Cytochromes P450 are essential players in the vitamin D signaling system.
From earliest development on, the vitamin D receptor (VDR) is expressed in most cells of the mammalian body. The VDR is a nuclear, ligand-induced transcription factor that regulates in complex with hormonally active vitamin D the expression of more than 900 genes involved in a wide array of physiological functions (e.g. calcium homeostasis, growth control, differentiation, cognition, immune response, etc.). Accordingly, severe health problems are associated to vitamin deficiencies. Synthesis of the major active form 1α,25(OH)₂D₃ from vitamin D and subsequent metabolism are exclusively controlled by specific P450-forms. Synthesis, a two-step process, starts with a 25-hydroxylation primarily by CYP2R1 (CYP27A1, CYP2J2, and CYP3A4 may also contribute) and a subsequent 1α-hydroxylation via CYP27B1. Circulating in the bloodstream, 1α,25(OH)₂D₃ acts at sites of VDR expression (target sites) in an endocrine way. However, it is also capable of autocrine/paracrine functions since various target tissues are fully competent in 1α,25(OH)₂D₃ synthesis, as illustrated by three examples. 1α,25(OH)₂D₃ levels are short-lived: the hormone upregulates its rapid metabolism by CYP24A1 that attacks repeatedly the vitamin D C₂₀₋₂₇ side chain, thereby producing a complex cascade of transient metabolites with increasing polarity. Most of these metabolites still retain 1α,25(OH)₂D₃-like activities on the VDR, contributing to the overall effect that is commonly attributed to 1α,25(OH)₂D₃. As selective inhibitors of CYP24A1 increase the lifetime and thereby the function of vitamin D metabolites, they will help exploring whether and which intrinsic activities distinct metabolites possess. It appears likely that this strategy may unmask important regulators of new functions.
Schuster
Inge
I
Department of Theoretical Chemistry, University of Vienna, Währingerstraße 17, A 1090 Wien, Austria. inge@tbi.univie.ac.at
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D006801:Humans; D006900:Hydroxylation; D053858:Metabolic Networks and Pathways; D015394:Molecular Structure; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D014807:Vitamin D / Q000737:chemistry / Q000378:metabolism*
D018167:Receptors, Calcitriol; D014807:Vitamin D; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase