24hydroxylase

24-hydroxylase, encoded by the CYP24A1 gene in humans, is a member of the cytochrome P450 superfamily involved in the catabolic pathway of vitamin D. It catalyzes the hydroxylation of vitamin D metabolites at the 24 position, most notably converting 25-hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to 24,25-dihydroxyvitamin D3 and 1,24,25-trihydroxyvitamin D3, respectively. These products are further oxidized to calcitroic acid and excreted, effectively inactivating vitamin D metabolites.

Physiological role and regulation: 24-hydroxylase serves as a key regulator of vitamin D activity and calcium homeostasis by promoting the breakdown of active vitamin D hormones when vitamin D levels are high. Its expression is induced by substrate and product levels through vitamin D receptor–mediated mechanisms, providing a negative feedback loop that limits the activity of 1,25(OH)2D3. This regulation helps prevent hypercalcemia and maintains mineral balance.

Clinical significance: Mutations in CYP24A1 can cause hereditary forms of hypercalcemia, such as hereditary infantile hypercalcemia, due to impaired degradation of vitamin D metabolites. Individuals with reduced enzyme activity may experience elevated levels of active vitamin D and increased calcium excretion, with potential nephrolithiasis or nephrocalcinosis. Conversely, overactivity of the enzyme can contribute to insufficient vitamin D signaling.

Therapeutic context: Pharmacological inhibition of CYP24A1 is explored as a strategy to raise endogenous 1,25(OH)2D3 levels in cancer and osteoporosis therapy, whereas activating or preserving CYP24A1 function is considered in conditions of vitamin D excess.