Calcitriol calcium concentration regulated

Vitamin D3 is transported to liver where it undergoes a hydroxylation at C-25 into 1a,25-dihydroxyvitamin D3 (calcitriol) (Fig. 64). In the kidney, it undergoes further hydroxylations at different sites, depending on the serum Ca + concentration. The most biologically active metabolite of vitamin D3 is calcitriol, which plays important roles in the regulation of calcium and phosphorus metabolism. It is used for treating bone diseases, but is also involved in the cell proliferation and the inducement of cell differentiation [151]. 

Calcidiol la-hydroxylase also acts on 24-hydroxycalcidiol, yielding cal-citetrol indeed, it has a relatively low specificity and will act on any secosteroid with hydroxyl groups at C-3 and C-25. Calcitriol has a short metabolic half-life after injection of the order of 4 to 6 hours (Holick, 1990). But, under normal conditions, the regulation of its synthesis means that the plasma concentration remains fairly constant, depending on the state of calcium balance (Hewison et al., 2000). 

Both calcidiol and calcitriol are substrates for24-hydroxylation, catalyzed by a cytochrome P4so-dependent enzyme in kidneys, intestinal mucosa, cartilage, and other tissues that contain calcitriol receptors. This enzyme is induced by calcitriol the activities of calcidiol 1-hydroxylase and 24-hydroxylase in the kidney are subject to regulation in opposite directions, so that decreased requirement for, and synthesis of, calcitriol results in increased formation of 24-hydroxycalcidiol. Kidney epithelial cells in culture show increased formation of 24-hydroxycalcidiol, and decreased formation of calcitriol, after the addition of calcitriol or high concentrations of calcium to the culture medium. 

Fig. 10.12 Combined actions of parathyroid hormone, calcitriol, and calcitonin on the calcium ion concentration of blood plasma (From Figure 13-11 in Biochemistry a case-oriented approach, 4th Ed. 1983. Authors Montgomery R, Dryer RL, Conway, TW and Spector AA. Chap. 13, Hormonal regulation of metabolism, page 675. The C.V. Mosby Co., St Louis, MO. Copyright Elsevier (2009))...

Regulation of Secretion Plasma Ca +is the major regulator of PTH secretion hypocalcemia stimulates and hypercalcemia inhibits PTH secretion. Sustained hypocalcemia also induces parathyroid hypertrophy and hyperplasia. Changes in Ca modulate PTH secretion by parathyroid cells via the calcium-sensing receptor (CaSR), a GPCR that couples with G -PLC and G. Occupancy of the CaSR by Ca inhibits PTH secretion thus, the extracellular concentration of Ca is controlled by an endocrine negative-feedback system, the afferent limb of which senses the ambient activity of Ca and the efferent hmb of which releases PTH that then acts to increase Ca. The active vitamin D metabolite calcitriol directly suppresses PTH gene expression. 

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). 

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