Vitamin A is a generic term for a large number of related compounds. Retinol (an alcohol) and retinal (an aldehyde) are often referred to as preformed vitamin A.
Vitamin A is a generic term for a large number of related compounds. Retinol (an alcohol) and retinal (an aldehyde) are often referred to as preformed vitamin A. Retinal can be converted by the body to retinoic acid, the form of vitamin A known to affect gene transcription. Retinol, retinal, retinoic acid, and related compounds are known as retinoids. Beta (b)-carotene and other carotenoids that can be converted by the body into retinol are referred to as provitamin A carotenoids. Hundreds of different carotenoids are synthesized by plants, but only about 10 % of them are provitamin A carotenoids (1). The following discussion will focus mainly on preformed vitamin A and retinoic acid. Beta-carotene and other carotenoids related to health will be discussed in the phytochemical section of the Micronutrient Information Center.
Retinol activity equivalency (RAE): Different dietary sources of vitamin A have different potencies. For example, b-carotene is less easily absorbed than retinol and must be converted to retinal and retinol by the body. The most recent international standard of measure for vitamin A is retinol activity equivalency (RAE), which represents vitamin A activity as retinol. Two mcg of b-carotene in oil provided as a supplement can be converted by the body to 1 mcg of retinol giving it an RAE ratio of 2:1. However, 12 mcg of b-carotene from foods are required to provide the body with 1 mcg of retinol, giving dietary b-carotene an RAE ratio of 12:1. Other provitamin A carotenoids in foods are less easily absorbed than b-carotene, resulting in RAE ratios of 24:1. The RAE ratios for b-carotene and other provitamin A carotenoids are shown in the table below (2).
Quantity Bioconverted to Retinol
Retinol Activity Equivalency (RAE) ratio
1 mcg of dietary or supplemental vitamin A
1 mcg of retinol
2 mcg of supplemental b-carotene
1 mcg of retinol
12 mcg of dietary b-carotene
1 mcg of retinol
24 mcg of dietary a-carotene
1 mcg of retinol
24 mcg of dietary b-cryptoxanthin
1 mcg of retinol
An older international standard, still commonly used, is the international unit (IU). One IU is equivalent to 0.3 mcg of retinol.
Vision: The retina is located at the back of the eye. When light passes through the lens, it is sensed by the retina and converted to a nerve impulse for interpretation by the brain. Retinol is transported to the retina via the circulation, where it moves into rod cells. The conversion of retinol to all-trans retinal is catalyzed by an enzyme within the outer segment of the rod cell. All-trans retinal can be converted to its isomer 11-cis retinal spontaneously or through the action of an enzyme (isomerase). 11-cis retinal binds to a protein called opsin to form the visual pigment, rhodopsin (visual purple). Rod cells with rhodopsin can detect very small amounts of light, making them important for night vision. When light hits rhodopsin it breaks down in a series of reactions known as bleaching because of the accompanying loss of color. The degradation of rhodopsin leads to the generation of an electrical signal to the optic nerve. The nerve impulse generated by the optic nerve is conveyed to the brain where it can be interpreted as vision. During the degradation of rhodopsin, 11-cis retinal is converted to all-trans retinal and released. The visual cycle is complete when all-trans retinal is converted to 11-cis retinal and bound again to rhodopsin (3). Inadequate retinol available to the retina results in impaired dark adaptation, known as “night blindness.”
Regulation of gene expression: Retinoic acid (RA) and its isomers act as hormones to affect gene expression and thereby influence numerous physiological processes. All-trans RA and 9-cis RA are transported to the nucleus of the cell bound to cytoplasmic retinoic acid-binding proteins (CRABP). Within the nucleus RA binds to retinoic acid receptor proteins. All-trans RA binds to retinoic acid receptors (RAR) and 9-cis RA binds to retinoid receptors (RXR). Once bound to retinoic acid, RAR and RXR form RAR/RXR heterodimers, which bind to regulatory regions of the chromosome called retinoic acid response elements (RARE). A dimer is a complex of two protein molecules. Heterodimers are complexes of two different proteins, while homodimers are complexes of two of the same protein. Binding of RAR/RXR heterodimers to RARE on genes influences their rate of transcription, thereby influencing the synthesis of certain proteins used throughout the body. RXR may also form heterodimers with thyroid hormone receptors (THR) or vitamin D receptors (VDR). In this way, vitamin A, thyroid hormone, and vitamin D may interact to influence gene transcription (4). Through the stimulation and inhibition of transcription of specific genes, retinoic acid plays a major role in cellular differentiation, the specialization of cells for highly specific physiological roles. Most of the physiological effects attributed to vitamin A appear to result from its role in cellular differentiation.
Immunity: Vitamin A is commonly known as the anti-infective vitamin, because it is required for normal functioning of the immune system (5). The skin and mucosal cells (cells that line the airways, digestive tract, and urinary tract) function as a barrier and form the body’s first line of defense against infection. Retinol and its metabolites are required to maintain the integrity and function of these cells (6). Vitamin A and retinoic acid (RA) play a central role in the development and differentiation of white blood cells, such as lymphocytes that play critical roles in the immune response. Activation of T-lymphocytes, the major regulatory cells of the immune system, appears to require all-trans RA binding of RAR (see Regulation of gene expression, above) (4).
Growth and Development: Both deficiencies and excesses of vitamin A are known to cause birth defects. Retinol and retinoic acid (RA) are essential for embryonic development (6). During fetal development, RA functions in limb development and formation of the heart, eyes, and ears (7). Additionally RA has been found to regulate expression of the gene for growth hormone (6).
Red blood cell production: Red blood cells, like all blood cells, are derived from precursor cells called stem cells. These stem cells are dependent on retinoids for normal differentiation into red blood cells. Additionally, vitamin A appears to facilitate the mobilization of iron from storage sites to the developing red blood cell for incorporation into hemoglobin, the oxygen carrier in red blood cells (8,9).
Zinc and vitamin A: Zinc deficiency is thought to interfere with vitamin A metabolism in several ways: 1) Zinc deficiency results in decreased synthesis of retinol binding protein (RBP), which transports retinol through the circulation to tissues (e.g., the retina). 2) Zinc deficiency results in decreased activity of the enzyme that releases retinol from its storage form, retinyl palmitate, in the liver. 3) Zinc is required for the enzyme that converts retinol into retinal (3,10). At present, the health consequences of zinc deficiency on vitamin A nutritional status in humans are unclear (11).
Iron and vitamin A: Vitamin A deficiency may exacerbate iron deficiency anemia. Vitamin A supplementation has been shown to have beneficial effects on iron deficiency anemia and improve iron status among children and pregnant women. The combination of vitamin A and iron seems to reduce anemia more effectively than either iron or vitamin A alone (12).
Vitamin A deficiency and vision: Vitamin A deficiency among children in developing nations is the leading preventable cause of blindness (13). The earliest evidence of vitamin A deficiency is impaired dark adaptation or night blindness. Mild vitamin A deficiency may result in changes in the conjunctiva (corner of the eye) called Bitot’s spots. Severe or prolonged vitamin A deficiency causes a condition called xeropthalmia (dry eye), characterized by changes in the cells of the cornea (clear covering of the eye) that ultimately result in corneal ulcers, scarring, and blindness (3,6)
Vitamin A deficiency and infectious disease: Vitamin A deficiency can be considered a nutritionally acquired immunodeficiency disease (14). Even children who are only mildly deficient in vitamin A have a higher incidence of respiratory disease and diarrhea, as well as a higher rate of mortality from infectious disease, than children who consume sufficient vitamin A. Supplementation of vitamin A has been found to decrease the severity of and deaths from diarrhea and measles in developing countries, where vitamin A deficiency is common (15). HIV-infected women who were vitamin A deficient were three to four times more likely to transmit HIV to their infants (16).
The onset of infection reduces blood retinol levels very rapidly. This phenomenon is generally believed to be related to decreased synthesis of retinol binding protein (RBP) by the liver. In this manner, infection stimulates a vicious cycle, because inadequate vitamin A nutritional status is related to increased severity and likelihood of death from infectious disease (17).
The Recommended Dietary Allowance (RDA): The RDA for vitamin A was revised by the Food and Nutrition Board (FNB) of the Institute of Medicine in January, 2001. The latest RDA is based on the amount needed to ensure adequate stores of vitamin A in the body to support normal reproductive function, immune function, gene expression, and vision. (2).
Adult men ages 19 and older: 900 micrograms (mcg)/day
Adult women ages 19 and older: 700 mcg/day
Cancer: Studies in cell culture and animal models have documented the capacity for natural and synthetic retinoids to reduce carcinogenesis significantly in skin, breast, liver, colon, prostate, and other sites (8). However, the results of human studies examining the relationship between the consumption of preformed vitamin A and cancer are less clear.
Lung cancer: At least ten studies have compared blood retinol levels at baseline among people who subsequently developed lung cancer and those who did not. Among those 10 studies both negative and positive associations were found between serum retinol levels and lung cancer risk. However, only one study showed a statistically significant protective effect. Of more concern are the results of the b-Carotene And Retinol Efficacy Trial (CARET), which was limited to people at high risk of lung cancer (smokers and people with asbestos exposure). About 9,000 people were assigned a daily regimen of 25,000 IU of retinol and 30 milligrams of b-carotene, while a similar number of people were assigned a placebo. After four years of follow up the incidence of lung cancer was 28% higher in the supplemented group (18). At present, it seems unlikely that retinol protects against lung cancer, though the situation may be different for nonsmokers compared to smokers (19).Breast cancer: Retinol and its metabolites have been found to reduce the growth of breast cancer cells in the test tube (20), but observational studies of dietary retinol intake in humans have been less optimistic. In general, epidemiologic studies have failed to find an association between retinol intake and breast cancer risk in women. While two epidemiologic studies have provided some evidence of an inverse association (protective effect), one study showed a positive association between retinol intake and breast cancer risk (21).
Diseases of the skin: Both natural and synthetic retinoids have been used as pharmacologic agents to treat disorders of the skin. Etretinate and acitretin are retinoids that have been useful in the treatment of psoriasis, while tretinoin (Retin-A) and isotretinoin (Accutane) have been used successfully to treat severe acne. Retinoids most likely affect the transcription of skin growth factors and their receptors (8).
Acute promyelotic leukemia: Normal differentiation of myeloid stem cells in the bone marrow gives rise to platelets, red blood cells, and white blood cells, which are important for the immune response. Altered differentiation of those stem cells results in the proliferation of immature leukemic cells, giving rise to leukemia. A mutation of the retinoic acid receptor RAR has been discovered in patients with a specific type of leukemia called acute promyelotic leukemia (APL). Treatment with all-trans retinoic acid or high doses of all-trans retinyl palmitate restores normal differentiation, and leads to improvement in some APL patients (8,17).
Pharmacologic doses of retinoids: It is important to note that treatment with high doses of natural or synthetic retinoids overrides the body’s own control mechanisms, and therefore carries with it risks of side effects and toxicity. Additionally, all of these compounds have been found to cause birth defects. Women who have a chance of becoming pregnant should avoid treatment with these medications. Retinoids tend to be very long acting; side effects and birth defects have been reported to occur months after discontinuing retinoid therapy(8). The retinoids discussed above are prescription drugs, and should not be used without medical supervision (see Safety).
Free retinol is not generally found in foods. Retinyl palmitate, a precursor and storage form of retinol, is generally found in foods from animals. Plants contain carotenoids, some of which are precursors for vitamin A (e.g., a-carotene and b-carotene). Yellow and orange vegetables contain significant quantities of carotenoids. Green vegetables also contain carotenoids, though the pigment is masked by the green pigment of chlorophyll (1). A number of good food sources of vitamin A are listed in the table below along with their vitamin A content in retinol activity equivalents (mcg RAE). In those foods where retionol activity comes mainly from provitamin A carotenoids, the carotenoid content and the retinol activity equivalents are presented. You may use the USDA-NCC carotenoid database to check foods for their content of several different carotenoids, including lutein and xeaxanthin. For more information on the nutrient content of foods you eat frequently, search the USDA food composition database.
Cod liver oil
1 cup (8 ounces)
1/2 cup, mashed
1/2 cup, chopped
1/2 medium melon
1/2 cup, cooked
1 piece of fruit
1/2 cup, cooked
1/2 cup, cooked
Toxicity: The condition caused by vitamin A toxicity is called hypervitaminosis A. It is caused by overconsumption of preformed vitamin A, not carotenoids. Preformed vitamin A is rapidly absorbed and slowly cleared from the body, so toxicity may result acutely from high-dose exposure over a short period of time, or chronically from much lower intake (8). Vitamin A toxicity is relatively rare. Symptoms include nausea, headache, fatigue, loss of appetite, dizziness, and dry skin. Signs of chronic toxicity include, dry itchy skin, loss of appetite, headache, and bone and joint pain. Severe cases of hypervitaminosis A may result in liver damage, hemorrhage, and coma. Generally, signs of toxicity are associated with long-term consumption of vitamin A in excess of 10 times the RDA (8,000 to 10,000 mcg/day or 25,000 to 33,000 IU/day). However, there is evidence that some populations may be more susceptible to toxicity at lower doses, including the elderly, chronic alcohol users, and some people with a genetic predisposition to high cholesterol (10). In January 2001, the Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper level (UL) of vitamin A intake at 3,000 mcg (10,000 IU) of preformed vitamin A/day (2).
Because excess preformed vitamin A consumed during pregnancy is known to cause birth defects, pregnant women are cautioned not to consume more than 800 mcg RE/day (2,600 IU/day) of vitamin A as a supplement (22). Additionally, etretinate and isotretinoin (Accutane), synthetic derivatives of retinol, are known to cause birth defects and should not be taken during pregnancy or if there is a possibility of becoming pregnant. Tretinoin (Retin-A), another retinol derivative, is prescribed as a topical preparation that is applied to the skin. Because of the potential for systemic absorption of topical tretinoin, its use during pregnancy is not recommended.
Drug Interactions: Chronic alcohol consumption results in depletion of liver stores of vitamin A, and may contribute to alcohol-induced liver damage (23). However, the liver toxicity of vitamin A (retinol) is enhanced by chronic alcohol consumption, thus narrowing the therapeutic window for vitamin A supplementation in alcoholics (24). Oral contraceptives that contain estrogen and progestin increase retinol binding protein (RBP) synthesis by the liver, increasing the export of RBP-retinol complex in the blood. Whether this increases the dietary requirement of vitamin A is not known. Etretinate and isotretinoin (Accutane), retinol derivatives, should not be used in combination with vitamin A supplementation, because they may increase the risk of vitamin A toxicity (25).
THE LINUS PAULING INSTITUTE RECOMMENDATION
Following the Linus Pauling Institute recommendation of taking a multivitamin/mineral supplement daily will generally supply more than the RDA for vitamin A. Multivitamins commonly provide 5,000 IU of vitamin A, some of which is in the form of b-carotene. 5,000 IU is equivalent to 1,500 mcg of retinol or less, depending on how much is in the form of b-carotene. Remember, supplemental b-carotene is converted to only one half the amount of retinol as preformed vitamin A (see above). There is no need for additional vitamin A supplementation, and high potency vitamin A supplements should be avoided due to the risk of toxicity (see Safety).
Older adults (65 years and older): Presently there is little evidence that the requirement for vitamin A in older adults differs from that of younger adults. Although, vitamin A insufficiency does not appear to be more common in older adults, vitamin A toxicity may occur at lower doses than in younger adults. In individuals already taking a multivitamin/mineral supplement daily, there is no need for additional vitamin A supplementation. Older adults should be especially careful to avoid vitamin A (retinol) intakes above the UL of 3,000 mcg (10,000 IU)/day (see Safety).
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