Bikle Daniel D.
Professor of Medicine, University of California, VA Medical Center, 4150 Clement St. (111N), San Francisco, CA.
Vitamin D production in the skin under the influence of sunlight (UVB) is maximized at levels of sunlight exposure that do not burn the skin. Further metabolism of vitamin D to its major circulating form (25(OH)D) and hormonal form (1,25(OH)2D) takes place in the liver and kidney, respectively, but also in other tissues where the 1,25(OH)2D produced serves a paracrine/autocrine function: examples include the skin, cells of the immune system, parathyroid gland, intestinal epithelium, prostate, and breast. Parathyroid hormone, FGF 23, calcium and phosphate are the major regulators of the renal 1-hydroxylase (CYP27B1, the enzyme producing 1,25(OH)2D); regulation of the extra renal 1-hydroxylase differs from that in the kidney and involves cytokines. The major enzyme that catabolizes 25(OH)D and 1,25(OH)2D is the 24-hydroxylase; like the 1-hydroxylase it is tightly controlled in the kidney in a manner opposite to that of the 1-hydroxylase, but like the 1-hydroxylase it is widespread in other tissues where its regulation is different from that of the kidney. Vitamin D and its metabolites are carried in the blood bound to vitamin D binding protein (DBP) and albumin—for most tissues it is the free (i.e.. unbound) metabolite that enters the cell; however, DBP bound metabolites can enter some cells such as the kidney and parathyroid gland through a megalin/cubilin mechanism. Most but not all actions of 1,25(OH)2D are mediated by the vitamin D receptor (VDR). VDR is a transcription factor that partners with other transcription factors such as retinoid X receptor that when bound to 1,25(OH)2D regulates gene transcription either positively or negatively depending on other cofactors to which it binds or interacts. The VDR is found in most cells, not just those involved with bone and mineral homeostasis (i.e.. bone, gut, kidney) resulting in widespread actions of 1,25(OH)2D on many physiological and pathologic processes. Animal studies indicate that vitamin D has beneficial effects on various cancers, blood pressure, heart disease, immunologic disorders, but these non-skeletal effects have been difficult to prove in humans in randomized controlled trials. Analogs of 1,25(OH)2D are being developed to achieve specificity for non-skeletal target tissues such as the parathyroid gland, skin, and cancers to avoid the hypercalcemia resulting from 1,25(OH)2D itself. The level of vitamin D intake and achieved serum levels of 25(OH)D that are optimal and safe for skeletal health and the non-skeletal actions remain controversial but are likely between an intake of 800-2000IU vitamin D in the diet and 20-50ng/ml 25(OH)D in the blood. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
在不会晒伤皮肤的阳光照射水平下，皮肤在阳光（紫外线B）影响下生成维生素D的量达到最大值。维生素D进一步代谢为其主要循环形式（25(OH)D）和激素形式（1,25(OH)₂D），分别在肝脏和肾脏中进行，但在其他组织中也会发生，在这些组织中产生的1,25(OH)₂D发挥旁分泌/自分泌功能：例如皮肤、免疫系统细胞、甲状旁腺、肠上皮、前列腺和乳腺。甲状旁腺激素、成纤维细胞生长因子23、钙和磷是肾脏1α-羟化酶（CYP27B1，产生1,25(OH)₂D的酶）的主要调节因子；肾外1α-羟化酶的调节与肾脏中的不同，涉及细胞因子。分解代谢25(OH)D和1,25(OH)₂D的主要酶是24-羟化酶；与1α-羟化酶一样，它在肾脏中受到严格控制，其方式与1α-羟化酶相反，但与1α-羟化酶一样，它在其他组织中广泛存在，其调节方式与肾脏不同。维生素D及其代谢产物在血液中与维生素D结合蛋白（DBP）和白蛋白结合运输——对于大多数组织来说，进入细胞的是游离（即未结合）的代谢产物；然而，与DBP结合的代谢产物可以通过巨膜蛋白/立方蛋白机制进入一些细胞，如肾脏和甲状旁腺。1,25(OH)₂D的大多数但并非所有作用都是由维生素D受体（VDR）介导的。VDR是一种转录因子，它与其他转录因子如视黄酸X受体合作，当与1,25(OH)₂D结合时，根据与其结合或相互作用的其他辅因子，对基因转录进行正向或负向调节。VDR存在于大多数细胞中，而不仅仅是那些参与骨骼和矿物质稳态的细胞（即骨骼、肠道、肾脏），这导致1,25(OH)₂D对许多生理和病理过程产生广泛作用。动物研究表明，维生素D对各种癌症、血压、心脏病、免疫紊乱有有益作用，但在随机对照试验中，这些非骨骼效应在人类中很难得到证实。正在开发1,25(OH)₂D的类似物，以实现对甲状旁腺、皮肤和癌症等非骨骼靶组织的特异性作用，避免1,25(OH)₂D本身导致的高钙血症。对于骨骼健康和非骨骼作用而言，维生素D的摄入量以及达到的血清25(OH)D水平的最佳和安全范围仍存在争议，但可能是饮食中维生素D摄入量为800 - 2000IU，血液中25(OH)D水平为20 - 50ng/ml。欲全面涵盖内分泌学的所有相关领域，请访问我们的在线免费网络文本，WWW.ENDOTEXT.ORG。
