Just as 11-cis-retinal is the analogue of vitamin A involved in vision, so 9-cis-retinoic acid is the analogue mainly involved in differentiation [Fig. 4.6(E), reaction 9]. The cell nucleus contains two principal types of high-affinity receptor proteins for retinoic acid, designated RAR and RXR. Each may be present in a, P or y isoforms. Furthermore, each set of receptors has six different domains that are involved in the transcription of genes. The receptors are coded by three different genes expressed at different times and places during differentiation. RAR bind either all-frans- or 9-cis-retinoic acids, whereas RXR bind only the 9-cis isomer. Retinoic acid isomers, together with their nuclear (or 'intracellular') receptors can both stimulate and inhibit gene expression, depending on the types of interactions described above. RXR appears to interact with a number of other intracellular receptors such as the vitamin D receptor and the PPAR. This raises the possibility of interesting interactions between vitamin A and other chemical messengers (see the later section on vitamin D).
Retinoic acid can also form covalent bonds with certain proteins. These retinoylated proteins are similar in size to the nuclear retinoic acid receptors and may play roles similar to those of lipid-anchored proteins described in Section 6.5.14.
Risk of infection is increased markedly in vitamin A deficiency and both humoral and cell-mediated immune responses are impaired. A major site of vitamin A action in the immune response is thought to be the T-helper cell and there seems to be a requirement for a specific form of vitamin A - 14-hydroxyretroretinoic acid - rather than retinoic acid. Understanding of the mechanisms by which vitamin A is involved in immunity at the molecular level, as well as in embryogenesis, spermatogenesis and taste perception is still in its infancy.
Major sources of vitamin A are green vegetables and carrots (provitamin A), liver (especially fish), milk and some fat spreads. No more than 750 p,g vitamin A is required by the average person daily. Compare this with the gram quantities required for EFA intake (Section 188.8.131.52).
The most tragic manifestation of vitamin A deficiency is blindness in young children. The first effects are seen as severe eye lesions, a condition known as xerophthalmia, which is eventually followed by keratomalacia with dense scarring of the cornea and complete blindness. Xerophthalmia is considered to be one of the four commonest pre ventable diseases in the world. Although there are large-scale programmes for the supplementation of children's diets with vitamin A, these are difficult to implement successfully and the World Health Organization considers that if the consumption of green leafy vegetables and suitable fruits by young children could be substantially increased, there is every reason to believe that the problem would be solved. There might be a case for trying to increase the overall fat content of the diet, too. Here, we are more concerned with solving problems of economics and distribution and with changing local eating habits than with biochemistry and nutrition, where the knowledge is already to hand.
Epidemiological evidence shows that people with above-average blood retinol concentrations or above-average P-carotene intakes have a lower than average risk of developing some types of cancer (Section 4.4.1).
In contrast to most water-soluble vitamins, excessive intakes of fat-soluble vitamins can be harmful, since in general they accumulate in tissues rather than being excreted. Thus, vitamin A, if taken in excess, accumulates in the liver. Chronic over-consumption may then cause not only liver necrosis, but also permanent damage to bone, vision, muscles and joints. Vitamin A can be excreted via its conversion into glucuronides formed from retinoic acid (Fig. 4.6, reaction 9) or from all-frans-retinol itself (Fig. 4.6, reaction 10).
Vitamin D is the generic name for two sterols with the property of preventing the disease rickets. Ergocalciferol (vitamin D2) is formed by irradiation of the plant sterol, ergosterol, and is the main dietary source of vitamin D. Cholecalciferol (vitamin D3) is produced in the skin by ultraviolet irradiation of 7-dehydrocholesterol present in the skin surface lipids. It is the main source of the vitamin for most human beings. Dietary sources are fish liver oils (e.g. cod), eggs, liver and some fat spreads.
The parent forms of vitamin D are biologically inactive. The active metabolites are formed in the liver and kidneys. After absorption from the diet or formation in the skin, vitamin D is carried in the circulation bound to a specific transport protein of the a-globulin class. In the liver, cholecalciferol is first hydroxylated to 25-hydroxycholecalciferol (Fig. 4.7). The 25-hydroxylase requires NADPH, molecular oxygen and Mg2+ ions. It is the main transport form of vitamin D and its concentration in plasma is used as an indicator of vitamin D status. Although this metabolite has modest biological activity, it is carried to the kidney, also attached to the transport protein, where it is further hydroxylated either to 1,25-dihydroxycholecalciferol (sometimes called calcitriol) or 24,25-dihydroxy derivative (Fig. 4.7) by enzymes similar to the liver 1-a-hydroxylase. 1,25-Dihydroxycholecalciferol is the most biologically active vitamin D metabolite, some 100 times more active than the 25-hydroxy metabolite. Its circulating concentration is tightly controlled by the plasma level of parathyroid hormone and the body's overall vitamin D status.
Fig. 4.7 Metabolism of vitamin D.
Thus, in relative vitamin D deficiency, the circulating concentration of 1,25-dihydroxy-cholecalciferol is high as a result of the stimulation of the liver 1-a-hydroxylase by parathyroid hormone, whereas that of the 24,25-dihydroxy metabolite is low. Calcitriol functions as a hormone in several distinct ways.
The best-studied function of calcitriol is in calcium homeostasis. Several mechanisms seem to be involved. The first is to increase the absorption efficiency of calcium by increasing its transport across the enterocyte brush border membrane and its subsequent export from the enterocyte into the blood. Calcitriol, a lipid-soluble compound, easily passes through the enterocyte cell membrane, binds to a specific receptor and is translocated to the nucleus where it binds to the DNA of specific response genes. Loops in the receptor, known as 'zinc fingers' enable the receptor to interact with DNA to induce the transcription of mRNA for a specific Ca-binding protein that aids active transport of Ca from the gut to maintain blood concentrations within the narrow range of 2.1-2.6 mM. A second role for calcitriol, in the presence of parathyroid hormone, is to activate bone osteoclasts to resorb calcium from bone, again to maintain an appropriate plasma calcium concentration. However, the role of calcitriol in bone is more complex than implied here, since it can also stimulate bone formation by osteoblasts, thus participating in the regulation of the overall process of bone turnover.
The discovery of receptors for 1,25-dihydroxy-cholecalciferol in many tissues other than those involved in calcium and bone metabolism (e.g. pancreatic islet cells, skin keratinocytes, mammary epithelium and some neurones) suggests a wider involvement in aspects of tissue development. Indeed, calcitriol seems to be a general developmental hormone, inhibiting proliferation and promoting differentiation in many tissues. Present knowledge suggests functions that include regula tion of gene products associated with mineral metabolism, differentiation of cells in skin and in the immune system and regulation of DNA replication and cell proliferation. A recent finding is that when 1,25-dihydroxycholecalciferol binds to a response element in the promoter region of its target gene, it requires an accessory protein. It is now thought that this protein may be identical to the retinoic acid X receptor discussed in the previous section, suggesting an interesting convergence of vitamin A and D functions that is yet to be properly elucidated.
It is difficult to decide upon a precise dietary requirement for vitamin D because much is derived from the skin lipids rather than the diet. Thus the UK committee that advises on dietary requirements set no dietary reference value for vitamin D for people between the ages of 4 and 50 years. Two groups of people, however, may have a special need to obtain vitamin D from the diet. In the first group are children and pregnant and lactating women whose requirements are particularly high. In the second group are people who are little exposed to sunlight, such as the housebound elderly and people in far northern latitudes or those who wear enveloping clothes. Dark-skinned immigrants to Northern Europe are especially vulnerable. Infants and children who obtain too little vitamin D develop rickets, with deformed bones that are too weak to support their weight. The reason why, in the UK and some other countries, vitamin D preparations are provided for children and pregnant women, and margarine is fortified with it, is because these degenerative changes soon become permanent if supplementation is not started early enough.
Like vitamin A, vitamin D is toxic in high doses. Even amounts that are no more than five times the normal intake can be toxic. Too high an intake causes more calcium to be absorbed than can be excreted, resulting in excessive deposition in, and damage to, the kidneys.
Vitamin E activity is possessed by eight tocopherols and tocotrienols (Fig. 4.8). a-Tocopherol is the most potent of these, the other compounds having between 10% and 50% of its activity. a-Tocopherol is also the most abundant form of vitamin E in animal tissues, representing 90% of the mixture. The form used in commercial preparations is synthetic racemic a-tocopherol (the natural compounds have optical activity), often in the acetylated form as a protection from oxidation.
In 1922, the Americans, Evans and Bishop, discovered that vitamin E prevented sterility in rats reared on fat-deficient diets fortified with vitamins A and D. Because vitamin E is so widespread in foods and like all other fat-soluble vitamins is stored in the body, deficiency states are rarely if ever seen, possible exceptions being in premature infants with low fat stores and in people with severe malabsorption. The richest sources are vegetable oils, cereal products and eggs.
Vitamin E is carried in the blood by the plasma lipoproteins (Section 5.2). There is evidence for
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