1,25-Dihydroxycholecalciferol synthesis

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 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. 

Hypocalcemia directly increases PTH synthesis and release and inhibits calcitonin release. PTH in turn restores plasma calcium by initially stimulating transport of free or labile calcium from bone into the blood. PTH also increases renal 1,25-dihydroxycholecalciferol (1,25-(0H)2D3) production, which is the most active form of D3. 1,25-(0H)2D3 induces enterocyte differentiation in the intestine, which in turn results in increased absorption of calcium. Finally, during long periods of hypocalcemia, PTH can mobilize more stable calcium deep in the hydroxyapatite of bone by activating deep osteoclasts. 

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-... 

Another important hormone derived from cholesterol is vitamin D. This steroid-like hormone is involved in regulating calcium and phosphorus metabolism. The complete synthesis of vitamin D requires ultraviolet light to convert 7-dehydrocholesterol to previtamin Dj. The reaction scheme is shown in Figure 34-3. The active hormone 1,25-dihydroxycholecalciferol (calcitriol)... 

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. 

Oxidation of la-hydroxycholecalciferol and la,25-dihydroxycholecalciferol with Mn02 gave the corresponding 1 -oxo-previtamins which could be reduced with LiAlH4 at —25 °C in each case to give a mixture of la-hydroxy- and IjS-hydroxy-previtamins in which the IjS-epimers (285) and (286) predominated. Thermal equilibration allowed the isolation of the 1/3-hydroxy-cholecalciferol and l/ ,25-dihydroxycholecalciferol. A similar independent synthesis of 1/3-hydroxycholecalciferol employed NaBH4 for the reduction... 

The bile acid derivative, 3P-acetoxychol-5-en-24-oic acid (32), has been converted in two steps in high yield to 25-hydroxycholesterol (80). The homocholenic acid derivative (33) prepared by a photochemical Wolff rearrangement in this transformation served as a key early intermediate in the first chemical synthesis of la,25-dihydroxycholecalciferol (171). Lithocholic acid, likewise, has been converted to an intermediate (16) used for the preparation of the dihydroxyvitamin (35). Hyodeoxy-cholic acid (34) also shows promise of being a desirable starting material for 25-hydroxycholesterol (132). 

Morisaki, M., N. Koizumi, and N. Ikekawa Synthesis of Active Forms of Vitamin D. Part IX. Synthesis of la,24-Dihydroxycholecalciferol. J. Chem. Soc. Perkin I 1975, 1422. 

The metabolic acid-base balance affects the sensitivity of bone to parathyroid hormone (PTH) and the synthesis of 1,25-dihydroxycholecalciferol. Therefore, acknowledging this when balancing the mineral content of the diet can have an effect on the incidence of milk fever. Conditions that promote an alkalotic state (high dietary cations, Na and IC ) reduce the sensitivity of bone to PTH and can limit the release of calcium. Conversely, an acidotic state (high dietary anions, CP and S ) increases the sensitivity to PTH, increases 1,25-dihydroxycholecalciferol production and hence increases the calcium supply. Through these metabolic responses, manipulation of the acid-base balance in the diet of the pre-calving cow has been successful in reducing the incidence of milk fever. 

Dihydroxycholecalciferol is able to act on a number of tissues with columnar epithelial cells, including intestinal mucosa, kidney tubules, the shell gland of birds and probably also various types of bone cell where it may assist the synthesis of osteocalcin (page 161). Its mode of action is very similar to that of steroid hormones (Figure 30.1). In this respect its precursor, vitamin Dj, may be considered to function as a prohormone rather than a vitamin. The ability of 1,25-DHCC and other metabolites of vitamin D3 to act on bone and kidney cells, as well as those of the intestine, means that vitamin D plays a key role in calcium and phosphorus metabolism (Hgure 30.2). 

Although it is generally agreed that steroid and thyroid hormones act in the nucleus of the target cell to induce specific protein synthesis, there are data which suggest that thyroid hormone (Sterling, 1979) and 1,25-dihydroxycholecalciferol (Bikle et al., 1979) may also act via extra-nuclear mechanisms. 

It has been found that 1,25-dihydroxycholecalciferol stimulates calcium and phosphate transport in the small intestine and calcium accumulation within the cells by means that do not require RNA or protein synthesis. Yet, many of the other changes in protein and enzyme activity require the induction of protein synthesis, which is compatible with the activation of DNA-dependent RNA synthesis in the nucleus by 1,25-dihydroxycholecalciferol. The stimulation of the brush border enzyme alkaline phosphatase by inhibitors of DNA-dependent RNA synthesis is puzzling. These various results suggest, but do not prove, that 1,25-dihydroxycholecalciferol has extranuclear actions (Bikle et al., 1979). 

---