CYP24A1 gene and Vitamin D - many studies

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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39+ VitaminDWiki pages with CYP24A1 in title

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11+ VitaminDWiki pages with both CYP24A1 AND CANCER in the title

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CYP24A1: cancer, autoimmune and inflamation via genetics and epigenetics - Oct 2024

Regulatory Mechanisms and Pathological Implications of CYP24A1 in Vitamin D Metabolism
Pathology - Research and Practice
https://doi.org/10.1016/j.prp.2024.155684 a portion of the PDF is online
KL Milan, KM Ramkumar

CYP24A1 is a crucial gene within the cytochrome P450 superfamily, responsible for encoding the enzyme 25-hydroxyvitamin D3-24-hydroxylase. This enzyme is involved in the catabolism of 1,25-dihydroxyvitamin D3, the biologically active form of vitamin D3, by hydroxylating its side chain. Through this process, CYP24A1 tightly regulates the bioavailability and physiological impact of vitamin D3 in the body.
Dysregulation of CYP24A1, particularly its overexpression, has been increasingly associated with the progression of various diseases, including

• cancers,
• autoimmune disorders, and
• chronic inflammatory conditions.

Elevated levels of CYP24A1 can lead to excessive degradation of vitamin D3, resulting in diminished levels of this critical hormone, which is essential for calcium homeostasis, immune function, and cellular proliferation. This review explores into the structural characteristics of CYP24A1, exploring how it influences its enzymatic activity. Furthermore, it examines the expression patterns of CYP24A1 across different diseases, emphasizing the enzyme's role in disease pathology. The review also discusses the regulatory mechanisms governing CYP24A1 expression, including

• genetic mutations,
• epigenetic modifications, and
• metabolite-mediated regulation.

By understanding these mechanisms, the review provides insight into the potential therapeutic strategies that could target CYP24A1, aiming to alleviate its overexpression and restore vitamin D3 balance in disease states.

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Antioxident Glutathione helps CYP24A1

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Rare CYP24A1 variant results in hypercalcemia in infants - Sept 2023

__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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77. Zayny, A, Almokhtar, M, Wikvall, K, Ljunggren, Ö, Ubhayasekera, K, Bergquist, J, et al.. Effects of glucocorticoids on vitamin D(3)-metabolizing 24-hydroxylase (CYP24A1) in Saos-2 cells and primary human osteoblasts. Mol Cell Endocrinol 2019;496:110525. https://doi.org/10.1016/j.mce.2019.110525 . - DOI
78. Hidalgo, AA, Trump, DL, Johnson, CS. Glucocorticoid regulation of the vitamin D receptor. J Steroid Biochem Mol Biol 2010;121:372–5. https://doi.org/10.1016/j.jsbmb.2010.03.081 . - DOI
79. Davidson, TG. Conventional treatment of hypercalcemia of malignancy. Am J Health Syst Pharm 2001;58:S8–15. https://doi.org/10.1093/ajhp/58.suppl_3.s8 . - DOI
80. Dufek, S, Seidl, R, Schmook, M, Arbeiter, K, Müller-Sacherer, T, Heindl-Rusai, K. Intracranial hypertension in siblings with infantile hypercalcemia. Neuropediatrics 2015;46:49–51. https://doi.org/10.1055/s-0034-1389900 . - DOI
81. Davidson Peiris, E, Wusirika, R. A case report of compound heterozygous CYP24A1mutations leading to nephrolithiasis successfully treated with ketoconazole. Case Rep Nephrol Dial 2017;7:167–71. https://doi.org/10.1159/000485243 . - DOI
82. Trutin, I, Škorić, I. AN infant with idiopathic hypercalciuria and nephrolithiasis associated with CYP24A1enzyme polymorphism: a case report. Acta Clin Croat 2022;60:544–7. https://doi.org/10.20471/acc.2021.60.03.27 . - DOI
83. Vescini, F, Buffa, A, La Manna, G, Ciavatti, A, Rizzoli, E, Bottura, A, et al.. Long-term potassium citrate therapy and bone mineral density in idiopathic calcium stone formers. J Endocrinol Invest 2005;28:218–22. https://doi.org/10.1007/bf03345376 . - DOI

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Many cancers increase the activation of the CYP24A1 gene – Feb 2023

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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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
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
 Download the PDF from Sci-Hub via VitaminDWiki

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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 and DeepDyve
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.

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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

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Search Google Scholar for cyp24a1 "vitamin d" 13,900 items

Google Scholar Aug 2024

• 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 D₃ 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

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CLICK HERE for Clinical Trials of CYP24A1: 25 as of July 2023

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Clinical trials of Genes and Vitamin D 272 as of July 2023

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

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

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)

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