Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPIDMT3)

• DOT Name: Oxidation resistance protein 1 (OXR1)
• Gene Name: OXR1
• Related Disease:
  Narcolepsy
  Amyotrophic lateral sclerosis
  Drug dependence
  Intellectual disability
  Isolated cerebellar hypoplasia/agenesis
  Parkinson disease
  Advanced cancer
  Clear cell renal carcinoma
  Eosinophilic esophagitis
  Ethylmalonic encephalopathy
  High blood pressure
  Neoplasm
  Prostate carcinoma
• UniProt ID: OXR1_HUMAN
• Pfam ID: PF01476 ; PF07534
• Sequence:
  MTKDKNSPGLKKKSQSVDINAPGFNPLAGAGKQTPQASKPPAPKTPIIEEEQNNAANTQK
  HPSRRSELKRFYTIDTGQKKTLDKKDGRRMSFQKPKGTIEYTVESRDSLNSIALKFDTTP
  NELVQLNKLFSRAVVTGQVLYVPDPEYVSSVESSPSLSPVSPLSPTSSEAEFDKTTNPDV
  HPTEATPSSTFTGIRPARVVSSTSEEEEAFTEKFLKINCKYITSGKGTVSGVLLVTPNNI
  MFDPHKNDPLVQENGCEEYGIMCPMEEVMSAAMYKEILDSKIKESLPIDIDQLSGRDFCH
  SKKMTGSNTEEIDSRIRDAGNDSASTAPRSTEESLSEDVFTESELSPIREELVSSDELRQ
  DKSSGASSESVQTVNQAEVESLTVKSESTGTPGHLRSDTEHSTNEVGTLCHKTDLNNLEM
  AIKEDQIADNFQGISGPKEDSTSIKGNSDQDSFLHENSLHQEESQKENMPCGETAEFKQK
  QSVNKGKQGKEQNQDSQTEAEELRKLWKTHTMQQTKQQRENIQQVSQKEAKHKITSADGH
  IESSALLKEKQRHRLHKFLCLRVGKPMRKTFVSQASATMQQYAQRDKKHEYWFAVPQERT
  DHLYAFFIQWSPEIYAEDTGEYTREPGFIVVKKIEESETIEDSSNQAAAREWEVVSVAEY
  HRRIDALNTEELRTLCRRLQITTREDINSKQVATVKADLESESFRPNLSDPSELLLPDQI
  EKLTKHLPPRTIGYPWTLVYGTGKHGTSLKTLYRTMTGLDTPVLMVIKDSDGQVFGALAS
  EPLKVSDGFYGTGETFVFTFCPEFEVFKWTGDNMFFIKGDMDSLAFGGGGGEFALWLDGD
  LYHGRSHSCKTFGNRTLSKKEDFFIQDIEIWAFE
• Function: May be involved in protection from oxidative damage.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[2]
Drug dependence	DIS9IXRC	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[4]
Isolated cerebellar hypoplasia/agenesis	DISLVUFG	Strong	Autosomal recessive	[4]
Parkinson disease	DISQVHKL	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]
Clear cell renal carcinoma	DISBXRFJ	Limited	Genetic Variation	[6]
Eosinophilic esophagitis	DISR8WSB	Limited	Biomarker	[7]
Ethylmalonic encephalopathy	DISH7SB9	Limited	Biomarker	[7]
High blood pressure	DISY2OHH	Limited	Altered Expression	[8]
Neoplasm	DISZKGEW	Limited	Posttranslational Modification	[6]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Oxidation resistance protein 1 (OXR1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Oxidation resistance protein 1 (OXR1).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Oxidation resistance protein 1 (OXR1).	[20]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Oxidation resistance protein 1 (OXR1).	[21]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Oxidation resistance protein 1 (OXR1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Oxidation resistance protein 1 (OXR1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Oxidation resistance protein 1 (OXR1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Oxidation resistance protein 1 (OXR1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Oxidation resistance protein 1 (OXR1).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Oxidation resistance protein 1 (OXR1).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Oxidation resistance protein 1 (OXR1).	[17]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Oxidation resistance protein 1 (OXR1).	[18]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo.Hum Mol Genet. 2019 Nov 1;28(21):3584-3599. doi: 10.1093/hmg/ddz190.
• [3] The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task.Brain Res. 2020 Mar 15;1731:146222. doi: 10.1016/j.brainres.2019.04.017. Epub 2019 Apr 16.
• [4] Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. Am J Hum Genet. 2019 Dec 5;105(6):1237-1253. doi: 10.1016/j.ajhg.2019.11.002. Epub 2019 Nov 27.
• [5] Serum secreted miR-137-containing exosomes affects oxidative stress of neurons by regulating OXR1 in Parkinson's disease.Brain Res. 2019 Nov 1;1722:146331. doi: 10.1016/j.brainres.2019.146331. Epub 2019 Jul 10.
• [6] Identification of clear cell renal cell carcinoma and oncocytoma using a three-gene promoter methylation panel.J Transl Med. 2017 Jun 29;15(1):149. doi: 10.1186/s12967-017-1248-y.
• [7] Environmental Enrichment During Adulthood Reduces Sucrose Binge-Like Intake in a High Drinking in the Dark Phenotype (HD) in C57BL/6J Mice.Front Behav Neurosci. 2019 Feb 15;13:27. doi: 10.3389/fnbeh.2019.00027. eCollection 2019.
• [8] Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats.J Am Heart Assoc. 2019 Jul 2;8(13):e011434. doi: 10.1161/JAHA.118.011434. Epub 2019 Jun 19.
• [9] Lack of expression of preproorexin and orexin receptors genes in human normal and prostate cancer cell lines.Folia Histochem Cytobiol. 2015;53(4):333-41. doi: 10.5603/fhc.a2015.0035.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] 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.
• [17] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [18] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [19] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.