Calcidiol 24Hydroxylase

Both calcidiol and calcitriol are substrates for 24-hydroxylation, catalyzed by a cytochrome P450-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 be because of genetically determined high activity of calcidiol 24-hydroxylase, rather than cultural and dietary factors (Awumey et al., 1998).

Early studies suggested that 24-hydroxylation of calcidiol was a pathway for inactivation of the vitamin, a conclusion that is supported by the observation that calcidiol 24-hydroxylase is activated and induced by calcitriol. Fish-eating mammals, such as seals, that have a very high intake of cholecalciferol, do not show vitamin D intoxication. Although they have plasma concentrations of calcitriol similar to those seen in other mammals, after the administration of [3H]cholecalciferol, label is found in calcidiol and 24-hydroxycalcidiol, not calcitriol, suggesting that 24-hydroxylation provides a means of inactivating excess calciferol and hence avoiding vitamin D intoxication (Keiver et al., 1988).

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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