Calcidiol 24-Hydroxylase

Both calcidiol and calcitriol are substrates for24-hydroxylation, catalyzed by a cytochrome P4so-dependent enzyme in kidneys, intestinal mucosa, cartilage, and other tissues that contain calcitriol receptors. This enzyme is induced by calcitriol the activities of calcidiol 1-hydroxylase and 24-hydroxylase in the kidney are subject to regulation in opposite directions, so that decreased requirement for, and synthesis of, calcitriol results in increased formation of 24-hydroxycalcidiol. Kidney epithelial cells in culture show increased formation of 24-hydroxycalcidiol, and decreased formation of calcitriol, after the addition of calcitriol or high concentrations of calcium to the culture medium. 

Conversely, the addition of parathyroid hormone results in decreased 24-hydroxylation and increased 1-hydroxylation (Juan and DeLuca, 1977 Omdahl et al 2001 Wikvall, 2001). There is evidence that the high prevalence of vitamin D deficiency among people from the Indian subcontinent may he because of genetically determined high activity of calcidiol 24-hydroxylase, rather than cultural and dietary factors (Awumey et al., 1998). 

There is evidence that 24-hydroxycalcidiol has physiological functions distinct from those of calcitriol, and the regulation of the 24-hydroxylase suggests that it functions to provide a metabolically active product, as well as diverting calcidiol away from calcitriol synthesis (Henry, 2001). Studies of knockout mice lacking the 24-hydroxylase show that 24-hydroxycalcidiol has a role in both in-tramembranous bone formation during development and the suppression of parathyroid hormone secretion (St-Arnaud, 1999 van Leeuwen et al., 2001). 

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Calcidiol la-hydroxylase is not restricted to the kidney, but is also found in placenta, bone cells (in culture), mammary glands, and keratinocytes. The placental enzyme makes a significant contribution to fetal calcitriol, but it is not clear whether the calcidiol 1-hydroxylase activity of other tissues is physiologically significant or not. Acutely nephrectomized animals given a single dose of calcidiol do not form any detectable calcitriol, but there is some formation of calcitriol in anephric patients, which increases on the administration of cholecalciferol or calcidiol. However, thus extrarenal synthesis is not adequate to meet requirements, so that osteomalacia develops in renal failure (Section 3.4.1). The enzyme is inhibited, or possibly repressed, by strontium ions this is the basis of strontium-induced vitamin D-resistant rickets, which responds to the administration of calcitriol or la-hydroxycalciol, but not calciferol or calcidiol (Omdahl and DeLuca, 1971). 

Calcitriol The major determinant ofthe relative activities of calcidiol 1 -hydroxylase and 24-hydroxylase is the avaUahUity of calcitriol. In vitamin D-deficient animals, with low circulating concentrations of calcitriol, the activity of 1 -hydroxylase in the kidneys is maximal. There is litde or no detectable 24-hydroxylase activity. Both in vivo and in isolated kidney cells in culture, the addition of calcitriol results in induction of the 24-hydroxylase and repression of 1 -hydroxylase removal of calcitriol from the culture medium results in induction of 1-hydroxylase and repression of 24-hydroxylase. 

Calcitriol acts like a steroid hormone, binding to, and activating, nuclear receptors that modulate gene expression. More than 50 genes are known to be regulated by calcitriol (see Table 3.3), but vitamin D response elements have only been identified in a relatively small number, including calcidiol 1-hydroxylase and 24-hydroxylase calbindin, a calcium binding protein in the... 

Strontium intoxication can cause vitamin D-resistant rickets because strontium is a potent inhibitor of calcidiol 1-hydroxylase (Omdahl and DeLuca, 1971). 

Renal failure is associated with an osteomalacia-like syndrome, renal osteodystrophy, as a result of the loss of calcidiol 1-hydroxylase activity. The condition may be complicated by defective reabsorption of calcium and phosphate from the urine. Furthermore, the half-life of parathyroid hormone is increased, because the principal site of its catabolism is the kidney, so there is increased parathyroid hormone-stimulated osteoclastic action without the compensatory action of calcitriol (Mawer etal., 1973). 

X-linked hypophosphatemic rickets is caused by abnormal reabsorption of phosphate in the proximal renal tubule, resulting in excessive excretion of phosphate and hence hypophosphatemia. There may also be blunting of the normal increase in calcidiol 1 -hydroxylase activity in response to hypophosphatemia. The gene responsible for the condition has been identified (the PHEX gene) its product is a membrane-bound endopeptidase that normally acts to clear the hormone phosphatonin from the circulation. Phosphatonin acts to decrease the activity of the sodium/phosphate cotransporter in the kidney (Drezner, 2000). 

Type 1 vitamin D-resistant rickets is due to a genetic defect in calcidiol 1-hydroxylase, so that litde or no calcitriol is formed. Patients respond well to the administration of la-hydroxycholecalciferol, which is a substrate for 25-hydroxylation in the liver, leading to normal circulating concentrations of calcitriol. 

Parathyroid hormone is secreted in response to a fall in plasma calcium. In the kidney it acts to increase the activity of calcidiol 1-hydroxylase and decrease that of the 24-hydroxylase. This is not an effect on protein synthesis, but the result of changes in the activity of existing enzyme protein, mediated by cAMP (section 10.3.2). In turn, both calcitriol and high concentrations of calcium repress the synthesis of parathyroid hormone. 

Calcium exerts its main effect on the synthesis and secretion of parathyroid hormone. However, calcium ions also have a direct effect on the kidney, reducing the activity of calcidiol 1-hydroxylase (but with no effect on the activity of 24-hydroxylase). 

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