Vitamin A is a general term that refers to fat-soluble compounds that are similar in structure and biologic activity to retinol. Vitamin A also refers to dietary precursors of vitamin A (6,11). The precursors of vitamin A (retinol) are the carotenoids (most commonly beta-carotene). The term retinoid refers to any compound that is structurally similar to retinal (aldehyde), retinol (alcohol), or any other substance that exhibits vitamin A activity (1). Retinoic acid, which is a metabolite of retinal (6), is such a substance that is often studied. Synthetic compounds within the vitamin A family have similar structures as the natural form, but may have few or no functions that the natural vitamin posses (11). Most compounds within the vitamin A family are soluble in fat and essential to numerous processes within the body. There have been several water-soluble retinoids, extracted from plasma, bile, and other tissue (11). For the purposes of this literature review, any discussion of vitamin A will focus on those retinoids with fat-soluble properties. The main discussion will involve retinol. Retinol is chemically a "pale yellow crystalline solid" (6). The solid and its metabolites exist in nature as various isomers. The biologic metabolites of retinol are unique in that, they contain five conjugated double bonds within their six-carbon ring (B-ionone) and isoform specific side chains (11). The double bonds contribute special properties; for example, the double bonding in retinol plays a unique role in multiple vision processes, which will be discussed in a subsequent section of this review. As mentioned earlier, most retinoids are soluble in organic solvents and fat. However, oxidation and polymerization are all detrimental to retinoids; therefore, the compounds must be protected from light, oxygen and high temperature.
Vitamin A is essential for numerous intrinsic processes. The most well-known and understood process is that of vision. The 11-cis retinal form of vitamin A is essential for the neural transmission of light into vision (11). Epithelial cells are highly dependent on retinoic acid and are commonly used to treat a variety of skin diseases. A developing fetus is also highly dependent on retinoic acid, as it is essential to the growth of the eyes, lungs, ears and heart (6). The retinoids are not only the most active form of vitamin A, but also a current area of interest to many scientists. The role of vitamin A as an antioxidant is debatable. Vitamin A has been shown to possibly have some antioxidant characteristics. However, the carotenoids such as beta-carotene have in recent years received more attention from the scientific community because of the harmful role they may play as pro-oxidants (14). A great deal more research is needed that addresses the role of vitamin A as an antioxidant to determine the exact role the vitamin and precursors play.
Retinol, the active form of vitamin A, is rarely found in foods. Instead, precursors to retinol, fatty acid retinyl esters, are found in the human diet. The esters are commonly found in foods of animal origin, such as egg yolks, liver, fish oil, whole milk and butter (6). Plants can synthesize the carotenoids, but cannot convert them to retinoids; this process occurs in the human body (11). The carotenoids are red, yellow, and orange in color and substantial in number (over 400 types). It is estimated that only 10% of the pigments have "vitamin A activity", with beta-carotene having the greatest activity, followed by the alpha and gamma forms (6). Fruits and vegetables that appear bright orange or yellow in color are usually high in carotenoids. All green vegetables also contain substantial amounts of carotenoids, but the orange or yellow color is masked by chlorophyll (6). The wide variety of vitamin A precursors allow for adequate amounts of the vitamin in all diet types.
Absorption and Bioavailability
Seventy to ninety percent of vitamin A from the diet is absorbed in the intestine. The efficiency of absorption for vitamin A continues to be high (60-80%) as intake continues to increase. Greater than 90% of the retinol store within the body enters as retinyl esters that are subsequently found within the lipid portion of the chylomicron (11). Absorption of vitamin A is very rapid, with maximum absorption occurring two to six hours after digestion (11). Within the intestinal lumen, the vitamin is incorporated into a micelle and absorbed across the brush border into the enterocytes. Within the enterocyte, precursors of vitamin A (carotenoids) are converted to active forms of the vitamin. The newly formed products and additional precursors are then packaged into chylomicrons and readied for transport throughout the body (6).
After leaving the enterocytes, chylomicronswhich carry retinyl esters, carotenoids, and unesterfired retinol along with triglycerides, are circulated first through the lymphatic system and then through the general circulation. Upon arriving at extra-hepatic cells, chylomicrons release triglycerides, however, vitamin A remains within the chylomicron. The vitamin A is then incorporated into a chylomicron remnant (6). The chylomicron remnant then travels back to the liver, where it is taken up and further metabolized or stored. When needed, retinol is mobilized from the liver and requires the use of a carrier for transport through the blood. Retinol-binding protein (RBP) is the specific carrier used to transport all-trans retinol in the plasma. The all-trans isoform accounts for more than 90% of all plasma vitamin A (11). This specific carrier is manufactured and secreted by the parenchymal cells of the liver (6,11). Each mole of retinol released binds equivocally with RBP to form holo-RBP. This compound then binds with a molecule of transthyretin (TTR), formerly known as prealbumin. This newly formed retinol-RBP-TTR complex is not filtered by the glomerulus, but instead, freely circulates throughout the plasma. Tissues are then able to take the retinol up as needed via cellular retinoid-binding protein (11). Retinoic acid is believed to be manufactured by the cells as needed. Therefore, transport of retinoic acid is likely not substantial. Instead, the cell possesses intra-cellular proteins that regulate the amount of retinoic acid produced. The proteins also help to determine the intracellular usage of retinoic acid (6).
Approximately, 50 to 85% of the total body retinol are stored in the liver when vitamin A status is adequate (11). Retinol returning to the liver is re-esterfied before storage. Because of this, over 90% of the retinol is stored in the form of retinyl esters. The retinol is stored in hepatic stellate (star-shaped) cells along with droplets of lipid (6,11). Thus constitutes the fat-soluble property of vitamin A. The size of stellate cells increases linearly with increasing retinol levels. Once hepatic stellate cells are saturated with all the retinol they can hold, hypervitaminosis can result. (11). The precursor to vitamin A, beta-carotene, can be stored in adipose cells of fat depots throughout the body (2). To date, the only side effect of excess beta-carotene supplementation appears to be yellowing of the skin. Serum levels of beta-carotene are an indicator of recent intake and not body stores (6).
The kidneys are the main paths of RBP and retinol excretion from the body. This is achieved mainly via renal catabolism and glomerular filtration (11). Those persons suffering from renal disease often experience elevated serum levels of RBP and retinol and therefore, must be more aware of vitamin A toxicity.
As previously mentioned, vitamin A is essential to vision. Within the photoreceptor cells of the retina are the rods, which detect small amounts of light and are specialized for motion detection and vision in dim light, and the cones that are specialized for color vision in bright light (11). Both rods and cones posses specialized outer segment disks that contain high amounts of rhodopsin and iodopsin respectively. These compounds are often referred to as the "visual pigment" (11). Photoreceptor cells detect light and undergo a series of reactions, which send signals to the brain, where they are deciphered as a particular visual image. A second very important function of vitamin A involves retinoic acid. Acting as a hormone, retinoic acid first binds to retinoic acid receptors. The receptors then interact with specific nucleotide sequences of DNA. The interaction directly affects gene expression and transcription, which in turn, control cellular development and body processes (6). For example, epithelial cells depend on retinoic acid for structural and functional maintenance. This role of vitamin A is important for growth mechanisms in a manner that is not completely understood (6). Retinoic acid is especially important in heart, eye, lung and ear development (11). The development of gap junctions between cells is also affected by retinoic acid (6). Besides the previously mentioned functions, vitamin A plays a role in numerous other processes. Vitamin A is thought to play a key role in glycoprotein synthesis. Once formed, glycoproteins are important in multiple cellular processes including: communication, recognition, adhesion, and aggregation. Reproductive processes, bone development, along with maintenance, and immune system function (6,11) are dependent upon different isoforms of vitamin A. Retinoids are most commonly used in the treatment of skin diseases. The role the retinoids play in epithelial cell formation is very important in the treatment of skin cancer, acne, and acne-related diseases (11). Vitamin A also has antioxidant properties. However, beta-carotene has been noted as having pro-oxidant properties. Despite these discrepancies, vitamin A is known to help repair damaged tissue and therefore may be beneficial in counter-acting free radical damage (11).
The Recommended Dietary Allowance (RDA) established in 1980 for vitamin A was set at 800-ug retinol equivalent (RE) for adult women and 1000 ug (1mg) retinol equivalent (RE) for adult men (6). It should be noted that 1 RE of vitamin A is equal to 3.33 IU of the vitamin. The levels (RDA) were not changed in 1989 when the RDAs were revised (6,11). One RE is equivalent to 1 ug of all-trans retinol, or 6 ug of all-trans beta-carotene (6). The RDA was based on the amount of vitamin needed to reverse night-blindness in vitamin A deficient subjects. The RDA has also been based on the amount needed to raise the plasma vitamin A levels to normal in depleted subjects. Starting in 2000, Dietary Reference Intakes (DRI) were developed to replace the RDA. A DRI for vitamin was not be established. The DRI incorporates a safety ceiling into the recommendation, however, due to a lack of evidence, a safe upper limit could not established. The absence of a safe upper limit plus the numerous carotenoids has led the National Academy of Sciences to not establish a DRI at this time. The RDA is the current dietary guideline being used in place of the DRI. For men the RDA is 1000 mg of retinol equivalents (RE) and for women the RDA currently stands at 800 mg RE (10).
Deficiency of vitamin A is very rare in the United States, unless confounding malabsorption conditions such as steatorrhea, or diseases of the liver, pancreas, or gallbladder are present. In contrast, vitamin A deficiency is prominent in young children (<5 years old) living in third world countries (6,11). At birth, many neonates experience low plasma vitamin A content, but the levels are corrected with a diet sufficient in vitamin A (6). Symptoms of vitamin A deficiency include metaplasia (changing of normal tissue into abnormal tissue), poor growth, xerophthalmia (dry corneas), and keratinization of epithelial cells resulting in a loss of differentiation (6,11). If vitamin A deficiency has not been chronic leading to permanent debilitation, the symptoms can often be reversed through supplementation.
The use of acne medicines (i.e. Acutane) has led to birth defects and even death (11) in children born to mothers using these compounds (6). This has helped make the public more aware of the toxic properties of vitamin A. In adults, a condition known as hypervitaminosis exhibits itself after chronic ingestion of the vitamin in doses that are ten times the RDA (10 mg RE). Symptoms of vitamin A toxicity include: anorexia, headache, bone and muscle pain, vomiting, alopecia, liver damage, and coma. These symptoms slowly reside as vitamin A intake levels are reduced (6,11). To date, the only side effect of excess beta-carotene has been yellowing of the skin, most commonly in the fatty areas of the hands and palms. The yellowing disappears as beta-carotene intake decreases. This commonly ingested dietary precursor to vitamin A has yet to exhibit any signs of toxicity even at levels as high as 180 mg per day (6). Researchers believe that the presentation of unbound retinol to the cell is a major factor in toxicity. Excessive intakes of vitamin A saturate RBP and instead of retinol being transferred bound to RBP, it is transferred to the tissue via plasma lipoproteins. When retinol reaches the tissue by a carrier other than RBP, it is hypothesized that the retinol is released and causes toxic side effects (6).
Effects of Exercise on Vitamin A Requirements
Data addressing vitamin A and any aspect of exercise are lacking at best. A literature review done by Stacewicz-Sapuntzakis (12) reports that there has been essentially no evidence to suggest that the vitamin A needs of athletes and exercisers are increased above those of sedentary individuals. For example, the author reports that cyclists in the Tour de France were found to consume adequate amounts of the vitamin during the race. The studies that have been performed have failed to account for training patterns or specify the percentages of vitamin A coming from meat and plant sources respectively. This has led to difficulty determining the carotenoid intake of individuals in these studies (12). In contrast, serum levels of retinol and beta-carotene have been studied in national teams from West Germany. The athletes tested came from a variety of sports: marathon runners, weightlifters, swimmers, and cyclists. The research showed that none of the athletes exhibited depressed retinol levels. Beta-carotene levels were distributed over a wide range of values (14.0-122.5 ug/dl). Results show that, although there was a wide range of intakes, none of the athletes were deficient in beta-carotene (12). Many athletes looking for a competitive edge will increase their daily vitamin intake. This has led to widespread vitamin A abuse among athletes. Toxic side effects from vitamin A consumption have so far only been documented in one subject. The subject, a high school soccer player, whose daily, two-month consumption of vitamin A was 100,000 IU vitamin A per day suffered from excessive leg pain (5).
The carotenoids, specifically beta-carotene has been shown to possess antioxidant properties. This precursor of vitamin A is considered the most efficient "quencher" of singlet oxygen (6). The antioxidant properties may actually be detrimental to the body however. The carotenoids may undergo oxidation, leaving byproducts in the lungs and arterial blood. This can result in additional oxidative damage and tumor growth in smokers and those exposed to either second-hand smoke or automobile fumes. Limited studies have been performed addressing the possible role of beta-carotene plays in prevention of muscle damage. Unfortunately the studies included vitamin A as part of antioxidant cocktail mixture (8,9). In a study by Kanter et al. (9), the antioxidant cocktails lowered markers of oxidative stress during exercise, but not before or after the exercise bout. Use of the cocktail makes it virtually impossible to assess the effects of vitamin A on lipid oxidation. The evidence addressing beta-carotene has actually shown detrimental effects in some subjects. This body of inconclusive and somewhat detrimental evidence has led to the recommendation that those who exercise should refrain from beta-carotene supplementation (14).
The role vitamin A plays in exercise recovery has yet to be determined. There is an obvious lack of credible evidence suggesting vitamin A plays a role in enhancing exercise performance or preventing lipid peroxidation. However, due to the ability of vitamin to repair muscle tissue damage (12) the vitamin may aid in recovery. This is strictly a hypothesis, as the possibility has yet to be proven or even investigated. In order to better understand the role of vitamin A in exercise recovery, studies need to be designed that address the issue.
The level of vitamin A intake in all persons, regardless of exercise seems to be more than adequate. This is mainly due to the wide variety of foods that contain vitamin A and its precursors. Vitamin A research is a very tedious process that has little room for error. To date, no research has conclusively shown that vitamin A alone (not part of a cocktail mixture) in any way improves exercise capacity, recovery, or lipid peroxidation. Furthermore, vitamin A can be toxic and beta-carotene has pro-oxidant capabilities. In summary, any supplementation of vitamin A for improvements in exercise is unwarranted, dangerous, and may involve risks.
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