VITAMIN A (RETINOL)
Vitamin A is a fat-soluble vitamin and one of the first vitamins to be discovered. Vitamin A is required for a healthy immune system, vision, growth and reproduction. Vitamin A supports normal tissue development, which accounts for its influence on taste and hearing. The liver stores 90% or more of this vitamin. Many plants produce a parent compound of vitamin A called BETA CAROTENE, also called “‘provitamin A.” This orange-yellow pigment is stored in fat tissue and other tissues, but comparatively little is stored in the liver, unlike vitamin A. Beta carotene is cleaved to form retinol and an inactive molecule called retinoic acid, which lacks vitamin A activity.
Vitamin A and vision: Perhaps the best known role for vitamin A is its effect on vision. Vitamin A forms a pigment in the eye called visual purple required for night vision, and outright deficiency causes NIGHT BLINDNESS. Large amounts of vitamin A taken daily can delay blindness caused by retinitis pigmentosa, an inherited disease that leads to degeneration of the retina. It is worth noting that vitamin A has no effect on defective vision from other causes, and most vision problems do not involve vitamin A.
Wound healing: Both vitamin A and beta-carotene speed wound healing in lab animals. The effect is quite pronounced when the animals are vitamin-A deficient.
Resistance to infection: Population studies in developing nations has demonstrated that vitamin A reduces death by increasing resistance to infections, such as measles. This is not surprising because vitamin A supports a healthy IMMUNE SYSTEM, including increased production of antibodies and various lymphocytes (disease-fighting cells). Beta-carotene, which is non-toxic, increases T-helper cells even in normal people. Lowered immunity due to surgery has been blocked in patients given large amounts of vitamin A, and it increases the resistance of the digestive system and the respiratory tract to infection. Vitamin A can minimize decreased immunity due to radiation and chemotherapy.
Cancer: Vitamin A and beta-carotene possess anticancer properties. Vitamin A can block cancer cells in cultures, and even block malignancy in animals exposed to cancer-causing agents (CARCINOGENS). A diet rich in beta-carotene and other carotenoids may lower the risk of lung, bladder, larynx, esophagus, stomach, prostate and colon cancer.
A product of vitamin A called retinoic acid and beta-carotene may be able to prevent or eliminate precancerous sores (leukoplakia) in the mouths of smokers. Retinoic acid may also prevent recurring tumors of the head and neck. Another derivative of vitamin A, tretinoin (retin A) may be able to combat precancerous cervical conditions.
Skin conditions: Vitamin A can clear Up ACNE but extremely large doses are required to do so, increasing the risk of toxicity. Derivatives are more effective; for example, tretinoin clears up the most common form of acne, acne vulgaris, and another derivative (etretinate) may be useful for psoriasis. Tretinoin helps with sun-damaged skin, though long-term effects on aging skin are not clear.
Other conditions: Vitamin A supports the mainte-nance and healing of lung tissue and the intestine, and it has been used to treat peptic ulcers and inflammatory bowel disease. Vitamin A deficiency associated with AIDS is linked to decreased T-helper lymphocytes and a higher rate of mortality due to HIV. Because retinoic acid may increase HIV replication, beta-carotene could be the preferred form for supplementation.
Vitamin A is either supplied as such in food, or it is formed from beta-carotene in the body. Fish liver oil and liver are rich in vitamin A. Milk is fortified with vitamin A. Vitamin A palmitate is often the form of the vitamin found in supplements. Its advantage is that it is easily suspended in water, herefore it is easily absorbed by the body. Beta-carotene occurs in yams, winter SQUASH, carrots and CANTALOUPE, as well as in dark-green leafy vegetables like KALE and SPINACH.
The amount of vitamin A in a food can be given in terms of retinol equivalents (RE). One RE is defined as 1 mcg of retinol or 6 mcg of beta-carotene. The uptake of beta-carotene is less than retinol and its conversion to retinol is incomplete. Vitamin A activity may also be expressed in international units (IU). One IU of vitamin A activity equals 0.3 mcg of retinol or 0.6 mcg of beta-carotene. Put another way, 1 retinol equivalent equals 3.33 IU of retinol (preformed vitamin A from animal sources) or 10 IU of beta-carotene (plant sources).
The RECOMMENDED DIETARY ALLOWANCE (RDA) for vitamin A for men (25 to 50 years) is 1,000 mcg of retinol or retinol equivalents (RE) and 800 mcg (RE) for non-pregnant women (or 5000IU daily). In pregnancy the requirement increases to 1,300 mcg. Vitamin A deficiency is common in non-industrialized societies, but a significant number of Americans might also be deficient in vitamin A, particularly young children and others consuming highly processed foods. Factors that increase the need for vitamin A include a high-fiber diet, chronic fat MALABSORPTION, stress and high alcohol consumption. Symptoms of deficiency include coarse dry skin, slow growth, night blindness, frequent infections and anemia.
Women who are pregnant should not take vitamin A supplements. Amounts greater than 10,000 IU (3,000 RE) increase the risk of birth defects. On the other hand, there is no evidence that beta carotene produces birth defects. Vitamin A is stored by the body and it is possible to accumulate too much, leading to toxicity (HYPERVITAMINOISIS). The response to high doses of vitamin A is quite variable. A high intake of 50,000 IU daily (15,000 RE) may be tolerated by some; others may have a reaction with 20,000 IU (6,000 RE). Symptoms of vitamin A overdose include headache, fatigue, dry skin, weakness, nausea, hair loss, blurred vision, bone aches and loss of appetite, jaundice and liver damage are possible. These symptoms usually disappear rapidly when vitamin A supplementation is stopped. In contrast, beta-carotene is relatively safe because it is converted to vitamin A only as needed.
Tretinoin, accutane and etretinate should not be taken by pregnant women or by women who do not use birth control because of the high risk of BIRTH DEFECTS. Vitamin A may cause bone disease in individuals with chronic kidney problems.
Bates, C.J., “‘Vitamin A,” Lancet, 345 (January 7,1995), pp. 31-35.
VITAMIN A: Biochemistry and Applications
The early history of vitamin A has been well described by Moore (1957). McCollum and Davis (1915) found growth factors in food fell into two classes according to their solubility, called by McCollum and Kennedy (1916) fat-soluble A and water-soluble B. Fat-soluble A was renamed vitamin A by Drummond (1920). Its structure was deduced by Karrer et al. (1931). For many years it continued to be called vitamin A or vitamin A alcohol and this usage has not completely died out. But in accordance with the principle that once the structure of a vitamin is known, a specific chemical name should be given to the molecule, it is now designated retinol (International Union of Pure and Applied Chemistry, 1960; International Union of Pure and Applied. Chemistry- International Union of Biochemistry Joint Committee on Biochemical Nomenclature, 1982).
Vitamin A2 (Dehydroretinol)
Vitamin A2 was the name given to a new form of the vitamin found by Edisbury et al. (1937) in some freshwater fish. Its synthesis by Farrar et al. (1952) proved its structure to be 3,4-didehydroretinol; its chemistry has been reviewed by Schwieter and Isler (1967).
Dehydroretinol can be found, mainly in the esterified form, in the liver and intestine of many fishes, both marine and freshwater, but the much higher amounts of retinol mask the presence of dehydroretinol in most marine fish (Lambertsen and Brxkkan, 1969). In many freshwater fish dehydroretinol predominates over retinol (Balasundararn et al., 1956) and, in some, all the vitamin A is in the form of dehydroretinol (Abdullah et al., 1954; Balasundaram et al., 1956).
Vitamin A deficiency
Animals on a diet deficient in vitamin A lose their appetite, cease to grow, show a variety of deficiency signs, including an increased susceptibility to infection, and die.
Some of the signs that have been reported in deficient animals are listed in the next section, which is adapted from Moore (1967). This is not intended to be a comprehensive catalogue; it is included to illustrate the diversity of vitamin A deficiency lesions.
Some lesions produced in experimental animals by vitamin A deficiency (adapted from Moore).
- Failure of appetite
- Cessation of growth
- Decline in body weight
- Drying and keratinization of membranes
- Loss of vision
- Constriction of optic nerve
- Thickening of bladder wall
- Metaplasia of bile ducts
- Degeneration of Kupffer cells
- Nerve degeneration
- Constriction at foramina
- Twisting of nerve
- Defective modeling
- Cancellous bone
- Restriction of brain cavity and spinal cord
- Narrowing at foramina
- Cessation of spermatogenesis
- Abnormal estrus cycle
- Resorption of fetuses
- Cleft palate
- Aortic arch deformities
- Kidney deformities
- Raised cerebrospinal fluid pressure
- Changed resistance to parasites
- Untidy hair or feathers
Moderate excesses of vitamin A can be consumed without harm; they merely increase the liver reserves of retinyl esters. Very large single doses may however be too much for the liver storage mechanisms and persistent overdosage may raise the amounts of retinyl esters in the liver beyond that which the organ is capable of holding or catabolizing.
In such conditions, Mallia et al. (1975) found retinyl esters appeared in rat plasma in large amounts, attached mainly to lipoproteins, evading the normally strict control on the plasma concentration of vitamin A; excessive amounts of the vitamin would reach tissues. Similar observations were made by Smith, F.R. and Goodman (1976) in human hypervitaminosis A.
A very characteristic lesion in experimental animals is thinning and fracture of long bones. Vitamin A is also very teratogenic (Cohlan, 1953; Morriss, 1976; Geelen, 1979).
In man, the main signs are seen in the skin (e.g. erythema, desquamation, and hair loss) and mucous membranes (e.g. cheilitis, stomatitis, and conjunctivitis), with hepatic dysfunction, muscle and joint pains and headache.
Functions of Vitamin A
The only function of vitamin A reasonably well understood at the molecular level is as retinaldehyde in the chromophoric group of the visual pigments, the photoreceptor molecules of eyes (in the rods and cones).
Vitamin A has a function different from and more important than its part in vision. Animals deficient in the vitamin die, and not from lack of visual pigments. This other vital function of vitamin A — the maintenance of life, growth and general health – is commonly referred to as its systemic role.
The systemic function of Vitamin A is different from that in the visual pigments and retinoic acid was capable of supporting life.
There is still much uncertainty, however, about the molecular mechanisms involved in this vital function. Vitamin A is involved in cellular differentiation and proper differentiation of epithelia. These processes involve selective expression of the genome. It is therefore predictable that vitamin A will influence RNA synthesis and it has been shown to affect the production of specific proteins.
When mRNAs from cells are isolated, mRNA from the deficient cells directed translation of the 67,000 Dalton keratin, whereas mRNA from the A-replete cells directed translation of the 52,000 keratin. These are clear demonstrations in vitro of the effect of vitamin A on mRNA and protein synthesis.
It is not known how vitamin A influences mRNA and protein synthesis but one major hypothesis currently under investigation is that it combines with a specific receptor protein in the cytosol to form a complex that is translated into the nucleus, where it influences the structure and function of nuclear chromatin material and thus the expression of the genome (genes).
The second major hypothesis for the mode of action of vitamin A investigated intensely in recent years is that it acts like a co-enzyme, as a sugar carrier in the biosynthesis of glycoproteins.
Vitamin A is necessary for reproduction. This was shown in experiments by Thompson et al. (1964) similar to those in which Dowling and Wald (1960) demonstrated the separation of the visual from the systemic function of the vitamin. Rats maintained on a diet deficient in retinol, but containing instead retinoic acid, grew well and were outwardly healthy. Besides going blind, they also lost the ability to reproduce. In males, spermatogenesis stopped (Howell et al., 1963). Females became pregnant, but the rate of cell division in both placenta and fetus was markedly reduced around the fourteenth day of pregnancy; around the sixteenth day lesions were visible in the placenta and the fetuses were resorbed (Howell et al., 1964); no young were born. Small amounts of retinol restored reproduction to normal (Thompson et al., 1964).
Dietary requirement in man
Vitamin A is needed in only small amounts, but lamentably many of us fail to obtain these amounts.
It should be provided in sufficient quantity to maintain normal health and provide adequate liver reserves for any emergency. Vitamin A requirements have been worked out on such lines. Recommended dietary intakes are published by many countries and FAO/WHO. There are some differences between the basic concepts on which recommended dietary intakes are based (International Union of Nutritional Sciences, 1982). For example, the British recommended daily amounts of nutrients are not minimal amounts that all individuals should consume, but the average amount of the nutrient that should be provided per head in a group of people, if the needs of practically all members of the group are to be met. Given differences in convention, it is not surprising that there are sizeable variations between countries in recommended daily intakes, ranging from 600 mcg retinol in Korea to 1500 mcg in USSR. Most recommended daily intakes however are for 750-1000 mcg retinol (International Union of Nutritional Sciences, 1982).
These are for retinol equivalents, and it is now customary to express the nutritional value of provitamin A carotenoids in terms of retinol equivalents, the convention being that 6 mcg beta-carotene or 12 mcg other provitamin A carotenoids are equivalent to 1 mcg retinol. This convention rests upon assumptions that frequently are not true but taken over a wide spread of plant foods, give an approximation to the truth.
As mentioned above, recommended dietary intakes are not usually minimal levels, and allow for variation between individuals. The International Vitamin A Consultative Group (1976) has suggested that the critical intake to prevent metabolic and chemical evidence of deficiency tends to be about half the recommended intake.
Vitamin A and cancer
The characteristic lesion of vitamin A deficiency is keratinization of normally mucous epithelia, i.e. failure of normal differentiation. Yet cell proliferation continues and vitamin A deficiency often involves hyperplasia of the affected tissue. Most of the fatal malignancies in man are carcinomas, which are tumors of epithelial cells, and some people regard cancer as a disease of differentiation (Hicks, 1983).
The squamous metaplastic changes seen in A-deficiency appear morphologically similar to certain precancerous lesions caused by carcinogens (Harris et al., 1972). Interest was awakened by Lasnitzki’s (1955, 1963) observation that the preneoplastic changes induced by methylcholanthrene in organ cultures of mouse prostate glands could be inhibited and reversed by the addition of vitamin A in vitro.
Many investigations have shown that vitamin A deficiency in experimental animals enhances susceptibility to chemical carcinogenesis and that large doses of vitamin A inhibit the development of some tumors.