Cytochromes P450 are essential players in the vitamin D signaling system.
Article Details
- CitationCopy to clipboard
Schuster I
Cytochromes P450 are essential players in the vitamin D signaling system.
Biochim Biophys Acta. 2011 Jan;1814(1):186-99. doi: 10.1016/j.bbapap.2010.06.022. Epub 2010 Jul 7.
- PubMed ID
- 20619365 [ View in PubMed]
- Abstract
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 1alpha,25(OH)(2)D(3) 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 1alpha-hydroxylation via CYP27B1. Circulating in the bloodstream, 1alpha,25(OH)(2)D(3) 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 1alpha,25(OH)(2)D(3) synthesis, as illustrated by three examples. 1alpha,25(OH)(2)D(3) levels are short-lived: the hormone upregulates its rapid metabolism by CYP24A1 that attacks repeatedly the vitamin D C(2)(0)(-)(2)(7) side chain, thereby producing a complex cascade of transient metabolites with increasing polarity. Most of these metabolites still retain 1alpha,25(OH)(2)D(3)-like activities on the VDR, contributing to the overall effect that is commonly attributed to 1alpha,25(OH)(2)D(3). 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Calcifediol 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial Protein Humans UnknownSubstrateDetails Calcitriol 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial Protein Humans UnknownSubstrateInducerDetails Cholecalciferol Cytochrome P450 2J2 Protein Humans UnknownSubstrateDetails Cholecalciferol Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Cholecalciferol Sterol 26-hydroxylase, mitochondrial Protein Humans UnknownSubstrateDetails Cholecalciferol Vitamin D 25-hydroxylase Protein Humans UnknownSubstrateDetails