Newly Identified Actions of the Vitamin D Endocrine System*

Abstract

VITAMIN D is a seco-steroid in which the B-ring of the cyclopentanoperhydrophenanthrene structure is cleaved. The vitamin is either obtained from the diet or is synthesized in the skin from 7-dehydrocholesterol (Fig. 1) and is itself biologically inert (for reviews see Refs. 1–8). Vitamin D and its metabolites circulate in the blood primarily bound to and in equilibrium association with the vitamin D-binding globulin [DBP]. In the liver, the enzyme 25-hydroxylase converts the vitamin to the inactive hormonal precursor 25-hydroxyvitamin D [25(OH)D]. Subsequently, the renal lα-hydroxylase enzyme converts 25(OH)D to the biologically active form 1,25-dihydroxyvitamin D [1,25(OH)2D]. Both hydroxylase enzymes are cytochrome P450-containing enzymes. la-Hydroxylase activity is tightly controlled by a number of ionic and endocrine factors including stimulation by PTH and reduced plasma Ca2+ or inhibition by 1,25(OH)2D in a classic negative feedback loop. Although not illustrated in Fig. 1, under conditions of adequate plasma Ca2+ levels, 25(OH)D is alternatively converted to 24,25(OH)2D by the reciprocally regulated renal P450- dependent 24-hydroxylase enzyme. Whether this metabolite of vitamin D is biologically effective or whether its production simply initiates a catabolic pathway has been a topic of active debate (2, 4, 5, 9). The seco-steroid hormone 1,25(OH)2D exerts its principal biological activities through specific intracellular receptors (Fig. 1), which are nuclear transcription factors of the steroidthyroid receptor gene superfamily (7, 10), a relationship previously postulated on the basis of the biochemical similarities between all these receptor species (1, 11). As now considered likely for many of these ligand-dependent transcription factors, the 1,25(OH)2D receptor (VDR) (12, 13), seems to be predominately a nuclear protein (1), a fact that will be of importance in later discussions of its signal transduction mechanisms. The mechanism of action of the VDR is similar to that of the other steroid hormone receptors (Fig. 2), involving specific interactions of the receptor zinc-finger regions with specific nucleotide sequences (hormone response elements) usually in the 5′-regulatory region of the affected genes (1, 7, 10, 15). Similarly, 1,25(OH)2D regulation of cell function by altering gene transcription and mRNA and protein synthesis is similar to that of the other members of this gene family (1).