Dihydroxy cholecalciferol

Sterol-specific cytoplasmic receptor proteins (vitamin D receptor) mediate the biological action of vitamin D (9). The active hormone is transported from the cytoplasm to the nucleus via the vitamin D receptor, and as a result of the interaction of the hormone with target genes, a variety of proteins are produced that stimulate the transport of calcium in each of the target tissues. Active vitamin D works in concert with PTH to enhance active intestinal absorption of calcium, to stimulate bone resorption, and to prohibit renal excretion of calcium (2,9). If serum calcium or 1,25-calcitriol concentrations are elevated, then vitamin D 24-hydroxylase (in renal mitochondria) is activated to oxidize 25(OH)D3 to inactive 24,25-dihydroxy-cholecalciferol and to further oxidize active vitamin D to the inactive 1,24,25-trihydroxylated derivative. Both the 1,24,25-trihydroxylated and the 24,25-dihydroxylated products have been found to suppress PTH secretion as well. Several factors have been identified in the regulation of the biosynthesis of vitamin D, including low phosphate concentrations (stimulatory) as well as pregnancy and lactation (stimulatory). 

Somjen, D., Sdmjen, G.J., Weisman, Y., Binderman, I. 1982b. Evidence for 24,25-dihydroxy-cholecalciferol receptors in long bones of newborn rats. Biochem. J. 204(1) 31-6. 

Calcium is the major mineral component of bone and normal repair and remodelling of bone is reliant on an adequate supply of this mineral. Calcium uptake in the gut, loss through the kidneys and turnover within the body are controlled by hormones, notably PTH and 1,25 dihydroxy cholecalciferol (1,25 DHCC or 1,25 dihydroxy vitamin D3 or calcitriol). Refer to Figure 8.12 for a summary of the involvement of PTH and vitamin D3 in controlling plasma calcium concentration. These two major hormones have complementary actions to raise plasma calcium concentration by promoting uptake in the gut, reabsorption in the nephron and bone resorption. Other hormones such as thyroxine, sex steroids and glucocorticoids (e.g. cortisol) influence the distribution of calcium. 

Horman, A. W., Henry, H. 1,25-dihydroxy cholecalciferol, a hormonally active form of vitamin D3. Recent Prog. Horm. Res. 30, 431 (1974)... 

Vitamin D Cholecalciferol Ergocalciferol 1,25-Dihydroxy- cholecalciferol Calcium uptake 1 i... 

The stratum corneum consists of denucleated corneocytes filled with cross-linked proteins, while the intercellular space is occupied by lipids synthesized prior to and during cornification [24], Formation of this barrier relies on the cornification of epidermal keratinocytes, which undergo growth arrest, terminal differentiation, and an epidermal-specific cell death, referred to as planned cell death [25], Abnormalities in any of these programmed events may lead to epidermal disorders such as psoriasis, atopic dermatitis, and cancer. Flowever, biological events that enable basal cells (stem cells) to proliferate, differentiate, and commit planned cell death are still poorly understood [10]. The keratinocyte differentiation process can be stimulated by prodifferentiation agents such as extracellular calcium and 1,25-dihydroxy cholecalciferol (referred to as vitamin D3 hereafter) [23], Aberrant or absent differentiation can be found in other skin disorders such as atopic keratosis, seborrheic keratosis, and rosacea. 

Dihydroxy cholecalciferol acts primarily on three tissues bone, kidney, and intestine. The effect is to increase blood calcium levels. Thus, Ca2+ (and phosphate) are mobilized from bone through the action of 1,25-dihydroxy-cholecalciferol, Ca2+ reabsorption by the kidney is increased, and the intestinal... 

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). 

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. 

Severin M, Bulla M. Homhautablagerung bei Kindern mit Dialysebehandlung unter einer Therapie mit Vitamin D3 und 1,25 Dihydroxy-Cholecalciferol. [Corneal deposits in children... 

C. Steroid hormones are synthesized from cholesterol, and 1,25-dihydroxy-cholecalciferol (active vitamin D3) is synthesized from a precursor of cholesterol (see Chapter 8). 

Gray TK. Radioimmunoassay for 1,25-dihydroxy-cholecalciferoL Clin Chem 1983 29 196-200. 

A -Ray crystallographic study of synthetic (235)-cholest-5-ene-3p,23,25-triol, and comparison of the derived 23,25-dihydroxycholecalciferol (1) with a new natural metabolite of vitamin D has established the configuration of the latter compound.1 Syntheses of the (255)- and (25R)-isomers of 25,26-dihydroxy-cholecalciferol, using C5 precursors of known configuration to elaborate the side-chain, have established the configuration of the natural compound as (255). The configuration was confirmed by A -ray crystallographic analysis of the intermediate compound (2).2... 

Fio. 12. Scheme of calcium and phosphorus homeostasis in progressive renal disease — , increases decreases GFR, glomerular filtration rate P, serum phosphorus Ca2+, serum ionized calcium Ca, calcium 1,25-DHCC, 1,25-dihydroxy cholecalciferol PTH, serum parathyroid hormone Cp, phosphate clearance. 

In addition, the kidneys have direct endocrine functions. Because they are a major site of synthesis of several hormones, including erythropoietin and 1,25-dihydroxy-cholecalciferol, the kidneys indirectly influence the regulation of blood pressure and vasopressor activity via the renin-angiotensin, prostaglandins, and kallekrein-kinin systems, which exert a regulatory effect on water and electrolyte homeostasis (Harris 1992 Parekh et al. 1993 Gonzalez et al. 1998 Campean et al. 2003 see also Chapters 6 and 10). 

Parathyroid hormone (PTH), vitamin D and calcitonin work in synchrony to regulate calcium homeostasis (not presented in tables). PTH is an 84 amino acid chain secreted by the parathyroid glands in response to low serum calcium. PTH induces bone resorption, which liberates calcium into the bloodstream. These actions are dependent on adequate serum concentrations of 1,25-dihydroxy cholecalciferol (a derivative of vitamin D). Bone resorption is counterregulated by calcitonin, which inhibits osteoclasts (the cells which degrade bone). 

Vitamin D, 1,25-dihydroxy- cholecalciferol Hormone, controlling calcium and phosphate metabolism deficiency causes rickets. 10 Mg... 

FIGURE 7.6 Structure and function of intracellular receptors. Glucocorticoid, mineralocorticoid and androgen receptors are located in the cytoplasm. Estrogen, progesterone, thyroid hormone, 1,25-dihydroxy-cholecalciferol and retinoic acid receptors are located in the nucleus. 

In this line it is shown one of the first studies which aimed to ascertain at what intestinal level the Sr/Ca discrirnination takes place. Vitamin D3, 25-hydroxy-cholecaldferol (25-OH-CC) and 1,25-dihydroxy-cholecalciferol (1,25 (OH)2-CC) were administered to rats. The apparent and... 

Vitamin D is the sunshine vitamin . It was originally discovered as a crude mixture called vitamin Dj (no longer available as a supplement). Ergosterol, the plant equivalent of cholesterol, is converted to vitamin D2 by ultraviolet light. Vitamin D3 (cholecalciferol) is formed in the skin from 7-dehydrocholesterol (an intermediate in the cholesterol biosynthesis pathway) in the presence of ultraviolet light, which opens the B-ring of the steroid nucleus (Fig. 51.3). Cholecalciferol is successively hydroxylated first in the liver forming 25-hydroxycholecalciferol (25-HCC) and then in the kidney to form the most active form 1,25-dihydroxy cholecalciferol (1,25-DHCC), also known as calcitriol. 

The K. is the site of synthesis of Erythropoietin (see) and Renin (see). Renin is synthesized in the juxtaglomerular cells it releases Angiotensin (see), which in turn stimulates the release of aldosterone by the adrenal cortex. 25-Hydroxycholecalciferol (produced in the liver from vitamin D3 or cholecalci-ferol) is converted by the kidney into 1,25-dihydroxy-cholecalciferol, which promotes calcium uptake by the intestine and calcium mobilization in bone. 

Chalmers, P. M., N. W. Davies, J. 0. Hunter, K. F. Szaz, B. Pelc, and E. Kodicek la-Hydroxycholatecalciferol as a Substitute for the Kidney Hormone 1,25-Dihydroxy-cholecalciferol in Chronic Renal Failure. Lancet 2,696 (1973). 

A metabolite formed in the kidney, 1,25-dihydroxy-cholecalciferol, is now believed to be the active compound. If vitamin D administration to vitamin D-defi-cient animals is preceded by actinomycin administration, the effect of the vitamin on calcium absorption in the intestine is abolished. In vitro experiments using intestinal sacs have excluded a direct effect of actinomycin on intestinal absorption. Actinomycin s effect results from interference with transcription of enzymes which in the kidney convert 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol [13]. The kidney is the only organ that can convert the monohydroxy to the dihydroxy derivative, and therefore the monohydroxy derivative has no effect on calcium absorption in anephric animals. Chronic renal damage [14, 15] impairs the biosynthesis of the active vitamin, and... 

The most active form of vitamin D is the 1, 25-dihydroxy-cholecalciferol or calcltriol (DeLuca, 1974). Vitamin D3 is first hydroxylated in the 25-position in the liver and then hydroxylated again in the alpha-position in the kidneys. Xt is understandable that for satisfactory vitamin D therapy, functional kidneys are important. 

Nemere, I. and Szego, C.M. 1981b. Early actions of parathyroid hormone and 1,25-dihydroxy-cholecalciferol on isolated epithelial cells from rat intestine II. Analyses of additivity, contribution of calcium, and modulatory influence of indomethacin. Endocrinology 109(6) 2180-5. 

Brumbaugh, P. F. and Haussler, M. R. (1974) 1 Alpha,25 dihydroxy-cholecalciferol receptors in intestine II. Temperature-dependent transfer of the hormone to chromatin via a specific cytosol receptor. J Biol. Chem. 249, 1258-1262... 

Cholecalciferol (vitamin D3) is formed by photolysis of 7-dehydrocholesterol, a precursor in cholesterol biosynthesis. As shown in Fig. 3.42, UV radiation opens the B ring. The precalciferol formed is then isomerized to vitamin D3 by a rearrangement of the double bond which is influenced by temperature. Side-products, such as lumi- and tachisterol, have no vitamin D activity. Cholecalciferol is converted into the active hormone, 1,25-dihydroxy-cholecalciferol, by hy-droxylation reactions in liver and kidney. 7-Dehydrocholesterol, the largest part of which is supplied by food intake and which accumulates in human skin, is transformed by UV light into vitamin D3. The occurrence and the physiological significance of the D vitamins are covered in Sect. 6.2.2. 

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