Metabolism and biological activity of 25-fluorocholecalciferol, 24-dehydrocholecalciferol and 25-dehydrocholecalciferol in the rat.
Three side-chain analogues of cholecalciferol (vitamin D3) modified at C-25, namely 25-fluorocholecalciferol, 24-dehydrocholecalciferol and 25-dehydrocholecalciferol, conceived as potential inhibitors of the cholecalciferol 25-hydroxylase have been prepared and tested in the rat. These compounds markedly diminish conversion in vivo of cholecalciferol into 25-hydroxycholecalciferol, but are not antagonists of vitamin D action, because they themselves possess significant biological activity in vivo. Each compound is capable of stimulating the intestinal transport of calcium and the mobilization of calcium from bone in vitamin D-deficient rats. Biological responses equivalent to those generated by a physiological dose of cholecalciferol (0.05 microgram) are produced, however, only when the analogues are administered at high doses (5-50 microgram). The biological activity of 24-dehydrocholecalciferol and 25-dehydrocholecalciferol is shown to result from conversion, in vivo, to the natural hormone, 1 alpha,25-dihydroxycholecalciferol, whereas 25-fluorocholecalciferol is metabolically activated in the rat by hydroxylation to 1 alpha-hydroxy-25-fluorocholecalciferol. This latter conversion is the first reported example of the 1 alpha-hydroxylation of a vitamin D compound lacking the 25-hydroxy group.
D000818:Animals; D001692:Biological Transport; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002762:Cholecalciferol / Q000138:chemical synthesis / Q000378:metabolism* / Q000031:analogs & derivatives; D002851:Chromatography, High Pressure Liquid; D006900:Hydroxylation; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D009392:Nephrectomy; D051381:Rats; D014808:Vitamin D Deficiency / Q000378:metabolism
D002762:Cholecalciferol; C021681:25-fluorocholecalciferol; C021656:25-dehydrocholecalciferol; D002118:Calcium