Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9S2BSW)

• DOT Name: Cholesterol 25-hydroxylase (CH25H)
• Synonyms: EC 1.14.99.38; Cholesterol 25-monooxygenase; h25OH
• Gene Name: CH25H
• Related Disease:
  Rabies
  Adult glioblastoma
  Arteriosclerosis
  Atherosclerosis
  Chronic obstructive pulmonary disease
  Colitis
  Familial hypercholesterolemia
  Glioblastoma multiforme
  Hepatitis C virus infection
  Herpes simplex infection
  Melanoma
  Multiple sclerosis
  Neuromyelitis optica
  Polycythemia vera
  Zika virus infection
  Bacterial infection
  Isolated congenital microcephaly
  leukaemia
  Leukemia
  Alzheimer disease
  Metabolic disorder
  Nervous system inflammation
  Osteoarthritis
  Pulmonary emphysema
  Type-1/2 diabetes
• UniProt ID: CH25H_HUMAN
• EC Number: 1.14.99.38
• Pfam ID: PF04116
• Sequence:
  MSCHNCSDPQVLCSSGQLFLQPLWDHLRSWEALLQSPFFPVIFSITTYVGFCLPFVVLDI
  LCSWVPALRRYKIHPDFSPSAQQLLPCLGQTLYQHVMFVFPVTLLHWARSPALLPHEAPE
  LLLLLHHILFCLLLFDMEFFVWHLLHHKVPWLYRTFHKVHHQNSSSFALATQYMSVWELF
  SLGFFDMMNVTLLGCHPLTTLTFHVVNIWLSVEDHSGYNFPWSTHRLVPFGWYGGVVHHD
  LHHSHFNCNFAPYFTHWDKILGTLRTASVPAR
• Function: Catalyzes the formation of 25-hydroxycholesterol from cholesterol, leading to repress cholesterol biosynthetic enzymes. Plays a key role in cell positioning and movement in lymphoid tissues: 25-hydroxycholesterol is an intermediate in biosynthesis of 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC), an oxysterol that acts as a ligand for the G protein-coupled receptor GPR183/EBI2, a chemotactic receptor for a number of lymphoid cells. May play an important role in regulating lipid metabolism by synthesizing a corepressor that blocks sterol regulatory element binding protein (SREBP) processing. As an interferon-stimulated gene, has broad antiviral activities against a wide range of enveloped viruses, such as vesicular stomatitis virus (VSV) and SARS coronavirus-2 (SARS-CoV-2). Its product, 25-hydroxycholesterol, activates the ER-localized enzyme ACAT to induce internalization of accessible cholesterol on the plasma membrane and restricts SARS-CoV-2 S protein-mediated fusion which inhibits virus replication. In testis, production of 25-hydroxycholesterol by macrophages plays a role in Leydig cell differentiation. Required to restrain inflammation in macrophages: production of 25-hydroxycholesterol protects macrophages from cholesterol overload, thereby preventing mitochondrial DNA release and subsequent activation of the AIM2 inflammasome.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Efferocytosis (hsa04148)
• Reactome Pathway: Synthesis of bile acids and bile salts (R-HSA-192105)
• BioCyc Pathway: MetaCyc:HS06462-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rabies	DISSC4V5	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[4]
Colitis	DISAF7DD	Strong	Biomarker	[5]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[6]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[7]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[8]
Melanoma	DIS1RRCY	Strong	Biomarker	[9]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[10]
Neuromyelitis optica	DISBFGKL	Strong	Biomarker	[10]
Polycythemia vera	DISB5FPO	Strong	Biomarker	[11]
Zika virus infection	DISQUCTY	Strong	Biomarker	[12]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[13]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[14]
leukaemia	DISS7D1V	moderate	Altered Expression	[15]
Leukemia	DISNAKFL	moderate	Altered Expression	[15]
Alzheimer disease	DISF8S70	Limited	Genetic Variation	[16]
Metabolic disorder	DIS71G5H	Limited	Genetic Variation	[17]
Nervous system inflammation	DISB3X5A	Limited	Genetic Variation	[18]
Osteoarthritis	DIS05URM	Limited	Biomarker	[17]
Pulmonary emphysema	DIS5M7HZ	Limited	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[19]

7 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 Cholesterol 25-hydroxylase (CH25H).	[20]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Cholesterol 25-hydroxylase (CH25H).	[21]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Cholesterol 25-hydroxylase (CH25H).	[22]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Cholesterol 25-hydroxylase (CH25H).	[24]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Cholesterol 25-hydroxylase (CH25H).	[25]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Cholesterol 25-hydroxylase (CH25H).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cholesterol 25-hydroxylase (CH25H).	[28]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Cholesterol 25-hydroxylase (CH25H).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cholesterol 25-hydroxylase (CH25H).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cholesterol 25-hydroxylase (CH25H).	[23]

References

• [1] Cholesterol 25-hydroxylase suppresses rabies virus infection by inhibiting viral entry.Arch Virol. 2019 Dec;164(12):2963-2974. doi: 10.1007/s00705-019-04415-6. Epub 2019 Sep 24.
• [2] On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment.Exp Cell Res. 2013 Jul 15;319(12):1828-1838. doi: 10.1016/j.yexcr.2013.03.025. Epub 2013 Mar 26.
• [3] Krppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility.Circulation. 2017 Oct 3;136(14):1315-1330. doi: 10.1161/CIRCULATIONAHA.117.027462. Epub 2017 Aug 9.
• [4] Cholesterol metabolism promotes B-cell positioning during immune pathogenesis of chronic obstructive pulmonary disease.EMBO Mol Med. 2018 May;10(5):e8349. doi: 10.15252/emmm.201708349.
• [5] The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis.Mucosal Immunol. 2019 May;12(3):733-745. doi: 10.1038/s41385-019-0140-x. Epub 2019 Feb 11.
• [6] Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.J Med Genet. 2014 Aug;51(8):537-44. doi: 10.1136/jmedgenet-2014-102405. Epub 2014 Jul 1.
• [7] Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation.Hepatology. 2015 Sep;62(3):702-14. doi: 10.1002/hep.27913. Epub 2015 Jul 28.
• [8] Herpes simplex virus type 1 abrogates the antiviral activity of Ch25h via its virion host shutoff protein.Antiviral Res. 2017 Jul;143:69-73. doi: 10.1016/j.antiviral.2017.04.004. Epub 2017 Apr 9.
• [9] An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles.Cancer Cell. 2019 Jan 14;35(1):33-45.e6. doi: 10.1016/j.ccell.2018.12.001.
• [10] Analysis of CH25H in multiple sclerosis and neuromyelitis optica.J Neuroimmunol. 2016 Feb 15;291:70-2. doi: 10.1016/j.jneuroim.2015.12.014. Epub 2015 Dec 31.
• [11] Cholesterol 25-hydroxylase acts as a host restriction factor on pseudorabies virus replication.J Gen Virol. 2017 Jun;98(6):1467-1476. doi: 10.1099/jgv.0.000797. Epub 2017 Jun 20.
• [12] IL-1/TNF-/IL-6 inflammatory cytokines promote STAT1-dependent induction of CH25H in Zika virus-infected human macrophages.J Biol Chem. 2019 Oct 4;294(40):14591-14602. doi: 10.1074/jbc.RA119.007555. Epub 2019 Aug 2.
• [13] Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation.Cell. 2017 Nov 16;171(5):1057-1071.e11. doi: 10.1016/j.cell.2017.09.029. Epub 2017 Oct 12.
• [14] 25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model.Immunity. 2017 Mar 21;46(3):446-456. doi: 10.1016/j.immuni.2017.02.012. Epub 2017 Mar 14.
• [15] Five-aza-2'-deoxycytidine-induced hypomethylation of cholesterol 25-hydroxylase gene is responsible for cell death of myelodysplasia/leukemia cells.Sci Rep. 2015 Nov 18;5:16709. doi: 10.1038/srep16709.
• [16] Association between selected cholesterol-related gene polymorphisms and Alzheimer's disease in a Turkish cohort.Mol Biol Rep. 2019 Apr;46(2):1701-1707. doi: 10.1007/s11033-019-04619-8. Epub 2019 Jan 25.
• [17] The CH25H-CYP7B1-ROR axis of cholesterol metabolism regulates osteoarthritis.Nature. 2019 Feb;566(7743):254-258. doi: 10.1038/s41586-019-0920-1. Epub 2019 Feb 6.
• [18] Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity.J Autoimmun. 2015 Jan;56:45-55. doi: 10.1016/j.jaut.2014.10.001. Epub 2014 Nov 10.
• [19] Hepatic Cholesterol-25-Hydroxylase Overexpression Improves Systemic Insulin Sensitivity in Mice.J Diabetes Res. 2017;2017:4108768. doi: 10.1155/2017/4108768. Epub 2017 Feb 19.
• [20] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [21] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [22] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [25] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [26] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [27] 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.
• [28] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.