25-Hydroxyvitamin D₃ 24-Hydroxylase: A Key Regulator of 1,25(OH)₂D₃ Catabolism and Calcium Homeostasis.

One of the most pronounced effects of the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is increased synthesis of 25-hydroxyvitamin D3 24-hydroxylase (CYP24A1), the enzyme responsible for the catabolism of 1,25(OH)2D3. Thus, 1,25(OH)2D3 regulates its own metabolism, protecting against hypercalcemia and limiting the levels of 1,25(OH)2D3 in cells. This chapter summarizes the catalytic properties of CYP24A1, the recent data related to the crystal structure of CYP24A1, the findings obtained from the generation of mice deficient for the Cyp24a1 gene as well as recent data identifying a causal role of a genetic defect in CYP24A1 in certain patients with idiopathic infantile hypercalcemia. This chapter also reviews the regulation of renal and placental CYP24A1 as well as the genomic mechanisms, including coactivators, repressors, and epigenetic modification, involved in modulating 1,25(OH)2D3 regulation of CYP24A1. We conclude with future research directions related to this key regulator of 1,25(OH)2D3 catabolism and calcium homeostasis.