Bouillon R, Verstuyf A, Branisteanu D, Waer M, Mathieu C
Departement Onderwijs en Navorsing, Universitair Ziekenhuis Gasthuisberg, Leuven.
Verh K Acad Geneeskd Belg. 1995;57(5):371-85; discussion 385-7.
Vitamin D has been discovered at the beginning of this century. 7-Dehydrocholesterol is converted to vitamin D3 in the skin and after several hydroxylations it is further converted to the active hormonal form, 1 alpha,25-(OH)2D3. Vitamin D stimulates the absorption of calcium and phosphate and is an essential link in bone resorption and formation and calcium metabolism. 1 alpha,25-(OH)2D3 acts through a vitamin D receptor. These receptors are not only present in clinical target organs (kidney, gut, liver) but can also be found in a wide variety of "non-classical" tissues (keratinocytes, cells belonging to the immune system). Moreover, numerous cells (keratinocytes, macrophages) can locally synthetize or can be induced to synthetize 1 alpha,25-(OH)2D3 and these cells are responsive to its action. When these data are combined, a possible paracrine function of 1 alpha,25-(OH)2D3 can be suspected. Via this paracrine function 1 alpha,25-(OH)2D3 can suppress the cellular and humoral immunity. Based on the discovery of these effects on immune cells in vitro it became clear that 1 alpha,25-(OH)2D3 might be an interesting molecule to prevent autoimmune diseases and organ transplantation. This has already been shown in several animal models (Heymann nephritis, diabetes mellitus, experimental allergic-encephalomyelitis, lupus). 1 alpha,25-(OH)2D3 demonstrates however some side-effects (hypercalciuria, hypercalcemia, bone resorption) and for this reason 1 alpha,25-(OH)2D3-analogs are developed with dissociated effects i.e. an activity profile that allows a specific action on non-classical tissues without calcemic effects. Some chemical modifications of the side chain, A and/or CD-ring results in "superanalogs" with 10 to 100-fold more activity on cell differentiation and the immune system then 1 alpha,25-(OH)2D3 but with less calcemic activity in vivo. These biological effects can be explained by differences in pharmacokinetics (low affinity for the plasma vitamin D-binding protein and short extracellular half-life) and increased intracellular activation and gen transactivation. Preclinical research must still be done to select the most potent superanalogs and to find the exact protocols for the prevention and treatment of autoimmune diseases and rejection of transplanted organs.
维生素D于本世纪初被发现。7-脱氢胆固醇在皮肤中转化为维生素D3，经过几次羟基化后进一步转化为活性激素形式，即1α,25-(OH)2D3。维生素D刺激钙和磷的吸收，是骨吸收与形成以及钙代谢中必不可少的一环。1α,25-(OH)2D3通过维生素D受体发挥作用。这些受体不仅存在于临床靶器官（肾脏、肠道、肝脏）中，还能在多种“非经典”组织（角质形成细胞、免疫系统细胞）中找到。此外，许多细胞（角质形成细胞、巨噬细胞）能够局部合成或被诱导合成1α,25-(OH)2D3，并且这些细胞对其作用有反应。当综合这些数据时，可以推测1α,25-(OH)2D3可能具有旁分泌功能。通过这种旁分泌功能，1α,25-(OH)2D3可以抑制细胞免疫和体液免疫。基于在体外对免疫细胞的这些作用的发现，很明显1α,25-(OH)2D3可能是预防自身免疫性疾病和器官移植的一个有趣分子。这已经在几种动物模型（海曼肾炎、糖尿病、实验性过敏性脑脊髓炎、狼疮）中得到证实。然而，1α,25-(OH)2D3表现出一些副作用（高钙尿症、高钙血症、骨吸收），因此开发了具有解离效应的1α,25-(OH)2D3类似物，即一种活性谱，允许对非经典组织产生特定作用而无血钙效应。侧链、A环和/或CD环的一些化学修饰产生了“超级类似物”，其对细胞分化和免疫系统的活性比1α,25-(OH)2D3高10至100倍，但在体内的血钙活性较低。这些生物学效应可以通过药代动力学差异（对血浆维生素D结合蛋白的低亲和力和短细胞外半衰期）以及细胞内活化和基因反式激活增加来解释。仍需进行临床前研究以选择最有效的超级类似物，并找到预防和治疗自身免疫性疾病以及移植器官排斥的确切方案。
