Vitamin D : Metabolism

1. 1,25-Dihydroxycholecalciferol formation: Vitamins D2 and D3 are not biologically active but are converted in vivo to calcitriol, the active form of the D vitamin, by two sequential hydroxylation reactions (Fig. 1).
The first hydroxylation occurs at the 25 position and is catalyzed by a specific 25-hydroxylase in the liver. The product of the reaction, 25-hydroxycholecalciferol ([25-OH-D3], calcidiol), is the predominant form of vitamin D in the serum and the major storage form. 25-OH-D3 is further hydroxylated at the 1 position by 25-hydroxycholecalciferol 1-hydroxylase found primarily in the kidney, resulting in the formation of 1,25-diOH-D3 (calcitriol). [Note: Both hydroxylases are cytochrome P450 proteins .]

Figure 1: Metabolism and actions of vitamin D. [Note: Calcitonin, a thyroid hormone, decreases blood calcium (Ca²⁺) by inhibiting mobilization from bone, absorption from the intestine, and reabsorption by the kidney. It opposes the actions of PTH.] mRNA = messenger RNA; 25-OH-D3 = 25-hydroxycholecalciferol; 1,25-diOH-D3 = 1,25-dihydroxycholecalciferol.
2. Hydroxylation regulation: Calcitriol is the most potent vitamin D metabolite. Its formation is tightly regulated by the level of serum phosphate (PO₄³⁻) and calcium ions (Ca²⁺) as shown in Figure 28.24. 25-Hydroxycholecalciferol 1-hydroxylase activity is increased directly by low serum PO₄³⁻ or indirectly by low serum Ca²⁺, which triggers the secretion of parathyroid hormone (PTH) from the chief cells of the parathyroid gland. PTH upregulates the 1-hydroxylase. Thus, hypocalcemia caused by insufficient dietary Ca2+ results in elevated levels of serum 1,25-diOH-D3. [Note: 1,25-diOH-D3 inhibits expression of PTH, forming a negative feedback loop. It also inhibits activity of the 1-hydroxylase.]

Figure 2: Response to low serum calcium. 1,25-diOH-D3 = 1,25-dihydroxycholecalciferol. [Note: Calcitriol also increases intestinal absorption and renal reabsorption of phosphate. In contrast, PTH decreases renal reabsorption of phosphate.]

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