Vitamin D2 and D3 are converted into the biologically active form, calcitriol, through two hydroxylation reactions. The first hydroxylation occurs in the liver, catalyzed by a specific 25-hydroxylase, resulting in the formation of 25-hydroxycholecalciferol (calcidiol). This is the major storage form of vitamin D found in the serum. The second hydroxylation takes place in the kidney, catalyzed by 25-hydroxycholecalciferol 1 hydroxylase, leading to the formation of 1,25-dihydroxycholecalciferol (calcitriol), which is the most potent vitamin D metabolite.

The formation of calcitriol is regulated by serum phosphate (PO43-) and calcium ions (Ca2+). Low levels of serum PO43- or Ca2+ increase the activity of 25-hydroxycholecalciferol 1-hydroxylase, either directly or indirectly through the secretion of parathyroid hormone (PTH) from the parathyroid gland. Elevated levels of 1,25-dihydroxycholecalciferol are observed in cases of hypocalcemia caused by insufficient dietary calcium.

The overall function of calcitriol is to maintain adequate levels of serum calcium. It achieves this by increasing calcium uptake in the intestine, minimizing calcium loss through kidney reabsorption, and stimulating bone resorption when blood calcium levels are low.

Calcitriol stimulates intestinal absorption of calcium by binding to a cytosolic receptor in the intestinal cell. The resulting 1,25-dihydroxycholecalciferol-receptor complex then interacts with response elements on DNA in the nucleus, leading to increased expression of the calcium-binding protein calbindin and enhanced calcium uptake.

When blood calcium levels are low, calcitriol stimulates bone resorption, a process further enhanced by PTH. This increases serum calcium levels and serves as an important reservoir of calcium to maintain adequate levels. PTH and calcitriol also work together to prevent renal loss of calcium.

In terms of distribution and requirement, the details are not provided in the given excerpt.
B. 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. 28.23). The first hydroxylation occurs at the 25 position and is catalyzed by a specific 25-hydroxylase in the liver. The product of the reaction, 25hydroxycholecalciferol ([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 (see p. 149).] 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.]
C. Function
The overall function of calcitriol is to maintain adequate serum levels of Ca2+ . It performs this function by 1) increasing uptake of Ca2+ by the intestine, 2) minimizing loss of Ca2+ by the kidney by increasing reabsorption, and 3) stimulating resorption (demineralization) of bone when blood Ca2+ is low (see Fig. 28.23).
1.
Effect on the intestine: Calcitriol stimulates intestinal absorption of Ca2+ by first entering the intestinal cell and binding to a cytosolic receptor. The 1,25-diOH-D3–receptor complex then moves to the nucleus where it selectively interacts with response elements on the DNA. As a result, Ca2+ uptake is enhanced by increased expression of the calcium-binding protein calbindin. Thus, the mechanism of action of 1,25-diOH-D3 is typical of steroid hormones (see p. 240).
2.
Effect on bone: Bone is composed of collagen and crystals of Ca5(PO4)3OH (hydroxylapatite). When blood Ca2+ is low, 1,25-diOH-D3 stimulates bone resorption by a process that is enhanced by PTH. The result is an increase in serum Ca2+ . Therefore, bone is an important reservoir of Ca2+ that can be mobilized to maintain serum levels. [Note: PTH and calcitriol also work together to prevent renal loss of Ca2+.]
D. Distribution and requirement