Vitamin D3 (Cholecalciferol)

VITAMIN D₃ (CHOLECALCIFEROL)

Vitamin D₃, through its active metabolite, 1,25-(OH)₂D₃, also plays an important role in maintaining calcium homeostasis by enhancing intestinal calcium absorption, PTH-induced mobilization of calcium from bone, and calcium reabsorption in the kidney.

Synthesis and Activation

The primary supply of vitamin D₃ in humans is not ob-tained from the diet but rather is derived from the ultravi-olet photoconversion of 7-dehydrocholesterol to vitamin D₃ in skin. Thus, vitamin D₃ synthesis varies with the sea-sons. D₃ is a prohormone and requires further metabolic conversion to exert biological activity in its target organs (Fig. 66.2). The liver and the kidney are the major sites of metabolic activation of this endogenous sterol hor-mone. The initial transformation of D₃ occurs in the liver and is catalyzed by the enzyme 25-OH-D₃-hydroxylase to form 25-(OH)D₃; this is the primary circulating form of D₃. Circulating 25-(OH)D₃ is then converted by the kidney to the most active form of D₃, 1,25-(OH)₂D₃, by the 1-(OH)-D₃-hydroxylase enzyme. Blood concentra-tions of 1,25-(OH)₂D₃ are approximately one five-hundredth of those of 25-(OH)D₃. 1, 25-(OH)₂D₃ is con-verted to the metabolite 24R,25-(OH)₂D₃, which is ca-pable of suppressing parathyroid secretion.

In addition to the endogenous metabolites, some ex-ogenous sterols possess biological activity similar to that of D₃. Ergocalciferol (vitamin D₂) is derived from the plant sterol ergosterol and may act as a substrate for both the 25-hydroxylase and the 1-hydroxylase enzyme systems of the liver and kidney to form 25-(OH)D₂ and 1,25-(OH)₂ D₂, respectively. Ergocalciferol (vitamin D₂) is the form used in commercial vitamins and supple-mented dairy products. Dihydrotachysterol, another sterol that is used as a therapeutic agent, also functions as a substrate for the hydroxylase enzymes in the liver and kidney.

Mechanism of Action

1, 25-(OH)₂D₃ exerts its influence within target tissues through high-affinity sterol-specific intracellular recep-tor proteins. The D₃ receptor, similar to steroid receptor systems, translocates the hormone from the cell cyto-plasm to the nucleus, where biological response is initi-ated via transcription and translation (Fig. 66.3).