Vitamin 1,25-dihydroxycholecalciferol

Vitamin D is composed of a number of related stmc-tures but the two most prominent members of the family are colecalciferol and ergocalciferol, which is formed from ergosterol rather than 7-dehydrocholesterol. Cole-calciferol is transformed into the most active form of the vitamin, 1,25-dihydroxycholecalciferol, by hydroxylation at the 25 position in the liver and finally at the 1 position in the kidneys. 

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). 

Fig. 2. Homeostatic control of blood Ca " level where PTH is parathyroid hormone [9002-64-6], CC, cholecalciferol, ie, vitamin D HCC, hydroxycholecalciferol DHCC, dihydroxycholecalciferol CaBP, calcium-binding protein NAD PH, protonated nicotinarnide-adenine dinucleotide...

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. 

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. 

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. 

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. 

Hypocalcemia (below-normal blood calcium) stimulates release of parathyroid hormone (PTH), which in turn binds to receptors on cells of the renal proximal tubules. The receptors are coupled through cAMP to activation of a la-hydroxylase important for the final, rate-hmiting step in the conversion of vitamin D to 1,25-DHCC (dihydroxycholecalciferol or caldtriol). 

In the human body, cholecalciferol and ergocalciferol undergo two metabolic transformations to yield the active vitamin D molecule. These are additions of hydroxyl groups, first in the liver to produce 25-hydroxyvitamin D and then in the kidney. The final product has the unwieldy name la, 25-dihydroxycholecalciferol, and is more commonly known by its simpler name 1,25-dihydroxy vitamin D or, even more simply, l,25(OH)2D. 

Ultraviolet light causes a chemical change in dihydrocholesterol to produce cholecalciferol, a precursor of vitamin D. The latter conforms better to the definition of a steroid hormone than a vitamin. Indeed, the classification of vitamin D as a vitamin is an historical accident. The precursor is released from the skin and is further modified in the liver and kidney to form dihydroxycholecalciferol, which is the active form of the hormone (see Chapter 15 for the reactions). It increases calcium absorption from the... 

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. 

Finally, PTH helps increase the absorption of calcium from the gastrointestinal tract. This effect appears to be caused by the interaction between PTH and vitamin D metabolism. PTH increases the conversion of vitamin D to 1,25-dihydroxycholecalciferol (calcitriol).36 Calcitriol directly stimulates calcium absorption from the intestine. 

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-... 

Vitamin D-binding protein and its associated vitamin are lost in nephrotic urine. Biochemical abnormalities in nephrotic patients (children and adults) include hypocalcemia, both total (protein-bound) and ionized hypocalciuria, reduced intestinal calcium absorption and negative calcium balance reduced plasma 25-hydroxycholecalciferol and 24,25-dihydroxycholecalciferol and, surprisingly, also 1,25-dihydroxycholecalciferol and blunted response to parathormon (PTH) administration and increased PTH levels. Clinically, both osteomalacia and hyperparathyroidism have been described in nephrotic patients, more commonly in children than in adults, but bone biopsies are commonly normal, and clinically significant bone disease is very rare in nephrotic subjects. There is, however, evidence that patients with renal failure accompanied by nephrotic range proteinuria may be particularly prone to develop renal osteodystrophy. 

I, 25-dihydroxyvitamin D j (1,25-dihydroxycholecalciferol). Activation of the receptor leads to expression of particular proteins, notably an intestinal Ca2+ binding protein, and regulation of intestinal Ca2+ uptake and Ca2+ sequestration in kidney and bone. Vitamin D2 (ergocalciferol) is industrially obtained from irradiation of yeast-derived ergosterol and is hydroxylated to form an active vitamin D receptor agonist. Vitamin D deficiency causes rickets. 

Q7 Calcium is present in both intracellular fluid (ICF) and ECF, but the concentration in the ECF is twice as high as that in the ICF. Calcium is found in both ionized and bound forms, and Ca2+ homeostasis is mainly controlled by parathyroid hormone, which increases absorption of calcium in the intestine and reabsorption in the nephron. Calcitonin also affects ECF calcium concentration by promoting renal excretion when there is an excess of calcium in the body. The normal kidney filters and reabsorbs most of the filtered calcium however, in renal disease this is reduced and blood calcium decreases. Calcium and phosphate imbalance can occur in patients with renal failure, leading to osteomalacia (defective mineralization of bone). Osteomalacia is mainly due to reduced production of 1,25-dihydroxycholecalciferol, an active form of vitamin D metabolized in the kidney. Deficiency of 1,25-dihydroxycholecalciferol reduces the absorption of calcium salts by the intestine. 

Both dietary and endogenously synthesized vitamin D undergo 25-hy-droxylation in the liver to yield calcidiol (25-hydroxycholecalciferol), which is the main circulating form of the vitamin. This undergoes 1 -hydroxylation in the kidney to produce the active hormone calcitriol (1,25-dihydroxy-cholecalciferol) or 24-hydroxylation in the kidney and other tissues to yield 24-hydroxycalcidiol (24,25-dihydroxycholecalciferol). 

Henry HL, Taylor AN, and Norman AW (1977) Response of chick parathyroid glands to the vitamin D metabolites, 1,25-dihydroxycholecalciferol and 24,25-dihydroxy-cholecaldietol. Journal of Nutrition 107,1918-26. 

Parathyroid hormone acts chiefly on kidney increasing renal tubular resorption and bone resorption of calcium it increases calcium absorption from the gut, indirectly, by stimulating the renal synthesis of la-25-dihydroxycholecalciferol (see Vitamin D). It increases the rate of bone remodelling (mineral and collagen) and osteocyte activity with, at high doses, an overall balance in favour of resorption (osteoclast activity) with a rise in plasma calcium con-... 

Further side-chain oxidation of vitamin metaboHtes may be necessary for phosphate transport (188,189). 24,25-Dihydroxycholecalciferol is... 

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