更新于：2024-09-19

CYP24A1

更新于：2024-09-19

基本信息

别名

维生素D3 24-羟化酶、1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial、24-OHase

+ [10]

简介

A cytochrome P450 monooxygenase with a key role in vitamin D catabolism and calcium homeostasis. Via C24- and C23-oxidation pathways, catalyzes the inactivation of both the vitamin D precursor calcidiol (25-hydroxyvitamin D(3)) and the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:24893882, PubMed:15574355, PubMed:8679605, PubMed:11012668, PubMed:16617161, PubMed:29461981). With initial hydroxylation at C-24 (via C24-oxidation pathway), performs a sequential 6-step oxidation of calcitriol leading to the formation of the biliary metabolite calcitroic acid (PubMed:24893882, PubMed:15574355). With initial hydroxylation at C-23 (via C23-oxidation pathway), catalyzes sequential oxidation of calcidiol leading to the formation of 25(OH)D3-26,23-lactone as end product (PubMed:11012668, PubMed:8679605). Preferentially hydroxylates at C-25 other vitamin D active metabolites, such as CYP11A1-derived secosteroids 20S-hydroxycholecalciferol and 20S,23-dihydroxycholecalciferol (PubMed:25727742). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via FDXR/adrenodoxin reductase and FDX1/adrenodoxin (PubMed:8679605).

关联

项与 CYP24A1 相关的药物

Lunacalcipol

靶点

CYP24A1 x VDR

作用机制

CYP24A1抑制剂 [+1]

在研机构-

原研机构

OPKO Health, Inc.

在研适应症-

非在研适应症

慢性肾病 [+4]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

RC-8800

靶点

CYP24A1 x VDR

作用机制

CYP24A1抑制剂 [+2]

在研机构-

原研机构

Helsinn Healthcare SA

在研适应症-

非在研适应症

前列腺癌

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 CYP24A1 相关的临床试验

NCT01453634 / Withdrawn临床2期

A Randomized, Open Label, Four Week, Pharmacodynamic/Pharmacokinetic, Efficacy, and Safety Study of Lunacalcipol (CTA018) Injection in Subjects With Stage 5 Chronic Kidney Disease With Secondary Hyperparathyroidism on Hemodialysis

Open-label, pharmacodynamic, safety, pharmacokinetic and efficacy study of Lunacalcipol Injection.

开始日期2013-01-01

申办/合作机构

OPKO Health, Inc.

NCT00742716 / Completed临床2期

An Open Label, Four Week, Dose Escalating Pharmacokinetic, Pharmacodynamic, Efficacy and Safety Study of CTA018 Injection in Subjects With Stage 5 Chronic Kidney Disease With Secondary Hyperparathyroidism on Hemodialysis

This study will investigate the levels of CTA018 in the body over time (pharmacokinetics, PK) in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT), undergoing regular hemodialysis. This study will also investigate the safety and effects of different strengths of CTA018, on parathyroid hormone (PTH) levels.

开始日期2008-10-01

申办/合作机构

OPKO IP Holdings II, Inc.

NCT00384098 / Completed临床2期

A Randomized, Double-blind, Parallel-group, 4-arm, 12-week Study to Evaluate the Safety and Efficacy of Topically Applied CTA018 vs Vehicle for the Treatment of Adult Subjects With Chronic Plaque Psoriasis

Vitamin D and its analogs are currently widely used for the treatment of psoriasis. The study drug (CTA018) is a novel analog of vitamin D, and this Phase 2 study will investigate the efficacy and safety of CTA018 in the treatment of psoriasis. Patients with chronic plaque psoriasis will receive one of three doses of CTA018 cream or vehicle (no study drug) daily for 12 weeks.

开始日期2006-09-01

申办/合作机构

OPKO Health, Inc.

100 项与 CYP24A1 相关的临床结果

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100 项与 CYP24A1 相关的转化医学

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0 项与 CYP24A1 相关的专利（医药）

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1,596

项与 CYP24A1 相关的文献（医药）

2024-12-01·Molecular Biology Reports

Gene expression profiling of vitamin D metabolism enzymes in leukemia and lymphoma patients: molecular aspect interplay of VDR, CYP2R1, and CYP24A1

Article

作者: Iriani, Anggraini ; Nugraha, Media Fitri Isma ; Fatina, Marsya Kaila ; Gemilang, Rizka Kurnia ; Trisnandi, Andi ; Rachman, Andhika

BACKGROUNDVitamin D deficiency is prevalent among the Indonesian population, particularly in individuals diagnosed with leukemia-lymphoma. The regulation of vitamin D metabolism is influenced by the expression of several enzymes, such as CYP2R1, CYP24A1, and the vitamin D receptor (VDR). This study aimed to scrutinize the gene expression profiles in both mRNA and protein levels of VDR, CYP2R1, and CYP24A1 in leukemia and lymphoma patients.METHODThe research was a cross-sectional study conducted at Cipto Mangunkusumo Hospital (RSCM) in Jakarta, Indonesia. The study included a total of 45 patients aged over 18 years old who have received a diagnosis of lymphoma or leukemia. Vitamin D status was measured by examining serum 25 (OH) D levels. The analysis of VDR, CYP2R1, and CYP24A1 mRNA expression utilized the qRT-PCR method, while protein levels were measured through the ELISA method.CONCLUSIONThe study revealed a noteworthy difference in VDR protein levels between men and women. The highest mean CYP24A1 protein levels were observed in the age group > 60 years. This study found a significant, moderately positive correlation between VDR protein levels and CYP24A1 protein levels in the male and vitamin D sufficiency groups. In addition, a significant positive correlation was found between VDR mRNA levels and CYP2R1 mRNA levels, VDR mRNA levels and CYP2R1 mRNA levels, and CYP2R1 mRNA levels and CYP24A1 mRNA levels. However, the expression of these genes does not correlate with the protein levels of its mRNA translation products in blood circulation.

2024-11-01·International Immunopharmacology

Focusing on non-responders to infliximab with ulcerative colitis, what can we do first and next?

Article

作者: Pu, Dan ; Zhang, Dekui ; Ma, Xueni ; Tian, Yonggang ; Wang, Xiang ; Gong, Hang ; Li, Muyang ; Wang, Pengfei

BACKGROUNDUlcerative colitis (UC) is a chronic immune-mediated inflammation of the colorectum, for which infliximab (IFX) is currently the mainstay of treatment. However, one-third of patients with UC still fail to benefit from the IFX therapy, and early exposure to IFX impairs the efficacy of other subsequent biologics. Therefore, personalized therapeutic system is urgently needed to assist in clinical decision-making and precision treatment.METHODSFour microarray datasets of colonic biopsies from UC patients treated with IFX were obtained from the GEO database to form the Training Cohort and Validation Cohort. Differentially expressed genes (DEGs) in Training Cohort were identified and enriched for GO, KEGG and immune cell infiltration analysis. A prediction model for IFX efficacy was developed based on the LASSO and Logistic regression. The predictive accuracy of the model was verified by the Validation Cohort, and the model-genes/proteins were validated by immunohistochemistry. Gene-drug, gene-ncRNA interaction analysis were performed to identify drugs or non-coding RNAs (ncRNAs) that potentially interacted with the model-genes. Homology Modeling and Molecular Docking were conducted to filter the optimal candidate as the subsequent adjuvant or alternative for IFX in predicted non-responders. At last, the down-regulation of the key model-gene/protein CYP24A1 by the drug candidate Deferasirox was verified by Western Blot and qRT-PCR Assay based on cellular experiments.RESULTSA total of 113 DEGs were identified in the Training Cohort, mainly enriched in inflammatory cell chemotaxis, migration, and response to molecules derived from intestinal microbiota. Activated pro-inflammatory innate immune cells, including neutrophils, M1 macrophages, activated dendritic cells and mast cells, were significantly enriched in colons of non-responders. The prediction model based on three model-genes (IFI44L, CYP24A1, and RGS1) exhibited strong predictive efficacy, with AUC values of 0.901 and 0.80 in the Training and Validation Cohorts, respectively. Higher expression of the three model-genes/proteins in colons of non-responders to IFX was confirmed by clinical colonic mucosal biopsies. 4 Drugs (Calcitriol, Lunacalcipol, Deferasirox, Telaprevir), 15 miRNAs and 66 corresponding lnRNAs interacting with model-genes were identified. The protein 3D structure of the key model-gene/protein (human-derived CYP24A1) was developed. Through the Molecular Docking and cellular experimental validation, Deferasirox, which significantly down-regulated both the RNA and protein expression of CYP24A1, was identified as the optimal adjuvant or alternative for IFX in predicted non-responders with UC.CONCLUSIONThis study developed a novel prediction model for pre-assessing the efficacy of IFX in patients with UC, as the first step towards personalized therapy. Meanwhile, drugs and non-coding RNAs were provided as potential candidates to develop the next-step precise treatment for the predicted non-responders. In particular, Defeasirox appears to hold promise as an adjuvant or alternative to IFX for the optimization of UC therapy.

2024-11-01·International Immunopharmacology

Gal-1-mediated cytochrome p450 activation promotes fibroblast into myofibroblast differentiation in pulmonary fibrosis

Article

作者: Yang, Jingwen ; Wang, Liang ; Ma, Yuan ; Chen, Chan ; Wang, Zhiyi ; Cheng, Qianhui ; Guan, Jiangan ; Zhang, Ran ; Jin, Haijuan ; Weng, Jie

Pulmonary fibrosis (PF) results from excessive extracellular matrix (ECM) deposition and tissue remodeling after activation of fibroblasts into myofibroblasts. Abnormally deposited fibrotic ECM, in turn, promotes fibroblast activation and accelerates loss of lung structure and function. However, the molecular mediators and exact mechanisms by which fibrotic ECM promotes fibroblast activation are unclear. In a bleomycin-induced PF mouse model, we found Galectin-1 (Gal-1) expression was significantly increased in lung tissue, and overexpression of Gal-1 plasmid-transfected fibroblasts were activated into myofibroblasts. Using the decellularization technique to prepare decellularized fibrotic ECM and constructing a 3D in vitro co-culture system with fibroblasts, we found that decellularized fibrotic ECM induced a high expression of Gal-1 and promoted the activation of fibroblasts into myofibroblasts. Therefore, Gal-1 has been identified as a pivotal mediator in PF. Further, we found that decellularized fibrotic ECM delivered mechanical signals to cells through the Gal-1-mediated FAK-Src-P130Cas mechanical signalling pathway, while the CYP450 enzymes (mainly involved in CYP1A1, CYP24A1, CYP3A4, and CYP2D6 isoforms) acted as a chemical signalling pathway to receive mechanical signals transmitted from upstream Gal-1, thereby promoting fibroblast activation. The Gal-1 inhibitor OTX008 or the CYP1A1 inhibitor 7-Hydroxyflavone prevented PF in mice and inhibited the role of fibrotic ECM in promoting fibroblast activation into myofibroblasts, preventing PF. These results reveal novel molecular mechanisms of lung fibrosis formation and identify Gal-1 and its downstream CYP1A1 as potential therapeutic targets for PF disease treatmnts.

项与 CYP24A1 相关的新闻（医药）

2024-05-11

·今日头条

再取进展！南京医科大学再发文：揭示乳腺癌中的抗癌新机制

本文为转化医学网原创，转载请注明出处作者：Jerry 导读：研究人员研究了25-羟基维生素D（25(OH)D）这种维生素D代谢产物在乳腺癌中的潜在新型抗癌机制。 5月9日，南京医科大学研究团队在期刊《Clinical And Translational Medicine》上发表了研究论文，题为“A 3′-pre-tRNA-derived small RNA tRF-1-Ser regulated by 25(OH)D promotes proliferation and stemness by inhibiting the function of MBNL1 in breast cancer”。本研究揭示了25(OH)D的抗癌新机制，揭示了tRF-1-Ser在乳腺癌（BRCA）进展中的重要功能，并提示tRF-1-Ser可能成为BRCA新的治疗靶点。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/ctm2.1681 研究背景 01 乳腺癌是全球影响女性的主要恶性肿瘤。尽管现代医学的进步逐渐缓解了乳腺癌的治疗复杂性，但它仍然是女性癌症中第二大死亡率的疾病。维生素D是人体中常见的营养元素，因其广泛的抗癌机制而受到研究人员的关注。许多体外和体内实验已经证明维生素D在乳腺癌中的强大抗癌作用，如抑制肿瘤细胞增殖、促进细胞凋亡、抑制转移和侵袭、促进癌细胞分化等。然而，关于维生素D的抗癌作用仍有有限的临床和流行病学证据。新兴的证据将维生素D缺乏与乳腺癌患者的不良预后联系在一起。然而，最近的一项大规模随机对照临床试验VITAL报告称，维生素D补充剂并不能显著降低癌症的发生率。同时，尚未发现血清25-羟基维生素D（25(OH)D）水平与乳腺癌的病理特征之间存在显著相关性。因此，维生素D的作用机制需要进一步阐明。维生素D以多种代谢产物的形式存在，包括25(OH)D、1,25-二羟基维生素D(1,25(OH)2D)和1,24,25-三羟基维生素D(1,24,25(OH)3D)。在这些代谢产物中，25(OH)D是最稳定的循环代谢产物，是评估个体整体维生素D状态的常见临床指标。活性形式1,25(OH)2D通过与维生素D受体(VDR)结合发挥生理作用。它由分布在各种组织中的酶1α-羟化酶(CYP27B1)从25(OH)D催化生成，主要分布在肾脏和乳腺、前列腺等外周组织中。高度生物活性的1,25(OH)2D可以转化为无生物活性的1,24,25(OH)3D。因此，CYP27B1、CYP24A1和VDR共同成为决定维生素D功能动态的关键因素。研究结果 02 考虑到CYP27B1、CYP24A1和VDR在维生素D途径中的关键调节作用，研究人员首先评估了这些基因在不同BRCA细胞系中的相对表达水平，以识别可能对25(OH)D有响应的细胞。结果发现，在MDA-MB-453、MDA-MB-415和MDA-MB-468细胞中，CYP27B1和VDR的表达显著升高，而CYP24A1的表达相对较低。为了进一步研究，研究人员选择了三个细胞系并指定MDA-MB-231作为对照。生理浓度的25(OH)D（100 nM）已被证明在体外可抑制肿瘤细胞的增殖能力。为了研究25(OH)D对乳腺癌细胞的影响，研究人员将乳腺癌细胞培养在含有100 nM 25(OH)D或相应溶剂的培养基中，并通过CCK8和EDU实验评估其增殖能力。将25(OH)D添加到培养基中，在不同程度上降低了这三种细胞系的增殖能力。MDA-MB-453细胞显示出最显著的增殖能力降低。正如预期的那样，25(OH)D不会影响MDA-MB-231细胞的增殖能力。将流式细胞术用于检测细胞周期，研究人员发现25(OH)D显著抑制了三种肿瘤细胞系从G1期向S期的转化。与观察到的对细胞增殖的影响相一致，25(OH)D的细胞周期阻滞效应在MDA-MB-453细胞中尤为明显。显微镜检查发现，25(OH)D治疗后MDA-MB-453细胞的形状发生了明显的变化，从椭圆形变为扁平状，这与1,25(OH)2D引起的效应相同。因此，生理浓度的25(OH)D对乳腺癌细胞的增殖能力具有抑制作用。此外，这种抑制作用可能与肿瘤细胞的自分泌和旁分泌分泌能力有关。 25-羟基维生素D (25(OH)D)抑制乳腺癌细胞增殖并在G1期阻滞细胞周期研究结论 03 总的来说，本研究为25(OH)D如何通过tsRNAs发挥其抗癌作用提供了新的认识，揭示了25(OH)D与tRF-1-Ser之间的调控关系，以及tRF-1-Ser与MBNL1的机制作用。本研究结果为25(OH)D调控的下游产物提供了新的见解，可以指导25(OH)D缺乏症乳腺癌患者的临床治疗。最终，tRF-1-Ser可以成为乳腺癌的治疗靶点。参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/ctm2.1681 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

临床结果抗体药物偶联物临床研究信使RNA

2007-03-06

·BioSpace

Cytochroma Inc. Completes Enrollment in Phase II Psoriasis Trial

MARKHAM, ON, March 6 /PRNewswire/ - Cytochroma Inc. announced today that it has completed the enrollment of patients in a Phase II clinical trial of CTA018 Cream for chronic plaque psoriasis. The ongoing Phase II trial is a randomized, double-blind, placebo-controlled study being conducted in 16 dermatology clinics located throughout the continental United States. A total of 147 subjects with chronic plaque psoriasis have been enrolled and are undergoing a 12-week course of treatment with one of three different concentrations of CTA018 Cream or a matching placebo. All subjects are receiving once daily topical treatment over a maximum of 15% body surface area. The primary efficacy endpoint of the trial is the Physician Static Global Assessment, which is a commonly used psoriasis severity assessment scale required by the United States Food and Drug Administration. The primary safety endpoints of the trial include adverse events and clinical laboratory measurements. Patient perceptions of CTA018 Cream are being evaluated in addition to several other secondary endpoints. "We are pleased that enrollment has been completed ahead of schedule by Mayo Clinical Trial Services of Rochester, MN," said Jukka Karjalainen, M.D., Ph.D., Executive Director, Product Development (Dermatology) at Cytochroma. "Based on the results obtained in two earlier clinical trials, we anticipate that CTA018 Cream, with its novel dual mechanism of action, will show a clear benefit over current treatment options when the results of this trial are released in July 2007." "Many chronic plaque psoriasis patients are not satisfied with the efficacy of current topical treatments, and even products that are effective are often discontinued over time due to side effects or treatment resistance," said Dr. Mark Lebwohl, Chairman of the Medical Board of the National Psoriasis Foundation and Professor and Chairman, Department of Dermatology, The Mount Sinai Medical Center, New York. "Topical treatments with greater efficacy and tolerability are needed to address this patient population, which represents the majority of the nearly 7 million psoriasis patients in the United States." About CTA018 CTA018 is a novel vitamin D analog with a dual mechanism of action designed to be both a strong activator of the vitamin D signaling pathway and a potent inhibitor of CYP24 activity (the enzyme responsible for the catabolism of vitamin D). This compound was specifically designed by Professor Gary H. Posner, Ph.D. and is protected under patents and patent applications exclusively licensed to Cytochroma Inc. from the Johns Hopkins University. CTA018 Cream was previously studied in two Phase I clinical trials and demonstrated to be both well tolerated and efficacious in the treatment of patients with psoriasis. About Psoriasis Psoriasis is a common immune-mediated chronic skin disease often characterized by red, scaly plaques that itch, burn, sting, and bleed easily. It afflicts approximately 125 million people worldwide; more than 70% of patients have the mild to moderate form. Psoriasis is found in all age groups and often seriously compromises the quality of life of those affected. Current methods of treatment are either inconvenient, show poor remission rates, and/or have serious side effects. Cytochroma has recognized that there is a need for improved therapies. About Cytochroma Inc. Cytochroma ( ) is an integrated specialty pharmaceutical company engaged in the development and commercialization of proprietary products to treat and prevent the clinical consequences of diseases and disorders related to vitamin D hormone deficiency. The company has an advanced portfolio of new products targeting vitamin D deficiency and secondary hyperparathyroidism in patients with moderate to severe chronic kidney disease and end-stage renal disease. In addition, the company is developing novel vitamin D therapies to treat hyperproliferative disorders such as cancer and psoriasis. Cytochroma Inc. CONTACT: Eric J. Messner, Vice President, Commercial Operations, (905)479-5306 ext. 338, eric.messner@cytochroma.com