Two groups of compounds have vitamin A activity
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p537-538
2025-12-15
60
Retinoids comprise retinol, retinaldehyde, and retinoic acid (preformed vitamin A, found only in foods of animal origin); carotenoids, found in plants, are a variety of carotenes and related compounds; many are precursors of vitamin A, as they can be cleaved to yield retinaldehyde, then retinol and retinoic acid (Figure 1). The α-, β-, and γ-carotenes and crypto xanthin are quantitatively the most important provitamin A carotenoids. β-Carotene and other provitamin A carotenoids are cleaved in the intestinal mucosa by carotene dioxygenase, yielding retinaldehyde, which is reduced to retinol, esterified and secreted in chylomicrons together with esters formed from dietary retinol. The intestinal activity of carotene dioxygenase is low, so that a relatively large proportion of ingested β-carotene may appear in the circulation unchanged. There are two isoenzymes of carotene dioxygenase. One catalyzes cleavage of the central bond of β-carotene; the other catalyzes asymmetric cleavage leading to the formation of 8′-, 10′-, and 12′-apo-carotenals, which are oxidized to retinoic acid, but cannot be used as sources of retinol or retinaldehyde.
Fig1. β-Carotene and the major vitamin A vitamers. Asterisk shows the site o symmetrical cleavage o β-carotene by carotene dioxygenase, to yield retinaldehyde.
Although it would appear that one molecule of β-carotene should yield two of retinol, this is not so in practice; 6 μg of β-carotene is equivalent to 1 μg of preformed retinol. The total amount of vitamin A in foods is therefore expressed as micro grams of retinol equivalents = μg preformed vitamin A + 1/6 × μg β-carotene + 1/12 × μg other provitamin A carotenoids. Before pure vitamin A was available for chemical analysis, the vitamin A content of foods was determined by biological assay and the results expressed as international units (IU). 1 IU = 0.3 μg retinol; 1 μg retinol = 3.33 IU. Although obsolete, IU is sometimes still used in food labeling. The term retinol activity equivalent takes account of the incomplete absorption and metabolism of carotenoids; 1 RAE = 1 μg all-trans retinol, 12 μg β-carotene, 24 μg α-carotene or β-cryptoxanthin. On this basis, 1 IU of vitamin A activity is equal to 3.6 μg β-carotene or 7.2 μg of other provitamin A carotenoids.
Vitamin A Has a Function in Vision
In the retina, retinaldehyde functions as the prosthetic group of the light-sensitive opsin proteins, forming rhodopsin (in rods) andiodopsin (in cones). Any one cone cell contains only one type of opsin and is sensitive to only one color. In the pigment epithelium of the retina, all-trans-retinol is isomerized to 11-cis-retinol and oxidized to 11-cis-retinaldehyde. This reacts with a lysine residue in opsin, forming the holoprotein rhodopsin. As shown in Figure 2, the absorption of light by rhodopsin causes isomerization of the retinaldehyde from 11-cis to all-trans, and a conformational change in opsin. This results in the release of retinaldehyde from the protein, and the initiation of a nerve impulse. The formation of the initial excited form of rhodopsin, bathorhodopsin, occurs within picoseconds of illumination. There is then a series of conformational changes leading to the formation of metarhodopsin II, which initiates a guanine nucleotide amplification cascade and then a nerve impulse. The final step is hydrolysis to release all-trans-retinaldehyde and opsin. The key to initiation of the visual cycle is the availability of 11-cis-retinaldehyde, and hence vitamin A. In deficiency, both the time taken to adapt to darkness and the ability to see in poor light are impaired.
Fig2. The role of retinaldehyde in the visual cycle.
Retinoic Acid Has a Role in the Regulation of Gene Expression and Tissue Differentiation
A major role of vitamin A is the control of cell differentiation and turnover. All-trans-retinoic acid and 9-cis-retinoic acid (Figure 1) regulate growth, development, and tissue differ entiation; they have different actions in different tissues. Like the thyroid and steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors: the retinoic acid receptors (RAR) bind all-trans-retinoic acid or 9-cis-retinoic acid, and the retinoid X receptors (RXR) bind 9-cis-retinoic acid. RXRs also form hetero dimers with vitamin D, thyroid, and other nuclear acting hormone receptors. Deficiency of vitamin A impairs vitamin D and thyroid hormone function because of lack of 9-cis-retinoic acid to form active receptor dimers. Unoccupied RXRs form dimers with occupied vitamin D and thyroid hormone receptors, but not only are these unable to activate gene expression, they may repress it. Consequently vitamin A deficiency has a more severe effect on vitamin D and thyroid hormone function than simply interfering with gene expression. Excessive vitamin A also impairs vitamin D and thyroid hormone function, because of formation of RXR homodimers, meaning that there are not enough RXR available to form heterodimers with the vitamin D and thyroid hormone receptors.
Vitamin A Deficiency Is a Major Public Health Problem Worldwide
Vitamin A deficiency is the most important preventable cause of blindness. The earliest sign of deficiency is a loss of sensitivity to green light, followed by impairment to adapt to dim light, then night blindness, an inability to see in the dark. More prolonged deficiency leads to xerophthalmia: keratinization of the cornea, and blindness. Vitamin A also has an important role in differentiation of immune system cells, and even mild deficiency leads to increased susceptibility to infectious diseases. The synthesis of retinol-binding protein, which is required to transport the vitamin in the bloodstream, is reduced in response to infection (it is a negative acute phase protein), decreasing the circulating concentration of the vitamin, and further impairing immune responses.
Vitamin A Is Toxic in Excess
Humans possess only a limited capacity to metabolize vita min A, and excessive intakes lead to accumulation beyond the capacity of intracellular binding proteins; unbound vitamin A causes membrane lysis and tissue damage. Symp toms of toxicity affect the central nervous system (headache, nausea, ataxia, and anorexia, all associated with increased cerebrospinal fluid pressure); the liver (hepatomegaly with histological changes and hyperlipidemia); calcium homeostasis (thickening of the long bones, hypercalcemia, and calcification of soft tissues); and the skin (excessive dryness, desquamation, and alopecia).
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