|Proper activation||makes sure that Vitamin D does not accumulate in the body|
|Too much activation||Less vitamin D actually gets to cells|
|Too little activation||Vitamin D accumulates to toxic levels ( <1 in 10,000 people)|
Blood test does not show when a poor CYP24A1 gene stops Vitamin D from getting to cells
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Several Cancers and health problems appear to protect themselves by changing CYP24A1 activation
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- Rare CYP24A1 variant results in hypercalcemia in infants - Sept 2023
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__Clinical heterogeneity and therapeutic options for idiopathic infantile hypercalcemia caused by CYP24A1 pathogenic variant
J Pediatr Endocrinol Metab . 2023 Sep 29. doi: 10.1515/jpem-2023-0147
Zhichao Zheng 1, Yujie Wu 2, Huiping Wu 1, Jiahui Jin 1, Yue Luo 1, Shunshun Cao 1, Xiaoou Shan 1
Objectives: Infantile hypercalcemia-1(HCINF1) is a rare disease caused by pathogenic variants in the CYP24A1 gene, resulting in the inability to metabolize active vitamin D. This leads to hypercalcemia and severe complications.
Content: On December 8th, 2022, a systematic literature search was conducted in PubMed, Wanfang, and CNKI using the keywords "hypercalcemia" and "CYP24A1". Data extraction included patient demographics, clinical presentation, treatment medications, and outcomes. The findings were synthesized to identify common patterns and variations among cases and to assess the efficacy of different therapies in reducing serum calcium. Our findings revealed two distinct peaks in the incidence of HCINF1 caused by CYP24A1 pathogenic variant.
Kidney stones or renal calcifications were the most common clinical manifestations of the disease, followed by polyuria and developmental delay. Laboratory investigations showed hypercalcemia, elevated vitamin D levels, hypercalciuria, and low parathyroid hormone. Genetic analysis remains the only reliable diagnostic tool. Although there is no definitive cure for HCINF1, multiple drugs, including bisphosphonates, calcitonin, and rifampicin, have been used to control its symptoms. Blocking the production and intake of vitamin D is the preferred treatment option.
Summary and outlook: Our review highlights the basic clinical and biochemical features of HCINF1 and suggests that targeted diagnostic and therapeutic strategies are needed to address the clinical heterogeneity of the disease. The insights gained from this study may facilitate the development of innovative treatments for HCINF1.
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Vitamin D metabolism in cancer: potential feasibility of vitamin D metabolism blocking therapy
Med Mol Morphol . 2023 Feb 7. doi: 10.1007/s00795-023-00348-x Publisher wants $39 for the PDF
Sakura Kamiya 1, Yuna Nakamori 1 2, Akira Takasawa 1, Kumi Takasawa 1, Daisuke Kyuno 1, Yusuke Ono 1, Kazufumi Magara 1, Makoto Osanai 3
In this review, we discuss the possibility of the vitamin D metabolizing enzyme CYP24A1 being a therapeutic target for various tumors including breast, colorectal and prostate tumors. Given the pleiotropic cellular activity of vitamin D, its deficiency impairs its physiological function in target cells and results in various pathologies including cancer. In addition, accumulated data have shown that elevated expression of CYP24A1 promotes carcinogenesis in various cancer subtypes by decreasing the bioavailability of vitamin D metabolites.
Thus, we propose the potential feasibility of vitamin D metabolism-blocking therapy in various types of human malignancies that express constitutive CYP24A1.
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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.
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
Download the PDF from Sci-Hub via VitaminDWiki
Rifampin (an anti-TB drug) reactivated the CYP24A1 gene in one person, stopping Hypercalcemia - May 2022
Long-term efficacy and safety of rifampin in the treatment of a patient carrying a CYP24A1 loss-of-function variant
J Clin Endocrinol Metab . 2022 May 15;dgac315. doi: 10.1210/clinem/dgac315 PDF is behind a $39 paywall
Alessandro Brancatella 1, Daniele Cappellani 1, Martin Kaufmann 2, Antonella Semeraro 1, Simona Borsari 1, Chiara Sardella 3, Fulvia Baldinotti 4, Maria Adelaide Caligo 4, Glenville Jones 2, Claudio Marcocci 1 3, Filomena Cetani 3
Background: Pharmacological therapy may be useful in the treatment of moderate to severe hypercalcemia in patients with infantile hypercalcemia-1 (HCINF1) due to pathogenic variants in the cytochrome P450 24 subfamily A member 1 (CYP24A1). Rifampin is an antituberculosis drug that is a potent inducer of cytochrome P450 3 subfamily A member 4 (CYP3A4), involved in an alternative catabolic pathway of vitamin D. The efficacy of rifampin in improving hypercalcemia was previously reported but many questions remain on the long-term efficacy and safety. Aim of the study is to test the long-term efficacy and safety of rifampin in a patient with HCINF1.
Methods: We report clinical, biochemical and imaging features of a 23-year-old man affected by HCINF1 with moderate hypercalcemia (12.9 mg/dL), symptomatic nephrolithiasis, nephrocalcinosis and impaired kidney function (eGFR 60 mL/min/1.73 m2) treated with rifampin for an overall period of 24 months. Kidney, liver and adrenal function were evaluated at every follow-up visit.
Results: In 2 months, rifampin induced a normalization of serum calcium (9.6 mg/dL) associated with an improvement of kidney function (eGFR 92 mL/min/1.73 m2) stable during the treatment. After 15 months, rifampin was temporally withdrawn because of asthenia, unrelated to impairment of adrenal function. After three months, the timing of drug administration was shifted from the morning to the evening, obtaining the remission of asthenia. At the end of follow-up, the nephrolithiasis disappeared and the nephrocalcinosis was stable.
Conclusions: Rifampin could represent an effective choice to induce a stable reduction of calcium levels in patients with HCINF1, with a good safety profile.
Curr Opin Nephrol Hypertens. 2011 May 22.
PMID: 21610497 full text online
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
PMID: 21654390 full text online
- Vitamin D receptor (VDR) and metabolizing enzymes CYP27B1 and CYP24A1 in breast cancer - Dec 2020 https://doi.org/10.1007/s11033-020-05780-1
- Bone Metastases of Diverse Primary Origin Frequently Express the VDR (Vitamin D Receptor) and CYP24A1 - Nov 2022 https://doi.org/10.3390/jcm11216537 FREE PDF
- Genetic Polymorphism of Vitamin D Family Genes CYP2R1, CYP24A1, and CYP27B1 Are Associated With a High Risk of Non-alcoholic Fatty Liver Disease: A Case-Control Study - Nov 2021 FREE PDF
- 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
- 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: 25 as of July 2023
Clinical trials of Genes and Vitamin D 272 as of July 2023
Family Function Members Names CYP1 drug and steroid (especially estrogen) metabolism, benzoapyrene toxification (forming (+)-benzoapyrene-7,8-dihydrodiol-9,10-epoxide) 3 subfamilies, 3 genes, 1 pseudogene CYP1A1, CYP1A2, CYP1B1 CYP2 drug and steroid metabolism 13 subfamilies, 16 genes, 16 pseudogenes CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1 CYP3 drug and steroid (including testosterone) metabolism 1 subfamily, 4 genes, 2 pseudogenes CYP3A4, CYP3A5, CYP3A7, CYP3A43 CYP4 arachidonic acid or fatty acid metabolism 6 subfamilies, 12 genes, 10 pseudogenes CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1 CYP5 thromboxane A2 synthase 1 subfamily, 1 gene CYP5A1 CYP7 bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus 2 subfamilies, 2 genes CYP7A1, CYP7B1 CYP8 varied 2 subfamilies, 2 genes CYP8A1 (prostacyclin synthase), CYP8B1 (bile acid biosynthesis) CYP11 steroid biosynthesis 2 subfamilies, 3 genes CYP11A1, CYP11B1, CYP11B2 CYP17 steroid biosynthesis, 17-alpha hydroxylase 1 subfamily, 1 gene CYP17A1 CYP19 steroid biosynthesis: aromatase synthesizes estrogen 1 subfamily, 1 gene CYP19A1 CYP20 unknown function 1 subfamily, 1 gene CYP20A1 CYP21 steroid biosynthesis 2 subfamilies, 1 gene, 1 pseudogene CYP21A2 CYP24 vitamin D degradation 1 subfamily, 1 gene CYP24A1 CYP26 retinoic acid hydroxylase 3 subfamilies, 3 genes CYP26A1, CYP26B1, CYP26C1 CYP27 varied 3 subfamilies, 3 genes CYP27A1 (bile acid biosynthesis), CYP27B1 (vitamin D3 1-alpha hydroxylase, activates vitamin D3), CYP27C1 (unknown function) CYP39 7-alpha hydroxylation of 24-hydroxycholesterol 1 subfamily, 1 gene CYP39A1 CYP46 cholesterol 24-hydroxylase 1 subfamily, 1 gene CYP46A1 CYP51 cholesterol biosynthesis 1 subfamily, 1 gene, 3 pseudogenes CYP51A1 (lanosterol 14-alpha demethylase)
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.
- There have been