Regulation of 1,25-Dihydroxyvitamin D Synthesis by Intracellular Vitamin D Binding Protein-1

• Published in: Endocrinology (Philadelphia) 2002-10, Vol.143 (10), p.4135-4135
• Main Authors: Wu, Shaoxing, Chun, Rene, Gacad, Mercedes A, Ren, Songyang, Chen, Hong, Adams, John S
• Format: Article
• Language: English
• Subjects: 25-Hydroxyvitamin D; Animals; Calciferol; Carrier Proteins - physiology; COS Cells; Gene expression; Hydroxylase; Hydroxylation - drug effects; Intracellular; Intracellular Membranes - metabolism; Oxygen; Protein biosynthesis; Proteins; Steroid Hydroxylases - metabolism; Steroid Hydroxylases - pharmacology; Synthesis; Transfection; Vitamin D; Vitamin D - analogs & derivatives; Vitamin D - biosynthesis; Vitamin D - metabolism; Vitamin D - pharmacology; Vitamin D receptors; Vitamin D-24-hydroxylase
• ISSN: 0013-7227; 1945-7170
• 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; CYP1α) 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 CYP1α 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 CYP1α gene product and 2) CYP1α product 1,25-(OH)2D to the vitamin D receptor for upregulation of expression of the catabolic CYP24 gene.