1 a,25-Dihydroxycholecalciferol

Although it is being found that vitamin D metaboUtes play a role ia many different biological functions, metaboHsm primarily occurs to maintain the calcium homeostasis of the body. When calcium semm levels fall below the normal range, 1 a,25-dihydroxy-vitainin is made when calcium levels are at or above this level, 24,25-dihydroxycholecalciferol is made, and 1 a-hydroxylase activity is discontiaued. The calcium homeostasis mechanism iavolves a hypocalcemic stimulus, which iaduces the secretion of parathyroid hormone. This causes phosphate diuresis ia the kidney, which stimulates the 1 a-hydroxylase activity and causes the hydroxylation of 25-hydroxy-vitamin D to 1 a,25-dihydroxycholecalciferol. Parathyroid hormone and 1,25-dihydroxycholecalciferol act at the bone site cooperatively to stimulate calcium mobilization from the bone (see Hormones). Calcium blood levels are also iafluenced by the effects of the metaboUte on intestinal absorption and renal resorption. 

The vitamin D3 metabolite la,25-dihydroxycholecalciferol is a lifesaving drug in treatment of defective bone formation due to renal failure. Retrosynthetic analysis (E.G. Baggjolint, 1982) revealed the obvious precursors shown below, a (2-cyclohexylideneethyl)diphenylphosphine oxide (A) and an octahydro-4f/-inden-4-one (B), to be connected in a Wittig-Homer reaction (cf. section 1.5). 

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. 

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. 

Many factors are involved in the regulation of bone metabolism, only a few of which will be mentioned here. Some stimulate osteoblasts (eg, parathytoid hormone and 1,25-dihydroxycholecalciferol) and others inhibit them (eg, corticosteroids). Parathyroid hormone and 1,25-dihydroxycholecalciferol also stimulate osteoclasts, whereas calcitonin and estrogens inhibit them. 

Calcitonin is a polypeptide hormone that (along with PTH and the vitamin D derivative, 1,25-dihydroxycholecalciferol) plays a central role in regulating serum ionized calcium (Ca2+) and inorganic phosphate (Pi) levels. The adult human body contains up to 2 kg of calcium, of which 98 per cent is present in the skeleton (i.e. bone). Up to 85 per cent of the 1 kg of phosphorus present in the body is also found in the skeleton (the so-called mineral fraction of bone is largely composed of Ca3(P04)2, which acts as a body reservoir for both calcium and phosphorus). Calcium concentrations in human serum approximate to 0.1 mg ml-1 and are regulated very tightly (serum phosphate levels are more variable). 

The active vitamins are produced by conversion of provitamins by ultraviolet light. Ergosterol, a yeast sterol, is converted to its active form, ergocalciferol (vitamin D2), and 7-dehydrocholesterol, which is found in many natural foods and is also synthesized in man, is converted to cholecalciferol (vitamin D3). Fish liver oils are virtually the only source of vitamin D3 in nature. The most active form of vitamin D3 is 1,25-dihydroxycholecalciferol and this is produced by the hydroxylation of cholecalciferol at position 25 in the liver and then at position 1 in the kidney. 

In the skin, cholesterol is converted to 7-dehydrocholes-terol by desaturation of the 9,10-carbon bond and ultraviolet light breaks this bond to produce cholecalciferol (Figure 15.12). The cholecalciferol is transported via the bloodstream to the liver where the first step in the activation of the hormone occurs, namely hydroxylation by a monooxygenase to produce 25-hydroxy cholecalciferol, which is transported to the kidney where a further hydroxylation takes place at the 1-position to produce la,25-dihydroxycholecalciferol, which is the active form of the hormone (Figure 15.13). 

Vitamin D is synthesized in the skin in the presence of ultraviolet light, and it is unusual to become dependent on dietary intake except when exposed to inadequate UV light. The active form of vitamin D is 1,25-dihydroxycholecalciferol (1,25-OHCC), also termed calcitriol. For vitamin D synthesis, cholecal-ciferol (also termed vitamin D3) is synthesized in the skin from cholesterol via 7-dehydrocholesterol, and is 25-hydroxylated in the liver and 1-hydroxylated in the kidney. Dietary vitamin D is actually a mixture of sterols which includes 7-dehydrocholesterol, and is mainly found in fish and eggs. 

The term vitamin D is used for a range of compounds which possess the property of preventing or curing rickets. They include ergocalciferol (calciferol, vitamin D ), chole-calciferol (vitamin Dg), dihydrotachysterol, alfacalcidol (la-hydroxycholecalciferol) and calcitriol (1,25-dihydroxycholecalciferol). 

The administration of a small dosis of 1.25-dihydroxycholecalciferol normalizes calcium absorption, but not bone mineralization556,557. EHDP might inhibit the renal 1-hydroxylase directly553, 558. The EHDP-induced inhibition of 1.25-(OH)2D3 production has been shown to be reduced by a low Ca diet or by vitamin D deficiency554, 55S. The influence of EHDP on the renal 1-hydroxylation is indirect and dependent on dietary vitamin D, calcium, and phosphorus559. ... 

T FIGURE 10-20 Vitamin D3 production and metabolism, (a) Cholecalciferol (vitamin D3) is produced in the skin by UV irradiation of 7-dehydrocholesterol, which breaks the bond shaded pink. In the liver, a hydroxyl group is added at C-25 (pink) in the kidney, a second hydroxylation at C-1 (pink) produces the active hormone, 1,25-dihydroxycholecalciferol. This hormone regulates the metabolism of Ca2+ in kidney, intestine, and bone, (b) Dietary vitamin D prevents rickets, a disease once common in cold climates where heavy clothing blocks the UV component of sunlight necessary for the production of vitamin D3 in skin. On the left is a 21/2-year-old boy with severe rickets on the right, the same boy at age 5, after 14 months of vitamin D therapy. 

Vitamin D3, also called cholecalciferol, is normally formed in the skin from 7-dehydrocholesterol in a photochemical reaction driven by the UV component of sunlight (Fig. 10-20). Vitamin D3 is not itself biologically active, but it is converted by enzymes in the liver and kidney to 1,25-dihydroxycholecalciferol, a hormone that regulates calcium uptake in the intestine and calcium levels in kidney and bone. Deficiency of vitamin D... 

Vitamin D Retinoid 1,25-Dihydroxycholecalciferol Retinoic acid From cholesterol From vitamin A Nuclear receptors transcriptional regulation... 

The D vitamins are a group of sterols that have a hormone-like funciion. The active molecule, 1,25-dihydroxycholecalciferol (1,25 diOH D3), binds to intracellular receptor proteins. The 1,25-diOH D3-receptor complex interacts with DNA in the nucleus of target cells in a manner simiar to that of vitamin A (see Figure 28.20), and either selectively stimulates gene expression, or specifically represses gene transcription. The most prominent actions of 1,25-diOH D3 are to regulate the plasma levels of calcium and phosphorus. 

Formation of 1,25-diOH D3 Vitamins D2 and D3 are not biologically active, but are converted in vivo to the active form of the D vitamin by two sequential hydroxylation reactions (Figure 28.23). The first hydroxylation occurs at the 25-position, and is catalyzed by a specific hydroxylase in the liver. The product of the reaction, 25-hydroxycholecalciferol (25-OH D3), is the predominant form of vitamin D in the plasma and the major storage form of the vitamin. 25-OH D3 is further hydroxylated at the one position by a specific 25-hydroxycholecalciferol 1 -hydroxylase found primarily in the kidney, resulting in the formation of 1,25-dihydroxycholecalciferol j (1,25-diOH D3). [Note This hydroxylase, as well as the iver 25-hydroxylase, employ cytochrome P450, molecular oxygen, and NADPH.]... 

Which one of the following statements concerning vitamin D is correct A. Chronic renal failure requires the oral administra tion of 1,25-dihydroxycholecalciferol. B. It is required in the diet of individuals exposed to sunlight. C. 25-Hydroxycholecalciferol is the active form of the vitamin. D. Vitamin D opposes the effect of parathyroid hor mone. E. A deficiency in vitamin D results in an increased secretion of calcitonin. Correct answer = A. Renal failure results in the decreased ability to form the active form of the vitamin, which must be supplied. The vitamin is not required in individuals exposed to sunlight. 1,25-dihydroxycholecalciferol is the active form of the vitamin. Vitamin D and parathyroid hormone both increase serum calcium. A deficiency of vitamin D decreases the secretion of calcitonin. 

Vitamin-E-binding sites have been demonstrated in a number of tissues. Catignani [240] has shown that the vitamin can bind to a cytoplasmic protein, with a molecular weight of about 31000, extracted from rat liver. Similar cytoplasmic proteins have been reported for 1,25-dihydroxycholecalciferol [241,242], retinol [243,244] and retinoic acid [245,246]. The vitamin-E-... 

Target tissue for 1,25-dihydroxycholecalciferol, among others, is the intestine, where a Ca2+-binding protein is synthesized under its influence. 

Q2 The hormones that are normally involved in the control of calcium balance are parathyroid hormone (PTH) from the parathyroid gland calcitonin, which is secreted by the thyroid gland and 1,25-dihydroxycholecalciferol (1,25-DHCC, or calcitriol), which is produced in the kidneys. Calcitonin reduces the level of plasma calcium by attenuating its release from bone and by increasing its excretion. The PTH and 1,25-DHCC increase the level of plasma calcium by two mechanisms (1) a combination of an increase in calcium absorption by the gut and an increase in the release of calcium from bone and (2) a reduction in both bone formation and calcium excretion. The three hormones act together to maintain the physiological level of calcium and normal bone turnover. Over 95% of body calcium is located in bone as hydroxyapatite. 

Subsequently there was introduced a la-hydroxylated form (la-hydroxycholecalciferol) alfacalcidol (One-Alpha), that requires only hepatic hydroxylation to become the highly active la-25-dihydroxycholecalciferol (calcitriol). Alfacalcidol (and of course calcitriol) is therefore effective in renal failure since the defective renal hydroxylation stage is bypassed. Its extraordinary potency and efficacy is indicated by the usual adult maintenance dose, often only 0.25-1 micrograms/d. 

OH D3 is further hydroxylated at 1-position by a specific 25-OH-cholecalciferol 1-hydroxylase enz5une, primarily present in the proximal convoluted tubules of kidney, forming 1,25-dihydroxy cholecalciferol (DHCC) with the help of cytochromP-450, molecular oxygen NADPH. 1,25-dihydroxycholecalciferol, or active Vitamin D, contains three hydroxyl groups at 1, 3 and 25 positions. So it is called calcitriol and it is biologically active form of vitamin D. 

In patients with renal failure, the occurrence of conditioned zinc deficiency may be the result of a mixture of factors, which at present are ill defined. If 1,25-dihydroxycholecalciferol plays a role in the intestinal absorption of zinc, an impairment in its formation by the diseased kidney would be expected to result in malabsorption of zinc. It seems likely that plasma and soft tissue concentrations of zinc may be "protected in some individuals with renal failure by the dissolution of bone which occurs as a result of increased parathyroid activity in response to low serum calcium. In experimental animals, calcium deficiency has been shown to cause release of zinc from bone. In some patients who are successfully treated for hyperphosphatemia and hypocalcemia, the plama zinc concentration may be expected to decline because of the deposition of zinc along with calcium in bone. Thus, in the latter group in particular, a diet low in protein and high in refined cereal products and fat would be expected to contribute to a conditioned deficiency of zinc. Such a diet would be low in zinc. The patients reported by Mansouri et al. (37), who were treated with a diet containing 20-30 g of protein daily and who had low plasma concentrations of zinc, appear to represent such a clinical instance. Presumably the patients of Halsted and Smith (38) were similarly restricted in dietary protein. In other patients with renal failure whose dietary protein was not restricted, plasma zinc concentration were not decreased. Patients on dialysis had even higher levels, particularly... 

Vitamin D Analogues - A patent covering the photochemical conversion of the diene (112) into the triene (113) within what is called a microreactor has been published. The microreactor system is a zeolite with the appropriate size of the cavity to provide stereochemical control of the reaction. The use of the 2,7-dimethyl-3,6-diazacyclohepta-1,6-diene tetrafluoroborate/biphenyl filter solution has allowed the double wavelength irradiation (290-300 nm and X. > 330 nm) of procalcitriol as a route to la,25-dihydroxycholecalciferol. A study of the control that can be exercised upon the reaction by changes in temperature was carried out. The results of a study of the influence of intensity on the picosecond laser irradiation of provitamin D have been published. Other research has been aimed at the examination of the photochemical behaviour of previtamin 03. ... 

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