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The form of the vitamin implicated in the intoxication is 25OHD (Vieth, 1990; Jones, 2008). In fact, it has been shown in dietary supplementation studies using the CYP27B1 knockout mouse, which is incapable of making calcitriol, sufficiently high concentrations of serum levels of 25OHD can cause changes in vitamin D–dependent general expression even in the absence of calcitriol (Rowling et al., 2007; Fleet et al., 2008).

FUNCTIONS AND PHYSIOLOGICAL ACTIONS OF VITAMIN D

Calcium and Phosphate Homeostasis

The dominant function of vitamin D in its hormonal form (calcitriol or 1,25-dihydroxyvitamin D) is the elevation of plasma calcium and phosphate levels, which are required for mineralization of bone (DeLuca, 1979b; Holick, 1996). Furthermore, the elevation of plasma calcium to normal levels is also required for the functioning of the neuromuscular junction as well as vasodilatation, nerve transmission, and hormonal secretion.

Calcitriol—functioning as part of the endocrine system for maintaining serum calcium levels as outlined in Chapter 2—elevates plasma ionized calcium levels to the normal range by three different mechanisms (see Figure 2-1 in Chapter 2). The first mechanism, which does not require PTH, is the well-established role of calcitriol in stimulating intestinal calcium absorption throughout the entire length of the intestine, although its greatest activity is in the duodenum and jejunum. It is clear that calcitriol directly stimulates intestinal calcium and, independently, phosphate absorption.

In the second mechanism, calcitriol plays an essential role in the mobilization of calcium from bone, a process requiring PTH (Garabedian et al., 1972; Lips, 2006). It induces the formation and activation of the osteoclast to function in the mobilization of calcium from bone, as discussed in Chapter 2. In short, calcitriol facilitates the formation of osteoclasts by stimulating the secretion of a protein called receptor activator for nuclear factor κ B (RANK) ligand, which, in turn, is responsible for osteoclastogenesis and bone resorption (Suda et al., 1992; Yasuda et al., 2005).

In the third mechanism, calcitriol together with PTH stimulates the renal distal tubule reabsorption of calcium, ensuring retention of calcium by the kidney when calcium is needed (Sutton et al., 1976; Yamamoto et al., 1984). These well-known functions dominate vitamin D physiology and many of the functional proteins involved in these processes have been identified, although the exact molecular mechanisms of all of these systems have yet to be elucidated.

Thus, overall, calcitriol acts on the intestine, bone, and kidney as described above, and as illustrated in Figure 2-1 in Chapter 2, to elevate



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