Whether vitamin A nutritional status plays a role in the development or prevention of certain cancers in humans is still uncertain. The homeostasis of the thyroid hormones appears to be disturbed by vitamin A deficiency. An effect on the brain's thyroid hormone receptors through glycoprotein synthesis has been postulated.
