Vitamin A was the first recognized fat-soluble vitamin. Although identified as a necessary growth factor in 1913, it was not chemically characterized until 1930. Two groups of researcher, McCollum and Davis at the University of Wisconsin, and Osborne and Mendel at Yale University, make the initial discovery of vitamin A almost simultaneously. They found that young animals fed a diet deficient in natural fats became very unhealthy, as evidenced by their inability to grow and their poor immune function. These researchers also noted that the animals’ eyes became severely inflamed and infected on the restricted diet-conditions quickly relieved by the addition of butterfat or cad liver oil to the diet. Once known as the "anti-infective vitamin," vitamin A recently regained recognition as a major determinant of immune status., Carotenes, some of which can be converted into vitamin A, are also gaining a great deal of attention as immune system enhancers. Because of the vitamin A activity of some carotenes, this chapter explores both vitamin A and carotenes.
Carotenes
Carotenes represent the most widespread group of naturally occurring pigments in nature. They are an intensely colored (red and yellow) group of fat-soluble compounds. All organisms that transform sunlight into chemical energy via the process of photosynthesis do so with the help of carotenes. These compounds not only play a role in the process of photosynthesis, but also play a crucial role in protecting the organism or plant against the tremendous amount of free radicals produced during photosynthesis.
Scientists have characterized over 600 carotenoids, of which only 30 to 50 seem to have vitamin A activity. Biological activity of a carotene has historically been considered synonymous with its corresponding vitamin A activity. However, recent research suggests that this function of carotenes has been overemphasized, and carotenoids have been found to exhibit many other activities. Researchers have described beta-carotene as the most active of the carotenoids because of this higher provitamin A activity, but several other carotenes exert grater antioxidant effects.
Retinol
When isolated in its pure form, vitamin A is a pure yellow crystal that is fat-soluble. Vitamin A is termed retinol, signifying that it is an alcohol involved in the function of the retina of the eye. We find retinol in nature primarily as long-chains. The aldehyde form of retinol is commonly designated retinaldehyde or retinal, while the acidic form is termed retinoic acid. Some scientists suggest that retinol serves only as a precursor to these two active forms of vitamin A – retinal being primarily involved with vision and reproduction, retinoic acid being important in other body functions, such as growth and differentiation.
Synthetic derivatives of retinoic acid have been developed to treat many skin conditions and, more recently, certain forms of cancer. Isotretinoin (13-cis retinoic acid; trade name, Accutane) is used in treating severe cystic acne and disorders of keratinization, such as Darier’s disease and lamellar ichthyosis. Etretinate, an aromatic derivative of retinoic acid, has no appreciable activity against acne, but some consider it more potent than isotretinoin in the treatment of psoriasis. These compounds, however, are not without side effects such as liver damage, nausea and vomiting, and muscle pain.
Absorption
A variety of factors influence the absorption efficacy of vitamin A and carotenes. Unlike retinol, carotenes require bile acids to facilitate absorption. Other factors that affect vitamin A and carotene absorption include: the presence of fat, protein, and antioxidants in the food; the presence of bile and a normal complement of pancreatic enzymes in the intestinal lumen; and the integrity of the mucosal cells. The absorption efficiency of dietary vitamin A is usually quite high (80 to 90 percent) with only a slight reduction in efficiency at high doses. In contrast, beta-carotene’s absorption efficiency is much lower (40 to 60 percent) and it decreases rapidly with increasing dosage. Carotene supplements are better absorbed than the carotenes from foods.
Conversion of Carotenes into Vitamin A
The conversion of provitamin A carotenes to vitamin A depends on several factors, including protein status, thyroid hormones, zinc, and vitamin C. The conversion diminishes as carotene intake increases and when serum retinol levels are adequate. Scientists originally believed beta-carotene and other provitamin A carotenes were cleaved by an enzyme (carotene dioxygenase) in a manner that would yield two molecules of retinal. However, they currently believe that the enzyme nonspecifically attacks any one of the double bonds of the beta-carotene. Therefore, it sometimes may result in the formation of two retinal molecules, but mot often it does not. The retinal formed is then converted to retinol.
Recommended Dietary Allowance
Vitamin A activity was originally measured in International Units (I.U.) One I.U. is defined as .3 micrograms of crystalline retinol or .6 micrograms of beta-carotene. In 1967, an FAO/WHO Expert Committee (Food and Agriculture Organization of the United Nations/World Health Organization) recommended that vitamin A activity be referred to in terms of retinol equivalents rather than in I.U., with 1 microgram of retinol being equivalent to 1 retinol equivalent (R.E.). The amount of beta-carotene required for 1 R.E. is 6 micrograms, while the amount required for other provitamin A carotenes is 12 micrograms. In 1980, The Food and Nutrition Board of the NRC/NAS (National Research Council/National Academy of Sciences) adopted this recommendation. Therefore, the 1980 RDA for vitamin A is stated in micrograms and retinol equivalents.
Recommended Dietary Allowance of Vitamin A
Group Retinol Equivalents International Units
Infants Under 1 Year 375 1,875
Children
1-3 years 400 2,000
4-6 years 500 2,500
7-10 years 700 3,500
Young Adults and Adults
Males 11+ years 1,000 5,000
Females 11+ years 800 4,000
Pregnant females 800 4,000
Lactating females 800 4,000
Beneficial Effects
Science best understands the role of vitamin A with regard to its effects on the visual system. The human retina has four kinds of vitamin A containing photopigments: rhodopsin, present in the rods(the retinal cells responsible for night vision); and three iodopsins, present in each of the different cones that are responsible for day vision (blue, yellow, and red). The vitamin A form found in these pigments is the 11-cis isomer of vitamin A aldehyde (retinal). When a photon of light strikes the rod, the 11-cis retinal splits from the rhodopsin molecule to yield opsin and all-trans retinol. This reaction leads to a change in membrane potential and subsequent transmission of the visual impulse.
When there is bright flash of light (such as oncoming headlights), there is a temporary bleaching of rhodopsin. It may take a moment or two before the retinal is regenerated and sight is returned. It takes longer to adapt if vitamin A levels are low. Poor adaptation to changes in light and poor vision at night are some of the initial findings in low vitamin A states.
Principal Uses
Vitamin A is used primarily as an immune enhancer in viral illnesses and in the treatment of numerous skin disorders. Carotenes are used as antioxidants in the prevention of cancer and cardiovascular disease, as immune-enhancing agents, and in the treatment of photosensitivity disorders.
Dosage Ranges
Intent of use determines dosage ranges for vitamin A. For general health purposes, a dosage of 5,000 I.U. for men and 2,500 for women appears reasonable. During an acute viral infection, a single oral dosage of 50,000 I.U. for one or two days is safe even in infants.
Women who might be pregnant must not use vitamin A supplements;
Instead, use beta-carotene.
Although high-dose therapy of vitamin A may be useful for the treatment of acne and hyperkeratotic skin disorders, a physician should closely monitor the therapy.
With carotenes, a daily dosage of 25,000 I.U. (15 milligrams of beta-carotene) appears to be reasonable for general health. For the treatment of precancerous lesions and immune enhancement, he dosage range is 25,000 to 300,000 I.U. In the treatment of EPP, the dosage should maintain blood carotene levels between 600 to 800 micrograms per deciliter.
Safety Issues
Women must avoid vitamin A supplementation during pregnancy. A recent study published in the prestigious New England Journal of Medicinedemonstrated that dosages greater than 10,000 I.U. during pregnancy (specifically during the first 7 weeks after conception) have probably been responsible for 1 out of each 57 cases of birth defects in the United States. Women who are at risk for becoming pregnant should keep their supplemental vitamin A levels below 5,000 I.U. or, better yet, look to carotenes.
Accidental ingestion of a single large dose of vitamin A (100,000 to 300,000 I.U.) produces acute toxicity in children, resulting in raised intracranial pressure with vomiting, headache, joint pain, stupor, and occasionally papilledema. Symptoms rapidly subside upon withdrawal of the vitamin, and complete recovery always results.
Vitamin A toxicity may occur in adults who take in excess of 50,000 I.U. per day for several years. Smaller daily doses may produce toxicity symptoms if there are defects in storage and transport of vitamin A, which occurs in cirrhosis of the liver, hepatitis, protein calorie malnutrition and in children and adolescents. Signs of vitamin A toxicity generally include dry, fissured skin; brittle nails; alopecia; gingivitis; cheilosis; anorexia; irritability; fatigue; and nausea. Serum levels of vitamin A of 250 to 6600 I.U. per deciliter are typical of toxicity. Prolonged, severe hypervitaminosis A results in bone fragility and thickening of the long bones.
Toxicity is typically encountered during high dose vitamin A therapy for various skin conditions. Although dosages below 300,000 I.U. per day for a few months rarely cause toxicity symptoms, early recognition is still very important. Cheilitis (chapped lips) and xerosis (dry skin) generally appear in the majority of patients, particularly in dry weather. The first significant toxicity symptom is usually headache, followed by fatigue, emotional lability, and muscle and joint pain. Laboratory tests are of little value in monitoring toxicity because serum vitamin A levels correlate poorly with toxicity, and SGOT and SGPT are elevated only in symptomatic patients.
On the other hand, supplementing the diet with beta-carotene does not produce any significant toxicity despite its use in very high doses in the treatment of numerous photosensitive disorders. Occasionally, patients complain of "loose stools," but this usually clears up spontaneously and does not necessitate stopping treatment. Elevated carotene levels in the blood do not lead to vitamin A toxicity, nor do they lead to any other significant disturbance besides a yellowing of the skin (carotenodermia). The ingestion of large amounts of carrots or carrot juice (.45 to 1.0 kilograms of fresh carrots per day for several years) can, however, cause a neutropenia ads well as menstrual disorders. Although the blood carotene levels (221 to 1,007 micrograms per deciliter) of these patients did reach levels similar to those of patients taking high doses of beta-carotene (typically 800 micrograms per deciliter), the disturbances were because of some other factor in carrots. Neither these effects nor any others have been observed in subjects consuming very high doses of pure beta-carotene over long periods of time – e.g., 300,000 to 600,000 I.U. per day 9180 to 360 milligrams beta-carotene, which is equivalent to 4 to 88 pounds of raw carrots). Doses up to 1,000 milligrams per kilogram of body weight have been given to rats and rabbits for long periods of time with on signs of embryotoxicity, toxicity, tumorigenicity, or interference in reproductive functions.
Interactions
Vitamin E and zinc are particularly important to the proper function of vitamin A. A deficiency of zinc, vitamin C, protein, or thyroid hormone impairs the conversion of pro-vitamin A carotenes to vitamin A.
REFERENCE: Encyclopedia of Nutritional Supplements; by Michael T. Murray, N.D.
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