Vitamin D is suppressed by both Roundup and Genes

Category page = Glyphosate and Vitamin D - many studies

10 most-visited pages in Glyphosate category in Vitamin D Life

Cytochrome P450-mediated metabolism of vitamin D – April 2013

The Journal of Lipid Research, jlr.R031534. April 6, 2013, doi: 10.1194/jlr.R031534
Glenville Jones gj1 at queensu.ca, David E. Prosser and Martin Kaufmann
Queen's University, Canada

The vitamin D signal transduction system involves a series of cytochrome P450-containing sterol hydroxylases to generate and degrade the active hormone, 1α,25-dihydroxyvitamin D3 which serves as a ligand for the vitamin D receptor-mediated transcriptional gene expression, described in companion chapters in this review series. This review will update our current knowledge of the specific anabolic cytochrome P450s involved in 25- and 1α-hydroxylation, as well as the catabolic cytochrome P450 involved in 24- and 23-hydroxylation steps, which are believed to initiate inactivation of the vitamin D molecule. We will focus on the biochemical properties of these enzymes; key residues in their active sites derived from crystal structures and mutagenesis studies; the physiological roles of these enzymes as determined by animal knockout studies and human genetic diseases; and the regulation of these different cytochrome P450s by extracellular ions and peptide modulators. We will highlight the importance of these cytochrome P450s in the pathogenesis of kidney disease, metabolic bone disease and hyperproliferative diseases such as psoriasis and cancer; as well as to explore potential future developments in the field.

Received August 22, 2012. Accepted April 6, 2013.
Copyright © 2013, The American Society for Biochemistry and Molecular Biology

Clipped from PDF: Future Perspectives

This study of the cytochrome P450s involved in vitamin D metabolism has come of age with the cloning and structural elucidation of several of the family members. Just as the crystal structure of the VDR has opened the door to new families of vitamin D analogs which more precisely position the vitamin D ligand in the ligand-binding pocket (See companion review on VDR), the substrate-binding pockets of the vitamin D-related CYPs, especially CYP24A1, will allow us to design "metabolism-resistant" or "metabolism-sensitive" vitamin D analogs as well as a second generation of CYP24A1 or CYP27B1 inhibitors using rational drug design [174]. From a biochemical perspective such information will also allow us to better understand the mechanism of multiple hydroxylation reactions executed by these enzymes

As was pointed out throughout this review, the number of CYP2R1, CYP27A1, CYP27B1 and CYP24A1 polymorphisms in the genomic databases is expanding at an exponential pace. Undoubtedly, the recent discovery of inactivating CYP24A1 mutations in IIH patients [168] will also drive clinical interest in CYP24A1 research. One would expect that more of these polymorphisms may be loss-of-function mutations associated with mild and more severe diseases in the hypercalcemic constellation, including IIH, but it remains to be seen whether CYP24A1 dysregulation can be connected with other disease states e.g. nephrolithiasis. There is no doubt that the CYP24A1-knockout mouse [133-137] still has much more to reveal about the roles of CYP24A1 in vivo. Likewise the development of the CYP2R1-null mouse [36] and its crossing with the CYP27A1-null mouse should lead to a much better understanding of the vitamin D-25-hydroxylase. Lastly, and perhaps most importantly, the exact role of the extra-renal CYP27B1 should also be clarified over the next few years. This is an exciting time to be involved in the study of vitamin D-related cytochromes P450 and vitamin D metabolomics.

Cytochromes P450 are essential players in the vitamin D signaling system - 2011

Biochim Biophys Acta. 2011 Jan;1814(1):186-99. doi: 10.1016/j.bbapap.2010.06.022. Epub 2010 Jul 7.
Cytochromes P450 are essential players in the vitamin D signaling system.
Schuster I1.

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.

Copyright © 2010 Elsevier B.V. All rights reserved., PMID: 20619365