Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU14HCN)

• DOT Name: Dual oxidase 2 (DUOX2)
• Synonyms: EC 1.11.1.-; EC 1.6.3.1; Large NOX 2; Long NOX 2; NADH/NADPH thyroid oxidase p138-tox; NADPH oxidase/peroxidase DUOX2; NADPH thyroid oxidase 2; Thyroid oxidase 2; p138 thyroid oxidase
• Gene Name: DUOX2
• Related Disease:
  Thyroid dyshormonogenesis 6
  Thyroid tumor
  Adenocarcinoma
  B-cell neoplasm
  Bladder cancer
  Carcinoma
  Cardiac failure
  Childhood acute lymphoblastic leukemia
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Diabetic kidney disease
  Epilepsy
  Familial thyroid dyshormonogenesis 1
  Goiter
  Hepatocellular carcinoma
  Hyperglycemia
  Hypothyroidism
  Metabolic disorder
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Pancreatic adenocarcinoma
  Pendred syndrome
  Stroke
  Systemic lupus erythematosus
  Thyroid gland carcinoma
  Tuberculosis
  Ulcerative colitis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Chronic obstructive pulmonary disease
  Crohn disease
  High blood pressure
  Type-1 diabetes
  Familial thyroid dyshormonogenesis
  Abdominal aortic aneurysm
  Advanced cancer
  Chronic granulomatous disease
  Colitis
  Coronary atherosclerosis
  Coronary heart disease
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Myocardial infarction
  Pancreatic ductal carcinoma
  Thyroid gland papillary carcinoma
• UniProt ID: DUOX2_HUMAN
• EC Number: 1.11.1.-; 1.6.3.1
• Pfam ID: PF03098 ; PF00036 ; PF13833 ; PF08022 ; PF01794 ; PF08030
• Sequence:
  MLRARPEALMLLGALLTGSLGPSGNQDALSLPWEVQRYDGWFNNLRHHERGAVGCRLQRR
  VPANYADGVYQALEEPQLPNPRRLSNAATRGIAGLPSLHNRTVLGVFFGYHVLSDVVSVE
  TPGCPAEFLNIRIPPGDPVFDPDQRGDVVLPFQRSRWDPETGRSPSNPRDLANQVTGWLD
  GSAIYGSSHSWSDALRSFSGGQLASGPDPAFPRDSQNPLLMWAAPDPATGQNGPRGLYAF
  GAERGNREPFLQALGLLWFRYHNLWAQRLARQHPDWEDEELFQHARKRVIATYQNIAVYE
  WLPSFLQKTLPEYTGYRPFLDPSISPEFVVASEQFFSTMVPPGVYMRNASCHFRKVLNKG
  FQSSQALRVCNNYWIRENPNLNSTQEVNELLLGMASQISELEDNIVVEDLRDYWPGPGKF
  SRTDYVASSIQRGRDMGLPSYSQALLAFGLDIPRNWSDLNPNVDPQVLEATAALYNQDLS
  QLELLLGGLLESHGDPGPLFSAIVLDQFVRLRDGDRYWFENTRNGLFSKKEIEDIRNTTL
  RDVLVAVINIDPSALQPNVFVWHKGAPCPQPKQLTTDGLPQCAPLTVLDFFEGSSPGFAI
  TIIALCCLPLVSLLLSGVVAYFRGREHKKLQKKLKESVKKEAAKDGVPAMEWPGPKERSS
  PIIIQLLSDRCLQVLNRHLTVLRVVQLQPLQQVNLILSNNRGCRTLLLKIPKEYDLVLLF
  SSEEERGAFVQQLWDFCVRWALGLHVAEMSEKELFRKAVTKQQRERILEIFFRHLFAQVL
  DINQADAGTLPLDSSQKVREALTCELSRAEFAESLGLKPQDMFVESMFSLADKDGNGYLS
  FREFLDILVVFMKGSPEDKSRLMFTMYDLDENGFLSKDEFFTMMRSFIEISNNCLSKAQL
  AEVVESMFRESGFQDKEELTWEDFHFMLRDHDSELRFTQLCVKGGGGGGNGIRDIFKQNI
  SCRVSFITRTPGERSHPQGLGPPAPEAPELGGPGLKKRFGKKAAVPTPRLYTEALQEKMQ
  RGFLAQKLQQYKRFVENYRRHIVCVAIFSAICVGVFADRAYYYGFASPPSDIAQTTLVGI
  ILSRGTAASVSFMFSYILLTMCRNLITFLRETFLNRYVPFDAAVDFHRWIAMAAVVLAIL
  HSAGHAVNVYIFSVSPLSLLACIFPNVFVNDGSKLPQKFYWWFFQTVPGMTGVLLLLVLA
  IMYVFASHHFRRRSFRGFWLTHHLYILLYALLIIHGSYALIQLPTFHIYFLVPAIIYGGD
  KLVSLSRKKVEISVVKAELLPSGVTYLQFQRPQGFEYKSGQWVRIACLALGTTEYHPFTL
  TSAPHEDTLSLHIRAVGPWTTRLREIYSSPKGNGCAGYPKLYLDGPFGEGHQEWHKFEVS
  VLVGGGIGVTPFASILKDLVFKSSLGSQMLCKKIYFIWVTRTQRQFEWLADIIQEVEEND
  HQDLVSVHIYVTQLAEKFDLRTTMLYICERHFQKVLNRSLFTGLRSITHFGRPPFEPFFN
  SLQEVHPQVRKIGVFSCGPPGMTKNVEKACQLVNRQDRAHFMHHYENF
• Function: Generates hydrogen peroxide which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO. Plays a role in thyroid hormones synthesis and lactoperoxidase-mediated antimicrobial defense at the surface of mucosa. May have its own peroxidase activity through its N-terminal peroxidase-like domain.
• Tissue Specificity: Expressed in colon, small intestine, duodenum and tracheal surface epithelial cells (at protein level). Expressed in thyrocytes. Also detected in kidney, liver, lung, pancreas, prostate, salivary glands, rectum and testis.
• KEGG Pathway: Thyroid hormone synthesis (hsa04918)
• Reactome Pathway: Thyroxine biosynthesis (R-HSA-209968)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid dyshormonogenesis 6	DISR34Y7	Definitive	Autosomal recessive	[1]
Thyroid tumor	DISLVKMD	Definitive	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Altered Expression	[7]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[8]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[7]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[10]
Epilepsy	DISBB28L	Strong	Altered Expression	[11]
Familial thyroid dyshormonogenesis 1	DISAXKZN	Strong	GermlineCausalMutation	[12]
Goiter	DISLCGI6	Strong	Genetic Variation	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[15]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[16]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Altered Expression	[18]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[19]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[20]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[18]
Pendred syndrome	DISZ1MU8	Strong	Genetic Variation	[21]
Stroke	DISX6UHX	Strong	Biomarker	[15]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[22]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[2]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[23]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[24]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[25]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[26]
High blood pressure	DISY2OHH	moderate	Altered Expression	[27]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[28]
Familial thyroid dyshormonogenesis	DISALTXN	Supportive	Autosomal recessive	[29]
Abdominal aortic aneurysm	DISD06OF	Limited	Biomarker	[30]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[18]
Chronic granulomatous disease	DIS9ZR24	Limited	Genetic Variation	[31]
Colitis	DISAF7DD	Limited	Altered Expression	[32]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[33]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[33]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[34]
Lung cancer	DISCM4YA	Limited	Posttranslational Modification	[35]
Lung carcinoma	DISTR26C	Limited	Posttranslational Modification	[35]
Lung neoplasm	DISVARNB	Limited	Posttranslational Modification	[35]
Myocardial infarction	DIS655KI	Limited	Altered Expression	[36]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[37]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual oxidase 2 (DUOX2).	[39]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dual oxidase 2 (DUOX2).	[40]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dual oxidase 2 (DUOX2).	[41]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Dual oxidase 2 (DUOX2).	[42]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Dual oxidase 2 (DUOX2).	[43]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Dual oxidase 2 (DUOX2).	[45]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Dual oxidase 2 (DUOX2).	[46]

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 Dual oxidase 2 (DUOX2).	[44]

References

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• [3] High Immunoreactivity of DUOX2 Is Associated With Poor Response to Preoperative Chemoradiation Therapy and Worse Prognosis in Rectal Cancers.J Cancer. 2017 Aug 23;8(14):2756-2764. doi: 10.7150/jca.19545. eCollection 2017.
• [4] Adiponectin/AdiopR1 signal inactivation contributes to impaired angiogenesis in mice of advanced age.Int J Cardiol. 2018 Sep 15;267:150-155. doi: 10.1016/j.ijcard.2018.05.089. Epub 2018 May 24.
• [5] DUOX2 promotes the elimination of the Klebsiella pneumoniae strainK5 from T24 cells through the reactive oxygen species pathway.Int J Mol Med. 2015 Aug;36(2):551-8. doi: 10.3892/ijmm.2015.2234. Epub 2015 Jun 3.
• [6] NADPH oxidases and cancer.Clin Sci (Lond). 2015 Jun;128(12):863-75. doi: 10.1042/CS20140542.
• [7] Loss of p47phox subunit enhances susceptibility to biomechanical stress and heart failure because of dysregulation of cortactin and actin filaments.Circ Res. 2013 Jun 7;112(12):1542-56. doi: 10.1161/CIRCRESAHA.111.300299. Epub 2013 Apr 3.
• [8] Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors.Pharmgenomics Pers Med. 2019 Apr 11;12:33-45. doi: 10.2147/PGPM.S192924. eCollection 2019.
• [9] DUOX2-mediated production of reactive oxygen species induces epithelial mesenchymal transition in 5-fluorouracil resistant human colon cancer cells.Redox Biol. 2018 Jul;17:224-235. doi: 10.1016/j.redox.2018.04.020. Epub 2018 Apr 23.
• [10] Zingerone attenuates diabetic nephropathy through inhibition of nicotinamide adenine dinucleotide phosphate oxidase 4.Biomed Pharmacother. 2018 Mar;99:422-430. doi: 10.1016/j.biopha.2018.01.051.
• [11] Activation of nicotinamide adenine dinucleotide phosphate oxidase is the primary trigger of epileptic seizures in rodent models.Ann Neurol. 2019 Jun;85(6):907-920. doi: 10.1002/ana.25474. Epub 2019 Apr 12.
• [12] Genetic causes of congenital hypothyroidism due to dyshormonogenesis.Curr Opin Pediatr. 2011 Aug;23(4):421-8. doi: 10.1097/MOP.0b013e32834726a4.
• [13] Congenital Hypothyroidism due to Oligogenic Mutations in Two Sudanese Families.Thyroid. 2019 Feb;29(2):302-304. doi: 10.1089/thy.2018.0295. Epub 2018 Dec 18.
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• [16] Double variants in TSHR and DUOX2 in a patient with hypothyroidism: case report.J Pediatr Endocrinol Metab. 2019 Nov 26;32(11):1299-1303. doi: 10.1515/jpem-2019-0051.
• [17] The Role of NADPH Oxidases in the Etiology of Obesity and Metabolic Syndrome: Contribution of Individual Isoforms and Cell Biology.Antioxid Redox Signal. 2019 Oct 1;31(10):687-709. doi: 10.1089/ars.2018.7674.
• [18] IL-4 and IL-17A Cooperatively Promote Hydrogen Peroxide Production, Oxidative DNA Damage, and Upregulation of Dual Oxidase 2 in Human Colon and Pancreatic Cancer Cells.J Immunol. 2019 Nov 1;203(9):2532-2544. doi: 10.4049/jimmunol.1800469. Epub 2019 Sep 23.
• [19] Active vitamin D supplementation alleviates initiation and progression of nonalcoholic fatty liver disease by repressing the p53 pathway.Life Sci. 2020 Jan 15;241:117086. doi: 10.1016/j.lfs.2019.117086. Epub 2019 Nov 20.
• [20] Influence of antioxidants' gene variants on risk of diabetes mellitus and its complications: a systematic review.Minerva Endocrinol. 2019 Sep;44(3):310-325. doi: 10.23736/S0391-1977.17.02632-3. Epub 2017 May 26.
• [21] Exome sequencing identifies SLC26A4, GJB2, SCARB2 and DUOX2 mutations in 2 siblings with Pendred syndrome in a Malaysian family.Orphanet J Rare Dis. 2017 Feb 21;12(1):40. doi: 10.1186/s13023-017-0575-7.
• [22] Activation of Peroxisome Proliferator Activator Receptor / Improves Endothelial Dysfunction and Protects Kidney in Murine Lupus.Hypertension. 2017 Apr;69(4):641-650. doi: 10.1161/HYPERTENSIONAHA.116.08655. Epub 2017 Feb 27.
• [23] A Novel Genetic Variation in NCF2, the Core Component of NADPH Oxidase, Contributes to the Susceptibility of Tuberculosis in Western Chinese Han Population.DNA Cell Biol. 2020 Jan;39(1):57-62. doi: 10.1089/dna.2019.5082. Epub 2019 Dec 2.
• [24] Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature.J Clin Invest. 2014 Aug;124(8):3617-33. doi: 10.1172/JCI75436. Epub 2014 Jul 8.
• [25] Dual oxidase 1 and 2 expression in airway epithelium of smokers and patients with mild/moderate chronic obstructive pulmonary disease.Antioxid Redox Signal. 2008 Apr;10(4):705-14. doi: 10.1089/ars.2007.1941.
• [26] Genetic Complexity of Crohn's Disease in Two Large Ashkenazi Jewish Families.Gastroenterology. 2016 Oct;151(4):698-709. doi: 10.1053/j.gastro.2016.06.040. Epub 2016 Jul 1.
• [27] Attenuation of Angiotensin II-Induced Hypertension in BubR1 Low-Expression Mice Via Repression of Angiotensin II Receptor 1 Overexpression.J Am Heart Assoc. 2019 Dec 3;8(23):e011911. doi: 10.1161/JAHA.118.011911. Epub 2019 Nov 30.
• [28] Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) P22 Phox C242T gene polymorphism in type 1 diabetes.Ann N Y Acad Sci. 2003 Nov;1005:324-7. doi: 10.1196/annals.1288.051.
• [29] Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. doi: 10.1186/1750-1172-5-17.
• [30] Mesenchymal Stem Cells Attenuate NADPH Oxidase-Dependent High Mobility Group Box 1 Production and Inhibit Abdominal Aortic Aneurysms.Arterioscler Thromb Vasc Biol. 2016 May;36(5):908-18. doi: 10.1161/ATVBAHA.116.307373. Epub 2016 Mar 17.
• [31] Cytologic and Ultrastructural Findings of Bronchoalveolar Lavage in Patients With Chronic Granulomatous Disease.Pediatr Dev Pathol. 2018 Jul-Aug;21(4):347-354. doi: 10.1177/1093526617736188. Epub 2017 Oct 19.
• [32] 5-Hydroxytryptamine (5-HT)-exacerbated DSS-induced colitis is associated with elevated NADPH oxidase expression in the colon.J Cell Biochem. 2019 Jun;120(6):9230-9242. doi: 10.1002/jcb.28198. Epub 2018 Dec 7.
• [33] Association of nicotinamide adenine dinucleotide phosphate oxidase p22phox gene 549C>T polymorphism with coronary artery disease.Chin Med J (Engl). 2012 Apr;125(8):1416-9.
• [34] Functional Characterization of DUOX Enzymes in Reconstituted Cell Models.Methods Mol Biol. 2019;1982:173-190. doi: 10.1007/978-1-4939-9424-3_11.
• [35] Silencing of DUOX NADPH oxidases by promoter hypermethylation in lung cancer.Cancer Res. 2008 Feb 15;68(4):1037-45. doi: 10.1158/0008-5472.CAN-07-5782.
• [36] Canagliflozin, a sodium-glucose cotransporter2 inhibitor, normalizes renal susceptibility to type1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats.J Diabetes Investig. 2019 Jul;10(4):933-946. doi: 10.1111/jdi.13009. Epub 2019 Feb 25.
• [37] Dual oxidase 2 and pancreatic adenocarcinoma: IFN--mediated dual oxidase 2 overexpression results in H2O2-induced, ERK-associated up-regulation of HIF-1 and VEGF-A.Oncotarget. 2016 Oct 18;7(42):68412-68433. doi: 10.18632/oncotarget.12032.
• [38] Molecular characteristics of papillary thyroid carcinomas without BRAF mutation or RET/PTC rearrangement: relationship with clinico-pathological features.Endocr Relat Cancer. 2009 Jun;16(2):467-81. doi: 10.1677/ERC-08-0081. Epub 2009 Feb 10.
• [39] 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.
• [40] Quercetin reduces oxidative damage induced by paraquat via modulating expression of antioxidant genes in A549 cells. J Appl Toxicol. 2013 Dec;33(12):1460-7. doi: 10.1002/jat.2812. Epub 2012 Sep 20.
• [41] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [42] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [43] 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.
• [44] 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.
• [45] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [46] Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol In Vitro. 2020 Dec;69:105001. doi: 10.1016/j.tiv.2020.105001. Epub 2020 Sep 15.