Vitamin regulation

Effects of Vitamin D Deficiency.—The vitamin regulates the absolute and relative absorption of calcium and phosphate solutes from the intestinal tract, and may be regarded as a calcio-kinetic, or calcium-distributing, vitamin. Avitaminosis D is characterised by —... 

Methyl vinyl ketone is used as a comonomer in photodegradable plastics, and is an intermediate in the synthesis of steroids and vitamin A. It is highly toxic and faciUties handling over a threshold of 100 lbs (45.5 kg) are subject to special OSHA documentation regulations (273). 

Metabolites of vitamin D, eg, cholecalciferol (CC), are essential in maintaining the appropriate blood level of Ca ". The active metabolite, 1,25-dihydroxycholecalciferol (1,25-DHCC), is synthesized in two steps. In the fiver, CC is hydroxylated to 25-hydroxycholecalciferol (25-HCC) which, in combination with a globulin carrier, is transported to the kidney where it is converted to 1,25-DHCC. This step, which requites 1-hydroxylase formation, induced by PTH, may be the controlling step in regulating Ca " concentration. The sites of action of 1,25-DHCC are the bones and the intestine. Formation of 1,25-DHCC is limited by an inactivation process, ie, conversion of 25-HCC to 24,25-DHCC, catalyzed by 24-hydroxylase. 

Dihydroxyvitamin (283) is the endogenous ligand for the vitamin receptor (VDR). It modulates genomic function in a tissue and developmentaHy specific manner and affects ceU proliferation, differentiation, and mineral homeostasis (74). Vitamin mobilizes calcium from the bone to maintain plasma Ca " levels. Vitamin and VDR are present in the CNS where they may play a role in regulating Ca " homeostasis. Vitamin D has potent immunomodulatory activity in vivo. 

Many kinds of amino acids (eg, L-lysine, L-omithine, t-phenylalanine, L-threonine, L-tyrosine, L-valine) are accumulated by auxotrophic mutant strains (which are altered to require some growth factors such as vitamins and amino acids) (Table 6, Primary mutation) (22). In these mutants, the formation of regulatory effector(s) on the amino acid biosynthesis is genetically blocked and the concentration of the effector(s) is kept low enough to release the regulation and iaduce the overproduction of the corresponding amino acid and its accumulation outside the cells (22). 

Bde salts, cholesterol, phosphoHpids, and other minor components are secreted by the Hver. Bile salts serve three significant physiological functions. The hydrophilic carboxylate group, which is attached via an alkyl chain to the hydrophobic steroid skeleton, allows the bile salts to form water-soluble micelles with cholesterol and phosphoHpids in the bile. These micelles assist in the solvation of cholesterol. By solvating cholesterol, bile salts contribute to the homeostatic regulation of the amount of cholesterol in the whole body. Bile salts are also necessary for the intestinal absorption of dietary fats and fat-soluble vitamins (24—26). 

There are numerous synthetic and natural compounds called antioxidants which regulate or block oxidative reactions by quenching free radicals or by preventing free-radical formation. Vitamins A, C, and E and the mineral selenium are common antioxidants occurring naturally in foods (104,105). A broad range of flavonoid or phenoHc compounds have been found to be functional antioxidants in numerous test systems (106—108). The antioxidant properties of tea flavonoids have been characterized using models of chemical and biological oxidation reactions. 

Vitamins are sold for direct appHcation to foods and animal feeds. In addition, they are further processed into nutritional supplements. This last market is particularly significant in the United States. In many other countries, vitamins are regulated as dmgs, leading to a much lower supplement usage. 

Many carotenoids function in humans as vitamin A precursors however, not all carotenoids have provitamin A activity (Table 3). Of the biologically active carotenoids, -carotene has the greatest activity. Despite the fact that theoretically one molecule of -carotene is a biological source of two molecules of vitamin A, this relationship is not observed and 6 p.g -carotene is equivalent to 1 p. vitamin A. Although -carotene and vitamin A have complementary activities, they caimot totally replace each other. Because the conversion of -carotene to vitamin A is highly regulated, toxic quantities of vitamin A cannot accumulate and -carotene can be considered as a safe form of vitamin A (8). 

The metabohtes of vitamin D are usually more toxic than the vitamin because the feedback mechanisms that regulate vitamin D concentrations are circumvented. 25-Hydroxycholecalciferol has a one-hundredfold increase in toxicity over vitamin D when fed to chicks (220) and 1 a,25-dihydroxy vitamin D is several times more toxic than the 25-hydroxy analogue. Vitamin D2 seems to have less toxicity than vitamin D, a circumstance which is beheved to be caused by the more efficient elimination of 25-hydroxy and the 1 a,25-dihydroxy vitamin D2 from the animals. Estimated safe upper dietary levels are given in Table 11. 

Disease States. Rickets is the most common disease associated with vitamin D deficiency. Many other disease states have been shown to be related to vitamin D. These can iavolve a lack of the vitamin, deficient synthesis of the metaboUtes from the vitamin, deficient control mechanisms, or defective organ receptors. The control of calcium and phosphoms is essential ia the maintenance of normal cellular biochemistry, eg, muscle contraction, nerve conduction, and enzyme function. The vitamin D metaboUtes also have a function ia cell proliferation. They iateract with other factors and receptors to regulate gene transcription. 

Three hormones regulate turnover of calcium in the body (22). 1,25-Dihydroxycholecalciferol is a steroid derivative made by the combined action of the skin, Hver, and kidneys, or furnished by dietary factors with vitamin D activity. The apparent action of this compound is to promote the transcription of genes for proteins that faciUtate transport of calcium and phosphate ions through the plasma membrane. Parathormone (PTH) is a polypeptide hormone secreted by the parathyroid gland, in response to a fall in extracellular Ca(Il). It acts on bones and kidneys in concert with 1,25-dihydroxycholecalciferol to stimulate resorption of bone and reabsorption of calcium from the glomerular filtrate. Calcitonin, the third hormone, is a polypeptide secreted by the thyroid gland in response to a rise in blood Ca(Il) concentration. Its production leads to an increase in bone deposition, increased loss of calcium and phosphate in the urine, and inhibition of the synthesis of 1,25-dihydroxycholecalciferol. 

Vitamin An organie eompound present in variable, minute quantities in natural foodstuffs, and essential for the normal proeesses of growth and maintenanee of the body. Vitamins do not furnish energy, but are neeessary for energy transformation and for regulation of metabolism. 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

Therapeutic Function Calcium Regulator, Vitamin D Chemical Name 9,10-Secocholesta-5,7,10(19)-triene-1,3-diol Common Name la-Hydroxycholecalciferol 1a-Hydroxyvitamin D3 Structural Formula ... 

PTH is the most important regulator of bone remodelling and calcium homeostasis. PTH is an 84-amino acid polypeptide and is secreted by the parathyroid glands in response to reductions in blood levels of ionised calcium. The primary physiological effect of PTH is to increase serum calcium. To this aim, PTH acts on the kidney to decrease urine calcium, increase mine phosphate, and increase the conversion of 25-OH-vitamin D to l,25-(OH)2-vitamin D. PTH acts on bone acutely to increase bone resorption and thus release skeletal calcium into the circulation. However, due to the coupling of bone resorption and bone formation, the longer-term effect of increased PTH secretion is to increase both bone resorption and bone formation. 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

In addition to its classical role as regulator of calcium homeostasis, 1,25-dihydroxy vitamin D3 (calcitriol) displays immunosuppressive properties. Inhibition of T-lymphocyte proliferation seems to be mediated via regulation of CD80/86 costimulatory molecule expression on APCs. For clinical use as immunosuppressant, however, analogues of vitamin D3 that do not influence calcium metabolism are needed. 

Systemic regulators of osteoblast, osteocyte and osteoclast functions, and therefore of bone metabolism. The major bone-seeking hormones are parathyroid hormone (PIH), 1,25-dihydroxy vitamin D3 (calcitriol) and the various ex hormones. 

Vitamin A (retinol) and its naturally occurring and synthetic derivatives, collectively referred to as retinoids (chemical structure), exert a wide variety of profound effects in apoptosis, embryogenesis, reproduction, vision, and regulation of inflammation, growth, and differentiation of normal and neoplastic cells in vertebrates. 

The term vitamin E describes a family of eight antioxidants, four tocopherols, alpha (a), beta ((3), gamma (y) and delta (8), and four tocotrienols (also a, (3, y, and 8). a-Tocopherol is present in nature in only one form, RRR a-tocopherol. The chemical synthesis of a-tocopherol results in eight different forms (SRR, SSR, SRS, SSS, RSR, RRS, RSS, RRR), only one of which is RRR a-tocopherol. These forms differ in that they can be right (R) or left (S) at three different places in the a-tocopherol molecule. RRR a-tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore the form of vitamin E found in the largest quantities in the blood and tissue. A protein synthesized in the liver (a-TTP alpha-tocopherol transfer protein) preferentially selects the natural form of vitamin E (RRR a-tocopherol) for distribution to the tissues. However, the mechanisms for the regulation of vitamin E in tissues are not known... 

Azzi A, Gysin R, Kempna P et al (2004) Vitamin E mediates cell signaling and regulation of gene expression. Ann N YAcad Sci 1031 86-95... 

In bone, three proteins have been described which are vitamin K-dependent, osteocalcin (bone Gla protein), matrix Gla protein (MGP), and protein S. Osteocalcin is synthetized by osteoclasts, regulated by the active form of vitamin D, calcitriol. Its capacity to bind calcium needs a vitamin K-dependent y-carboxylation of three glutamic acid residues. The calcium binding capacity of osteocalcin indicates a possible role in bone mineralization, but its exact function is still unclear. However, it is widely used as a serum marker for bone mineralization. Protein S, mainly a coagulant, is also vitamin-K dependent and synthesized in the liver. Children with... 

Russell J et al Interaction between calcium and 1,25-dihydroxy-vitamin D3 in the regulation of preproparathyroid hormone and vitamin D receptor mRNA in avian parathyroids. Endocrinology 1993 132 2639. 

In addition to its role in regulating calcium homeostasis, vitamin D is required for the intestinal absorption of calcium. Synthesis of the intracellular calciumbinding protein, calbindin, required for calcium absorption, is induced by vitamin D, which also affects the permeability of the mucosal cells to calcium, an effect that is rapid and independent of protein synthesis. 

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the 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 (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

---