Dihydroxycholecalciferol, 1,25-, formation

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. 

In addition to being involved in the formation of urine, the kidney acts as an endocrine organ secreting renin, erythropoietin, prostaglandins (qv), and kinins it is also capable of synthesizing substances such as la,25-dihydroxycholecalciferol [32222-06-3] One of the principal functions of the... 

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.]... 

Cholecalciferol is hydroxylated at three positions in the carbon skeleton, 1, 24, and 25. In the liver, cholecalciferol is hydroxylated to 25-hydroxycholecalciferol. Further hydroxylation reactions occur in the kidney, resulting in the formation of three new metabolites. These are 1,25-dihydroxycholecalciferol 24,25-dihydroxycholecalciferol and 1,24,25-trihydroxycholecalciferol. 1,25-Dihydroxy- and 1,24,25-trihydroxycholecalciferol are active hormones involved in calcium uptake from the intestine. 

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. 

Mawer EB, Taylor CM, Backhouse J, Lumb GA, and Stanbury SW (1973) Failure of formation of 1,25-dihydroxycholecalciferol in chronic renal insufficiency. Lancet 1, 626-8. 

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... 

PTH also acts to increase absorption of calcium ion by the small intestine. It does this indirectly by promoting the formation of active vitamin D in the kidney. PTH acts on the final, rate-limiting step in vitamin D synthesis, the formation of 1,25-dihydroxycholecalciferol in the kidney. If PTH is low, formation of the inactive derivative, 24,25-dihydroxycholecalciferol, is stimulated instead. Vitamin D acts on intracellular receptors in the small intestine to increase transcription of genes encoding calcium uptake systems, to up-regulate their expression. 

This active vitamin D metabolite (1,25 dihydroxycholecalciferol) is an important cofactor for intestinal calcium absorption, which involves calbindins (calcium binding proteins) in the intestine and kidney. Calcitriol is produced in the kidneys by the conversion of 25-hydroxycholecalciferol (calcidiol) and its formation is stimulated by a reduction of plasma calcium and/or phosphate and increased production of parathyroid hormone and prolactin (Figure 6.3). Calcitriol also inhibits the release of calcitonin and, together with PTH, increases the absorption of calcium and phosphate from the gastrointestinal tract and the kidneys. Growth hormone, glucocorticoids, estrogens, testosterone, and the thyroid hormones also influence calcium metabolism. 

The parathyroid hormone also plays an important role in regulating the amount of the calcium absorbed from the intestine by influencing the production of 1,25-dihydroxycholecalciferol, a derivative of vitamin D, which is concerned with the formation of calcium-binding protein (see p. 80). Finally, the hormone stimulates the kidney to resorb urinary calcium. 

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