Regulation of expression of vitamin D hydroxylases
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5000.
Vitamin D is a secosteroid that is metabolically activated and degraded through the actions of three cytochrome P450 hydroxylase enzymes which are expressed in a wide range of tissues stimulating both endocrine and autocrine activities of vitamin D. Bioactivation occurs through the sequential actions of CYP2R1 and CYP27B1 enzymes, resulting in synthesis of the pleiotropic hormone 1,25-dihydroxyvitamin D (1,25D), which regulates over 100 genes whose actions include those associated with calcium homeostasis and immune responses as well as cellular growth, differentiation, and apoptosis. Inactivation of 1,25D occurs by C23/C24 oxidation pathways that are catalyzed by the multifunctional CYP24A1 enzyme. Both CYP27B1 and CYP24A1 are highly regulated genes whose differential expression is controlled in response to numerous cellular modulatory agents such as parathyroid hormone (PTH), calcitonin, interferon gamma, calcium, phosphorus, and pituitary hormones as well as the secosteroid hormone 1,25D. The upregulation of CYP27B1 by 1,25D has both a rapid nongenomic and a slower genomic component that are functionally linked. The rapid response involves protein kinase C and mitogen-activated protein kinase (MAPK) pathways that direct the phosphorylation of nuclear transcription factors. The slower genomic actions are linked to the binding of 1,25D to the vitamin D receptor (VDR) and the interaction of the VDR-1,25D complex with its heterodimer partner retinoid-X-receptor and associated coactivators. The regulatory complex is assembled on vitamin D response elements in the proximal promoter of the CYP24A1 gene and functions to increase the transcription rate.