Wu Shaoxing, Chun Rene, Gacad Mercedes A, Ren Songyang, Chen Hong, Adams John S
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, 90048, USA.
Endocrinology. 2002 Oct;143(10):4135. doi: 10.1210/en.2002-220568.
Control of 125-dihydroxyvitamin D (1,25-(OH)2D) synthesis is believed to be primarily at the level of expression of the vitamin D-1-hydroxylase (CYP1alpha; CYP1alpha) gene. Once transcribed, generation of product, as catalyzed by 1-hydroxylase, depends upon the availability of various co-factors, molecular oxygen, electrons as well as substrate to the enzyme. Here we provide evidence that the quantity of product 1,25-(OH)2D generated also relies on the presence and level of expression of the intracellular vitamin D binding protein-1 (IDBP-1) and its capacity to promote 24-hydroxylase (CYP24) gene expression. Stable transfection of the IDBP-1 cDNA increased 1,25-(OH)2D synthesis up to 700% (p < 0.001) in cells devoid of 24-hydroxylating potential but only 70% (p = 0.018) in cells in which the CYP24 gene is expressed. IDBP-1-mediated increase in 1,25-(OH)2D production was independent of any change in CYP1alpha expression but highly dependent on the ability of exogenously-added or endogenously-synthesized 1,25-(OH)2D to stimulate CYP24 gene expression. These data suggest that IDBP-1 is capable of controlling 1,25-(OH)2D production by modulating the delivery of 1) substrate 25-OHD to in the mitochondrial CYP1alpha gene product and 2) CYP1alpha product 1,25-(OH)2D to the vitamin D receptor for upregulation of expression of the catabolic CYP24 gene.
1,25 - 二羟基维生素D（1,25-(OH)₂D）合成的调控被认为主要发生在维生素D - 1 - 羟化酶（CYP1α）基因的表达水平。一旦转录，由1 - 羟化酶催化生成的产物，取决于各种辅助因子、分子氧、电子以及该酶的底物的可利用性。在此我们提供证据表明，生成的1,25-(OH)₂D产物的量还依赖于细胞内维生素D结合蛋白 - 1（IDBP - 1）的存在及其表达水平，以及它促进24 - 羟化酶（CYP24）基因表达的能力。IDBP - 1 cDNA的稳定转染使缺乏24 - 羟化潜能的细胞中1,25-(OH)₂D合成增加高达700%（p < 0.001），但在表达CYP24基因的细胞中仅增加70%（p = 0.018）。IDBP - 1介导的1,25-(OH)₂D生成增加与CYP1α表达的任何变化无关，但高度依赖于外源添加或内源性合成的1,25-(OH)₂D刺激CYP24基因表达的能力。这些数据表明，IDBP - 1能够通过调节以下两个方面来控制1,25-(OH)₂D的生成：1）底物25 - OHD向线粒体CYP1α基因产物的传递；2）CYP1α产物1,25-(OH)₂D向维生素D受体的传递，以上调分解代谢的CYP24基因的表达。
