1,25-Dihydroxycholecalciferol inhibition

Cantorna, M.T., Hayes, C.E. and DeLuca, H.F. (1998) 1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. The Journal of Nutrition, 128, 68-72. 

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. 

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. 

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. ... 

Vitamin D is a fat soluble vitamin derived from cholesterol. In the human epidermis (skin), sunlight spontaneously oxidizes cholesterol to 7-dehydrocholesterol (Fig. 10.10a). The 7-dehydrocholesterol leaks into the blood where it isomerizes to cholecalciferol (vitamin D3, Fig. 10.10b and c). Cholecalciferol is enzymatically hydroxylated at C25 in the liver (25-cholecalciferol) and then passes to the kidney where another enzyme is activated by parathyroid hormone to hydroxylate it at Cl, forming calcitriol (Fig. lO.lOd). The kidney hydroxylase is sensitive to feedback inhibition. As the amount of calcitriol increases, it binds to the hydroxylase and alters the specificity of the kidney enzyme. Additional 25-cholecal-ciferol is hydroxylated to 24,25-dihydroxycholecalciferol (inactive calcitriol) instead of 1,25 dihydroxycholecalciferol (calcitriol). Other vitamin D derivatives that can be converted to calcitriol are obtained enzymatically from cholesterol in other vertebrates. The most common of these are vitamin D3 (lamisterol) and D2 (ergosterol) from cold-water fish such as cod, where their presence keeps membranes fluid at low body temperatures 10-20°C. 

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. 

In addition to calcium binding protein, alkaline phosphatase activity is stimulated by 1,25-dihydroxycholecalciferol. This stimulation is inhibited by cycloheximide but not by actinomycin D or cordycepin. In fact, the latter two substances stimulate alkaline phosphatase activity (Bikle et al., 1979). Other enzymes are stimulated by 1,25-dihydroxycholecalciferol, including RNA polymerase and calcium-activated ATPase. 

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