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CYP24A1 enzyme and Vitamin D


It appears that differences in gene activation accounts for a noticeable difference in the blood level of vitamin D
Perhaps this means that some people will need much more vitamin D to get the same benefit


CYP24A1 and Vitamin D - 2011

25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D.
Arch Biochem Biophys. 2012 Jul 1;523(1):9-18. doi: 10.1016/j.abb.2011.11.003. Epub 2011 Nov 12.
Jones G1, Prosser DE, Kaufmann M.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada K7L 3N6. gj1 at queensu.ca

CYP24A1 is the cytochrome P450 component of the 25-hydroxyvitamin D(3)-24-hydroxylase enzyme that catalyzes the conversion of 25-hydroxyvitamin D(3) (25-OH-D(3)) and 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) into 24-hydroxylated products, which constitute the degradation of the vitamin D molecule. This review focuses on recent data in the CYP24A1 field, including biochemical, physiological and clinical developments. Notable among these are: the first crystal structure for rat CYP24A1; mutagenesis studies which change the regioselectivity of the enzyme; and the finding that natural inactivating mutations of CYP24A1 cause the genetic disease idiopathic infantile hypercalcemia (IIH). The review also discusses the emerging correlation between rising serum phosphate/FGF-23 levels and increased CYP24A1 expression in chronic kidney disease, which in turn underlies accelerated degradation of both serum 25-OH-D(3) and 1,25-(OH)(2)D(3) in this condition. This review concludes by evaluating the potential clinical utility of blocking this enzyme with CYP24A1 inhibitors in various disease states.
Outline
CYP24A1: biochemistry and catalytic properties
CYP24A1: crystal structure, homology modeling and mutagenesis studies
CYP24A1: physiological role
CYP24A1: regulation by 1,25-(OH)2D3, PTH and FGF-23
CYP24A1: pharmacological role
CYP24A1: human polymorphisms and genome-wide linkage studies
CYP24A1: pathological role and implications in disease
CYP24A1 and genetically-linked idiopathic infantile hypercalcemia
CYP24A1 and genetically-linked hypophosphatemia
CYP24A1: involvement in chronic kidney disease
CYP24A1: involvement in pathogenesis and treatment of hyperproliferative disorders
CYP24A1 inhibitors
Publisher wants $25 for the PDF

PMID: 22100522 DOI: 10.1016/j.abb.2011.11.003


CYP24A1 and kidney disease - May 2011

Curr Opin Nephrol Hypertens. 2011 May 22.
PMID: 21610497 full text online


Possibility of blocking CYP24A1 to enable the benefits of vitamin D - July 2012

25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D.


CYP24A1 as a potential target for cancer therapy.- Jan 2014

Anticancer Agents Med Chem. 2014 Jan;14(1):97-108.
Sakaki T, Yasuda K, Kittaka A, Yamamoto K, Chen TC1.

Increasing evidence has accumulated to suggest that vitamin D may reduce the risk of cancer through its biologically active metabolite, 1α,25(OH)2D3, which inhibits proliferation and angiogenesis, induces differentiation and apoptosis, and regulates many other cellular functions. Thus, it is plausible to assume that rapid clearance of 1α,25(OH)2D3 by highly expressed CYP24A1 could interrupt the normal physiology of cells and might be one cause of cancer initiation and progression. In fact, enhancement of CYP24A1 expression has been reported in literature for many cancers. Based on these findings, CYP24A1-specific inhibitors and vitamin D analogs which are resistant to CYP24A1-dependent catabolism might be useful for cancer treatment. CYP24A1-specific inhibitor VID400, which is an azole compound, markedly enhanced and prolonged the antiproliferative activity of 1α,25(OH)2D3 in the human keratinocytes. Likewise, CYP24A1-resistant analogs such as 2α-(3-hydroxypropoxy)-1α,25(OH)2D3 (O2C3) and its C2-epimer ED-71 (Eldecalcitol), and 19nor- 2α-(3-hydroxypropyl)-1α,25(OH)2D3 (MART-10) showed potent biological effects. Our in vivo studies using rats revealed that MART-10 had a low calcemic effect, which is a suitable property as an anticancer drug. Much lower affinity of MART-10 for vitamin D binding protein (DBP) as compared with 1α,25(OH)2D3 may be related to its more potent cellular activities.
Based on these results, we conclude that

  • (1) high affinity for VDR,
  • (2) resistance to CYP24A1-dependent catabolism,
  • (3) low affinity for DBP, and
  • (4) low calcemic effect

may be required for designing potent vitamin D analogs for cancer treatment. PMID: 23869781


Determinants of vitamin D status: focus on genetic variations.- July 2011

PMID: 21654390 full text online


CLICK HERE for PubMed cyp24a1 "vitamin d": 1122 hits June 2017

Some interesting titles

  • Genetic Variants in CYP2R1, CYP24A1 and VDR Modify the Efficacy of Vitamin D<sub>3</sub> Supplementation for Increasing Serum 25-Hydroxyvitamin D Levels in a Randomized Controlled Trial. - July 2014
  • Development of novel Vitamin D Receptor-Coactivator Inhibitors.Feb 2014
  • Common variants in CYP2R1 and GC genes predict vitamin D concentrations in healthy Danish children and adults.Feb 2014 full text online
  • Genetic Predictors of Circulating 25-Hydroxyvitamin D and Risk of Colorectal Cancer. Aug 2013
  • Stress and vitamin D: Altered vitamin D metabolism in both the hippocampus and myocardium of chronic unpredictable mild stress exposed rats. April 2013
  • Colonic vitamin D metabolism: Implications for the pathogenesis of inflammatory bowel disease and colorectal cancer. July 2011
  • Vitamin D-Related Genetic Variants, Interactions with Vitamin D Exposure, and Breast Cancer Risk among Caucasian Women in Ontario. July 2011
  • Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia June 2011 free text here and online
  • Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. May 2011 full text on-line
  • Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells.- with free paper
  • CYP24A1 Is an Independent Prognostic Marker of Survival in Patients with Lung Adenocarcinoma. Feb 2011
  • Effects of 25-hydroxyvitamin D3 on proliferation and osteoblast differentiation of human marrow stromal cells require CYP27B1/1?-hydroxylase.
  • Gender differences in 1,25 dihydroxyvitamin D3 immunomodulatory effects in multiple sclerosis patients and healthy subjects.
  • Vitamin D pathway gene variants and prostate cancer prognosis.
  • Cytochromes P450 are essential players in the vitamin D signaling system.
  • CYP24A1 inhibition enhances the antitumor activity of calcitriol.
  • Epigenetic regulation of vitamin D 24-hydroxylase/CYP24A1 in human prostate cancer.
  • Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet
  • Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease.
  • Epigenetic regulation of vitamin D converting enzymes.
  • The vitamin D / CYP24A1 story in cancer.
  • Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis.
  • Asthma and genes encoding components of the vitamin D pathway. - free text

CLICK HERE for Clinical Trials of CYP24A1: 9 as of June 2017


Clinical trials of Genes and Vitamin D 92 as of Nov 2015


See also VitaminDWiki

Wikipedia: P450 enzyme group (CYP24A1 is a member of the group)

https://en.wikipedia.org/wiki/Cytochrome_P450 June 2017

FamilyFunctionMembersNames
CYP1drug and steroid (especially estrogen) metabolism, benzoapyrene toxification (forming (+)-benzoapyrene-7,8-dihydrodiol-9,10-epoxide)3 subfamilies, 3 genes, 1 pseudogeneCYP1A1, CYP1A2, CYP1B1
CYP2drug and steroid metabolism13 subfamilies, 16 genes, 16 pseudogenesCYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1
CYP3drug and steroid (including testosterone) metabolism1 subfamily, 4 genes, 2 pseudogenesCYP3A4, CYP3A5, CYP3A7, CYP3A43
CYP4arachidonic acid or fatty acid metabolism6 subfamilies, 12 genes, 10 pseudogenesCYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1
CYP5thromboxane A2 synthase1 subfamily, 1 geneCYP5A1
CYP7bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus2 subfamilies, 2 genesCYP7A1, CYP7B1
CYP8varied2 subfamilies, 2 genesCYP8A1 (prostacyclin synthase), CYP8B1 (bile acid biosynthesis)
CYP11steroid biosynthesis2 subfamilies, 3 genesCYP11A1, CYP11B1, CYP11B2
CYP17steroid biosynthesis, 17-alpha hydroxylase1 subfamily, 1 geneCYP17A1
CYP19steroid biosynthesis: aromatase synthesizes estrogen1 subfamily, 1 geneCYP19A1
CYP20unknown function1 subfamily, 1 geneCYP20A1
CYP21steroid biosynthesis2 subfamilies, 1 gene, 1 pseudogeneCYP21A2
CYP24vitamin D degradation1 subfamily, 1 geneCYP24A1
CYP26retinoic acid hydroxylase3 subfamilies, 3 genesCYP26A1, CYP26B1, CYP26C1
CYP27varied3 subfamilies, 3 genesCYP27A1 (bile acid biosynthesis), CYP27B1 (vitamin D3 1-alpha hydroxylase, activates vitamin D3), CYP27C1 (unknown function)
CYP397-alpha hydroxylation of 24-hydroxycholesterol1 subfamily, 1 geneCYP39A1
CYP46cholesterol 24-hydroxylase1 subfamily, 1 geneCYP46A1
CYP51cholesterol biosynthesis1 subfamily, 1 gene, 3 pseudogenesCYP51A1 (lanosterol 14-alpha demethylase)

Omega-3 reduces problems due to CYP2E1 – Aug 2017

Omega-3 Polyunsaturated Fatty Acids Normalize the Functions of Mitochondria, Pro- and Antioxidant Enzymes of, and Cytochrome P450 2E1 Expression after Isoproterenol-Induced Myocardial Injury
International Journal of Physiology and Pathophysiology, DOI: 10.1615/IntJPhysPathophys.v8.i2.40 , pages 131-139

We studied the effect of dietary ω-3 polyunsaturated fatty acids (ω-3 PUFA) on the subsarcolemmal and interfibrillar mitochondrial fractions of rat myocardium, changes in expression of cytochrome P450 (CYP2E1), and the activity of pro-antioxidant enzymes after isoproterenol-induced myocardial injury. It has been found that ω-3 PUFA (Epadol 0.1 ml/100 g for 4 weeks) significantly reduces the swelling of the subsarcolemmal and interfibrillar mitochondrial fractions by 65.52% and 54.84%, respectively, indicating a decrease in damage to the mitochondrial function during isoproterenol-induced injury (two daily subcutaneous injections of isoproterenol at the dose of 60 mg/kg). In case of isoproterenol-induced myocardial injury, the use of ω-3 PUFAs prevents a decrease in the activity of antioxidant enzymes, namely catalase and superoxide dismutase (2.65 and 7.1 times, respectively). We have revealed that the development of oxidative stress after isoproterenol-induced myocardial injury can be triggered by a significant increase in the expression of cytochrome P450 2E1 (73.3%), and applying of ω-3 PUFAs prevents such changes.

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