Function of 1A,25-dihydroxycholecalciferol

Biologically active form of 1A,25-dihydroxycholecalciferol in calcium absorption and deposition. 1A,25-dihydroxycholecalciferol has widespread effects on cellular differentiation and proliferation, and can modulate immune responsiveness, and central nervous system function. Recent studies suggest that 1A,25-dihydroxycholecalciferol acts as a chemopreventive agent against several malignancies including cancers of the prostate and colon and shows synergy with other anticancer compounds.

1A,25-dihydroxycholecalciferol,32222-06-3

1A,25-dihydroxycholecalciferol increases blood calcium levels ( [Ca2+] ) by promoting absorption of dietary calcium from the gastrointestinal tract and increasing renal tubular reabsorption of calcium thus reducing the loss of calcium in the urine. 1A,25-dihydroxycholecalciferol also stimulates release of calcium from bone by its action on the specific type of bone cells referred to as osteoblasts, causing them to release RANKL, which in turn activates osteoclasts.


1A,25-dihydroxycholecalciferol acts in concert with parathyroid hormone (PTH) in all three of these roles. For instance, PTH also indirectly stimulates osteoclasts. However, the main effect of PTH is to increase the rate at which the kidneys excrete inorganic phosphate (Pi), the counterion of Ca2+. The resulting decrease in serum phosphate causes Ca5(PO4)3OH to dissolve out of bone thus increasing serum calcium. PTH also stimulates the production of 1A,25-dihydroxycholecalciferol (see below).


Many of the effects of 1A,25-dihydroxycholecalciferol are mediated by its interaction with the 1A,25-dihydroxycholecalciferol receptor, also called the vitamin D receptor or VDR. For instance, the unbound inactive form of the 1A,25-dihydroxycholecalciferol receptor in intestinal epithelial cells resides in the cytoplasm. When 1A,25-dihydroxycholecalciferol binds to the receptor, the ligand-receptor complex translocates to the cell nucleus, where it acts as a transcription factor promoting the expression of a gene encoding a calcium binding protein. The levels of the calcium binding protein increase enabling the cells to actively transport more calcium (Ca2+) from the intestine across the intestinal mucosa into the blood.


The maintenance of electroneutrality requires that the transport of Ca2+ ions catalyzed by the intestinal epithelial cells be accompanied by counterions, primarily inorganic phosphate. Thus 1A,25-dihydroxycholecalciferol also stimulates the intestinal absorption of phosphate.


The observation that 1A,25-dihydroxycholecalciferol stimulates the release of calcium from bone seems contradictory, given that sufficient levels of serum 1A,25-dihydroxycholecalciferol generally prevent overall loss of calcium from bone. It is believed that the increased levels of serum calcium resulting from 1A,25-dihydroxycholecalciferol-stimulated intestinal uptake causes bone to take up more calcium than it loses by hormonal stimulation of osteoclasts.Only when there are conditions, such as dietary calcium deficiency or defects in intestinal transport, which result in a reduction of serum calcium does an overall loss of calcium from bone occur.


1A,25-dihydroxycholecalciferol also inhibits the release of calcitonin,[citation needed] a hormone which reduces blood calcium primarily by inhibiting calcium release from bone.(The effect of calcitonin on renal excretion is disputed.)