Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG2T749)

DOT Name 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1)
Synonyms 24-OHase; Vitamin D(3) 24-hydroxylase; EC 1.14.15.16; Cytochrome P450 24A1; Cytochrome P450-CC24
Gene Name CYP24A1
Related Disease
Hypercalcemia, infantile, 1 ( )
Obsolete autosomal recessive infantile hypercalcemia ( )
UniProt ID
CP24A_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
1.14.15.16
Pfam ID
PF00067
Sequence
MSSPISKSRSLAAFLQQLRSPRQPPRLVTSTAYTSPQPREVPVCPLTAGGETQNAAALPG
PTSWPLLGSLLQILWKGGLKKQHDTLVEYHKKYGKIFRMKLGSFESVHLGSPCLLEALYR
TESAYPQRLEIKPWKAYRDYRKEGYGLLILEGEDWQRVRSAFQKKLMKPGEVMKLDNKIN
EVLADFMGRIDELCDERGHVEDLYSELNKWSFESICLVLYEKRFGLLQKNAGDEAVNFIM
AIKTMMSTFGRMMVTPVELHKSLNTKVWQDHTLAWDTIFKSVKACIDNRLEKYSQQPSAD
FLCDIYHQNRLSKKELYAAVTELQLAAVETTANSLMWILYNLSRNPQVQQKLLKEIQSVL
PENQVPRAEDLRNMPYLKACLKESMRLTPSVPFTTRTLDKATVLGEYALPKGTVLMLNTQ
VLGSSEDNFEDSSQFRPERWLQEKEKINPFAHLPFGVGKRMCIGRRLAELQLHLALCWIV
RKYDIQATDNEPVEMLHSGTLVPSRELPIAFCQR
Function
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)). 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. 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. Preferentially hydroxylates at C-25 other vitamin D active metabolites, such as CYP11A1-derived secosteroids 20S-hydroxycholecalciferol and 20S,23-dihydroxycholecalciferol. 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.
KEGG Pathway
Steroid biosynthesis (hsa00100 )
Metabolic pathways (hsa01100 )
Parathyroid hormone synthesis, secretion and action (hsa04928 )
MicroR.s in cancer (hsa05206 )
Reactome Pathway
Vitamins (R-HSA-211916 )
Defective CYP24A1 causes HCAI (R-HSA-5579010 )
Vitamin D (calciferol) metabolism (R-HSA-196791 )
BioCyc Pathway
MetaCyc:HS00395-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Hypercalcemia, infantile, 1 DIS5XT5M Strong Autosomal recessive [1]
Obsolete autosomal recessive infantile hypercalcemia DISWWUR1 Supportive Autosomal recessive [2]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Regulation of Drug Effects of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
ED-71 DMRLXAI Phase 3 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1) increases the metabolism of ED-71. [37]
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38 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [3]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [4]
Tretinoin DM49DUI Approved Tretinoin increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [5]
Acetaminophen DMUIE76 Approved Acetaminophen affects the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [6]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [7]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [8]
Estradiol DMUNTE3 Approved Estradiol increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [9]
Arsenic DMTL2Y1 Approved Arsenic increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [10]
Quercetin DM3NC4M Approved Quercetin decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [11]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [12]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [13]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [14]
Testosterone DM7HUNW Approved Testosterone increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [15]
Phenobarbital DMXZOCG Approved Phenobarbital increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [16]
Menadione DMSJDTY Approved Menadione affects the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [13]
Gemcitabine DMSE3I7 Approved Gemcitabine decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [17]
Rifampicin DM5DSFZ Approved Rifampicin increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [18]
Liothyronine DM6IR3P Approved Liothyronine increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [19]
Cholecalciferol DMGU74E Approved Cholecalciferol increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [20]
Ampicillin DMHWE7P Approved Ampicillin decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [11]
Teriflunomide DMQ2FKJ Approved Teriflunomide decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [21]
Calcidiol DMN4CV5 Approved Calcidiol increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [22]
Calcipotriol DM03CP7 Approved Calcipotriol increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [23]
Itraconazole DMCR1MV Approved Itraconazole decreases the activity of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [24]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [25]
Alfacalcidol DM1237M Phase 4 Alfacalcidol increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [26]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [27]
Curcumin DMQPH29 Phase 3 Curcumin increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [28]
Seocalcitol DMKL9QO Phase 3 Seocalcitol increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [29]
Genistein DM0JETC Phase 2/3 Genistein decreases the activity of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [30]
Pramiconazole DMBH7XI Phase 2 Pramiconazole decreases the activity of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [24]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [32]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [33]
Bisphenol A DM2ZLD7 Investigative Bisphenol A affects the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [34]
OXYQUINOLINE DMZVS9Y Investigative OXYQUINOLINE decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [11]
DM9CEI5 increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [35]
Hyperforin DM2L3PE Investigative Hyperforin increases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [18]
GW-788388 DMIBUW5 Investigative GW-788388 decreases the expression of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [36]
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⏷ Show the Full List of 38 Drug(s)
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1). [31]
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References

1 The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
2 Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011 Aug 4;365(5):410-21. doi: 10.1056/NEJMoa1103864. Epub 2011 Jun 15.
3 Valproic acid augments vitamin D receptor-mediated induction of CYP24 by vitamin D3: a possible cause of valproic acid-induced osteomalacia?. Toxicol Lett. 2011 Feb 5;200(3):146-53. doi: 10.1016/j.toxlet.2010.11.008. Epub 2010 Nov 27.
4 Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
5 Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
6 Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
7 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
8 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
9 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
10 Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
11 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
12 19-Nor-1,25(OH)2D2 (a novel, noncalcemic vitamin D analogue), combined with arsenic trioxide, has potent antitumor activity against myeloid leukemia. Cancer Res. 2005 Mar 15;65(6):2488-97.
13 Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
14 DNA microarray analysis of vitamin D-induced gene expression in a human colon carcinoma cell line. Physiol Genomics. 2004 Apr 13;17(2):122-9. doi: 10.1152/physiolgenomics.00002.2003.
15 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
16 Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
17 Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
18 Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest. 2005 Jan;115(1):177-86.
19 Similarities and differences between two modes of antagonism of the thyroid hormone receptor. ACS Chem Biol. 2011 Oct 21;6(10):1096-106.
20 Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation. J Clin Invest. 2005 Oct;115(10):2924-33.
21 Mitochondrial dysfunction induced by leflunomide and its active metabolite. Toxicology. 2018 Mar 1;396-397:33-45.
22 Retinoic acid via RARalpha inhibits the expression of 24-hydroxylase in human prostate stromal cells. Biochem Biophys Res Commun. 2005 Dec 30;338(4):1973-81. doi: 10.1016/j.bbrc.2005.10.178. Epub 2005 Nov 7.
23 Actions of Vitamin D3, analogs on human prostate cancer cell lines: comparison with 1,25-dihydroxyvitamin D3. Endocrinology. 1995 Jan;136(1):20-6.
24 The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp., and Microsporum canis. Antimicrob Agents Chemother. 2004 Sep;48(9):3272-8.
25 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
26 Dermal fibroblasts pretreated with a sterol Delta7-reductase inhibitor produce 25-hydroxyvitamin D3 upon UVB irradiation. J Photochem Photobiol B. 2006 Oct 2;85(1):72-8.
27 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
28 Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention. J Nutr Biochem. 2010 Dec;21(12):1153-61.
29 Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
30 Genistein potentiates the growth inhibitory effects of 1,25-dihydroxyvitamin D3 in DU145 human prostate cancer cells: role of the direct inhibition of CYP24 enzyme activity. Mol Cell Endocrinol. 2005 Sep 28;241(1-2):49-61.
31 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
32 CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
33 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
34 Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
35 The aryl hydrocarbon receptor activator benzo[a]pyrene enhances vitamin D3 catabolism in macrophages. Toxicol Sci. 2009 May;109(1):50-8.
36 Capturing time-dependent activation of genes and stress-response pathways using transcriptomics in iPSC-derived renal proximal tubule cells. Cell Biol Toxicol. 2023 Aug;39(4):1773-1793. doi: 10.1007/s10565-022-09783-5. Epub 2022 Dec 31.
37 Human hepatic metabolism of the anti-osteoporosis drug eldecalcitol involves sterol C4-methyl oxidase. Pharmacol Res Perspect. 2015 Mar;3(2):e00120.