Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU0NR39)

• DOT Name: Cytochrome c oxidase subunit 8A, mitochondrial (COX8A)
• Synonyms: Cytochrome c oxidase polypeptide VIII-liver/heart; Cytochrome c oxidase subunit 8-2
• Gene Name: COX8A
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Benign neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma
  Cerebellar ataxia
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Coronary atherosclerosis
  Coronary heart disease
  Glioma
  Hepatitis A virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  High blood pressure
  Intellectual disability
  Liver cirrhosis
  Lung carcinoma
  Obesity
  Protein S deficiency
  Schizophrenia
  Sensorineural hearing loss disorder
  Stomach cancer
  Systemic lupus erythematosus
  Von Willebrand disease 1
  Von Willebrand disease type 2N
  Asthma
  Cardiovascular disease
  Emery-Dreifuss muscular dystrophy
  Gastric cancer
  Lung cancer
  Mitochondrial disease
  Moderately severe hemophilia A
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Von willebrand disease
  Cytochrome-c oxidase deficiency disease
  Glioblastoma multiforme
  Acute lymphocytic leukaemia
  Coagulation defect
  Leigh syndrome
  Leukemia
  Mitochondrial complex 4 deficiency, nuclear type 15
  Stroke
• UniProt ID: COX8A_HUMAN
• PDB ID: 5Z62; 8D4T
• Pfam ID: PF02285
• Sequence:
  MSVLTPLLLRGLTGSARRLPVPRAKIHSLPPEGKLGIMELAVGLTSCFVTFLLPAGWILS
  HLETYRRPE
• Function: Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Cardiac muscle contraction (hsa04260)
  Thermogenesis (hsa04714)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Respiratory electron transport (R-HSA-611105)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
• BioCyc Pathway: MetaCyc:HS11040-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Benign neoplasm	DISDUXAD	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[9]
Coronary heart disease	DIS5OIP1	Strong	Altered Expression	[10]
Glioma	DIS5RPEH	Strong	Altered Expression	[11]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[12]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[14]
High blood pressure	DISY2OHH	Strong	Biomarker	[15]
Intellectual disability	DISMBNXP	Strong	Biomarker	[16]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[17]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[18]
Obesity	DIS47Y1K	Strong	Genetic Variation	[19]
Protein S deficiency	DISORLOT	Strong	Altered Expression	[20]
Schizophrenia	DISSRV2N	Strong	Biomarker	[21]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[22]
Stomach cancer	DISKIJSX	Strong	Biomarker	[23]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[24]
Von Willebrand disease 1	DISUGLZA	Strong	Altered Expression	[25]
Von Willebrand disease type 2N	DIS7S2QL	Strong	Biomarker	[26]
Asthma	DISW9QNS	moderate	Altered Expression	[27]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[28]
Emery-Dreifuss muscular dystrophy	DISYTPR5	moderate	Biomarker	[29]
Gastric cancer	DISXGOUK	moderate	Biomarker	[30]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[18]
Mitochondrial disease	DISKAHA3	moderate	Biomarker	[31]
Moderately severe hemophilia A	DISWXNMO	moderate	Biomarker	[32]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[33]
Prostate cancer	DISF190Y	moderate	Biomarker	[34]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[34]
Von willebrand disease	DIS3TZCH	moderate	Biomarker	[35]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Supportive	Autosomal recessive	[36]
Glioblastoma multiforme	DISK8246	Disputed	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Limited	Genetic Variation	[37]
Coagulation defect	DIS9X3H6	Limited	Biomarker	[38]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[39]
Leukemia	DISNAKFL	Limited	Genetic Variation	[40]
Mitochondrial complex 4 deficiency, nuclear type 15	DIS18BX8	Limited	Autosomal recessive	[41]
Stroke	DISX6UHX	Limited	Biomarker	[42]

12 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 Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[43]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[44]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[45]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[46]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[47]
Carfilzomib	DM48K0X	Approved	Carfilzomib decreases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[47]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[48]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[49]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[50]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[51]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[52]
XCT790	DMZ7N8D	Investigative	XCT790 decreases the expression of Cytochrome c oxidase subunit 8A, mitochondrial (COX8A).	[47]

References

• [1] Primary Glioblastoma of Cerebellopontine Angle in Adult Mimicking Acoustic Neuroma.World Neurosurg. 2019 Feb;122:48-52. doi: 10.1016/j.wneu.2018.10.073. Epub 2018 Oct 19.
• [2] CircRNA_104916 regulates migration, apoptosis and epithelial-mesenchymal transition in colon cancer cells.Front Biosci (Landmark Ed). 2019 Mar 1;24(5):819-832. doi: 10.2741/4753.
• [3] Radiosurgery treatment is associated with improved facial nerve preservation versus repeat resection in recurrent vestibular schwannomas.Acta Neurochir (Wien). 2019 Jul;161(7):1449-1456. doi: 10.1007/s00701-019-03940-2. Epub 2019 May 26.
• [4] FEAT expression correlates with tumor size, PR status, HER2 expression, Ki67 index, and molecular subtype and predicts recurrence in breast cancer.Neoplasma. 2017;64(1):123-130. doi: 10.4149/neo_2017_115.
• [5] Neoangiogenesis of gastric submucosa-invasive adenocarcinoma.Oncol Lett. 2018 Sep;16(3):3895-3900. doi: 10.3892/ol.2018.9116. Epub 2018 Jul 10.
• [6] The cerebellum and cognition.Neurosci Lett. 2019 Jan 1;688:62-75. doi: 10.1016/j.neulet.2018.07.005. Epub 2018 Jul 8.
• [7] Chemoprevention of colon and small intestinal tumorigenesis in APC(Min/+) mice by licofelone, a novel dual 5-LOX/COX inhibitor: potential implications for human colon cancer prevention.Cancer Prev Res (Phila). 2011 Dec;4(12):2015-26. doi: 10.1158/1940-6207.CAPR-11-0233. Epub 2011 Sep 1.
• [8] High Expression of RAR Is a Favorable Factor in Colorectal Cancer.Dis Markers. 2019 Mar 3;2019:7138754. doi: 10.1155/2019/7138754. eCollection 2019.
• [9] Combining high-sensitivity cardiac troponin and B-type natriuretic peptide in the detection of inducible myocardial ischemia.Clin Biochem. 2018 Feb;52:33-40. doi: 10.1016/j.clinbiochem.2017.10.014. Epub 2017 Nov 8.
• [10] High factor VIII levels and arterial thrombosis: illustrative case and literature review.Ther Adv Hematol. 2019 Nov 20;10:2040620719886685. doi: 10.1177/2040620719886685. eCollection 2019.
• [11] Small-molecule inhibition of prostaglandin E receptor 2 impairs cyclooxygenase-associated malignant glioma growth.Br J Pharmacol. 2019 Jun;176(11):1680-1699. doi: 10.1111/bph.14622. Epub 2019 Apr 29.
• [12] Detection of hepatitis A virus from clotting factors implicated as a source of HAV infection among haemophilia patients in Korea.Epidemiol Infect. 2006 Feb;134(1):87-93. doi: 10.1017/S0950268805004632.
• [13] Selective transmission of hepatitis C virus genotypes and quasispecies in humans and experimentally infected chimpanzees.J Gen Virol. 2006 Jan;87(Pt 1):83-91. doi: 10.1099/vir.0.81268-0.
• [14] Use of cyclooxygenase inhibitor and the risk of hepatocellular carcinoma in patients with chronic hepatitis B: A nested case-control study using a nationwide population-based data.J Viral Hepat. 2020 Jan;27(1):68-73. doi: 10.1111/jvh.13201. Epub 2019 Oct 2.
• [15] Brain Prostaglandin D2 Increases Neurogenic Pressor Activity and Mean Arterial Pressure in Angiotensin II-Salt Hypertensive Rats.Hypertension. 2019 Dec;74(6):1499-1506. doi: 10.1161/HYPERTENSIONAHA.119.13175. Epub 2019 Oct 7.
• [16] Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.Hum Mol Genet. 2013 Feb 1;22(3):417-32. doi: 10.1093/hmg/dds438. Epub 2012 Oct 18.
• [17] Use of Transthoracic Transdiaphragmatic Approach Assisted with Radiofrequency Ablation for Thoracoscopic Hepatectomy of Hepatic Tumor Located in Segment VIII.J Gastrointest Surg. 2019 Aug;23(8):1547-1548. doi: 10.1007/s11605-019-04172-6. Epub 2019 May 31.
• [18] Correlations of an Insertion/Deletion Polymorphism (rs10680577) in the RERT-lncRNA with the Susceptibility, Clinicopathological Features, and Prognosis of Lung Cancer.Biochem Genet. 2019 Feb;57(1):147-158. doi: 10.1007/s10528-018-9883-4. Epub 2018 Aug 2.
• [19] Prevalence of Obesity in Young Patients with Severe Haemophilia and Its Potential Impact on Factor VIII Consumption in Germany.Hamostaseologie. 2019 Nov;39(4):355-359. doi: 10.1055/s-0039-1677874. Epub 2019 Feb 5.
• [20] Pulmonary embolism and in situ pulmonary artery thrombosis in paediatrics. A systematic review.Thromb Haemost. 2017 Jun 2;117(6):1199-1207. doi: 10.1160/TH16-07-0529. Epub 2017 Mar 23.
• [21] Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease.Neuropsychopharmacology. 2019 Apr;44(5):837-849. doi: 10.1038/s41386-018-0090-0. Epub 2018 May 16.
• [22] Sensorineural hearing loss and cognitive impairments: Contributions of thalamus using multiparametric MRI.J Magn Reson Imaging. 2019 Sep;50(3):787-797. doi: 10.1002/jmri.26665. Epub 2019 Jan 29.
• [23] Liver metastases from gastric carcinoma: A Case report and review of the literature.Curr Probl Cancer. 2017 May-Jun;41(3):222-230. doi: 10.1016/j.currproblcancer.2017.03.003. Epub 2017 Mar 24.
• [24] Characteristics of Acquired Inhibitors to Factor VIII and Von Willebrand Factor Secondary to Systemic Lupus Erythematosus: Experiences From a Chinese Tertiary Medical Center.J Clin Rheumatol. 2021 Aug 1;27(5):201-205. doi: 10.1097/RHU.0000000000001284.
• [25] von Willebrand factor and factor VIII levels after desmopressin are associated with bleeding phenotype in type 1 VWD.Blood Adv. 2019 Dec 23;3(24):4147-4154. doi: 10.1182/bloodadvances.2019000863.
• [26] Abnormal von Willebrand factor secretion, factor VIII stabilization and thrombus dynamics in type 2N von Willebrand disease mice.J Thromb Haemost. 2017 Aug;15(8):1607-1619. doi: 10.1111/jth.13749. Epub 2017 Jul 17.
• [27] IL-4/IFN- inflammatory cytokine profile induces a deficient regulation of the IL-1/IL-1RI/EP(2)/COX-2 pathway in nasal mucosa.Respir Med. 2019 Apr;150:136-140. doi: 10.1016/j.rmed.2019.03.008. Epub 2019 Mar 20.
• [28] Thrombophilia in 153 Patients With Premature Cardiovascular Disease Age 45.Clin Appl Thromb Hemost. 2018 Mar;24(2):295-302. doi: 10.1177/1076029617703481. Epub 2017 Apr 12.
• [29] Linkage of Emery-Dreifuss muscular dystrophy to the red/green cone pigment (RGCP) genes, proximal to factor VIII.Neuromuscul Disord. 1992;2(1):51-7. doi: 10.1016/0960-8966(92)90027-4.
• [30] Tepoxalin a dual 5-LOX-COX inhibitor and erlotinib an EGFR inhibitor halts progression of gastric cancer in tumor xenograft mice.Am J Transl Res. 2018 Nov 15;10(11):3847-3856. eCollection 2018.
• [31] Disease progression in patients with single, large-scale mitochondrial DNA deletions.Brain. 2014 Feb;137(Pt 2):323-34. doi: 10.1093/brain/awt321. Epub 2013 Nov 25.
• [32] Bayesian pharmacokinetic-guided prophylaxis with recombinant factor VIII in severe or moderate haemophilia A.Thromb Res. 2019 Feb;174:151-162. doi: 10.1016/j.thromres.2018.12.027. Epub 2019 Jan 3.
• [33] Krppel-Like Factor 8 Overexpression Correlates with Poor Prognosis in Non-Small Cell Lung Cancer.Pathol Oncol Res. 2019 Jan;25(1):115-121. doi: 10.1007/s12253-017-0321-4. Epub 2017 Oct 6.
• [34] COX-2 mediates pro-tumorigenic effects of PKC in prostate cancer.Oncogene. 2018 Aug;37(34):4735-4749. doi: 10.1038/s41388-018-0318-9. Epub 2018 May 16.
• [35] FranceCoag: a 22-year prospective follow-up of the national French cohort of patients with inherited bleeding disorders.Eur J Epidemiol. 2019 May;34(5):521-532. doi: 10.1007/s10654-018-0468-7. Epub 2018 Dec 5.
• [36] Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy. Brain. 2016 Feb;139(Pt 2):338-45. doi: 10.1093/brain/awv357. Epub 2015 Dec 17.
• [37] Impact of baseline clinical and laboratory features on the risk of thrombosis in children with acute lymphoblastic leukemia: A prospective evaluation.Pediatr Blood Cancer. 2018 May;65(5):e26938. doi: 10.1002/pbc.26938. Epub 2018 Jan 15.
• [38] Desmopressin acetate (DDAVP) for preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders.Cochrane Database Syst Rev. 2019 Feb 13;2(2):CD009824. doi: 10.1002/14651858.CD009824.pub4.
• [39] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [40] Two chimaeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia.Hum Mol Genet. 1996 Dec;5(12):1945-51. doi: 10.1093/hmg/5.12.1945.
• [41] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [42] Recurrent risk of ischemic stroke due to Vertebrobasilar Dolichoectasia.BMC Neurol. 2019 Jul 17;19(1):163. doi: 10.1186/s12883-019-1400-9.
• [43] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [44] 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.
• [45] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [46] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [47] Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays. Molecules. 2019 Feb 27;24(5):841. doi: 10.3390/molecules24050841.
• [48] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [49] 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.
• [50] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [51] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [52] In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):216-24.