Onisko B L, Schnoes H K, DeLuca H F, Glover R S
Biochem J. 1979 Jul 15;182(1):1-9. doi: 10.1042/bj1820001.
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.
三种在C-25位修饰的胆钙化醇（维生素D3）侧链类似物，即25-氟胆钙化醇、24-脱氢胆钙化醇和25-脱氢胆钙化醇，被设想为胆钙化醇25-羟化酶的潜在抑制剂，并已在大鼠中制备和测试。这些化合物显著减少了胆钙化醇在体内向25-羟胆钙化醇的转化，但不是维生素D作用的拮抗剂，因为它们本身在体内具有显著的生物活性。每种化合物都能够刺激维生素D缺乏大鼠的肠道钙转运和骨钙动员。然而，只有当类似物以高剂量（5-50微克）给药时，才会产生与生理剂量的胆钙化醇（0.05微克）产生的生物反应相当的反应。已表明24-脱氢胆钙化醇和25-脱氢胆钙化醇的生物活性是由于它们在体内转化为天然激素1α,25-二羟胆钙化醇，而25-氟胆钙化醇在大鼠体内通过羟基化代谢活化为1α-羟基-25-氟胆钙化醇。后一种转化是缺乏25-羟基的维生素D化合物1α-羟基化的首个报道实例。
