Mode of Action of 1α,25-Dihydroxyvitamin D

Abstract

Vitamin D plays an essential role in calcium and phosphorus homeostasis. Before exerting biological activity, it must undergo metabolism (1–3); the major circulating form, 25-OH-D3, serves as a precursor for the production of 1,25(OH)2D3 or 24R,25(OH)2D3 in the kidney. Recent studies from our laboratory show that these two active forms of the vitamin can be further metabolized in the mammalian kidney. The metabolism of 24R,25(OH)2D3 leads through 25-OH-24-oxo-D3 and 23,25(OH)2-24- oxo-D3 to the cleavage of the side chain of the vitamin (4); l,25(OH)2D3 can be processed to yield either 1,24R,25(OH)3D3 or 1,25(OH)2D3-26,23- lactone (5). Whereas l,25(OH)2D3 and 24R,25(OH)2D3 are known as active forms of vitamin D (6), no biological role has yet been attributed to the other 21 metabolites that were chemically characterized (see Figure 1). l,25(OH)2D3 is the most active form known of vitamin D in terms of both calcium and phosphate absorption in the intestine and bone mineral mobilization. A current hypothesis concerning the mode of action of l,25(OH)2D3 in the target tissue is that the steroid associates first with a specific cytoplasmic receptor protein analogously to other steroid hormones. The cytoplasmic receptor-steroid complex then moves to the nucleus where it alters transcriptional events and leads to de novo synthesis of several proteins, of which vitamin D-dependent calcium binding protein is the most studied.