Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYDBO4L)

• DOT Name: Sulfiredoxin-1 (SRXN1)
• Synonyms: EC 1.8.98.2
• Gene Name: SRXN1
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Cerebral infarction
  Cerebrovascular disease
  Clear cell renal carcinoma
  Cryptococcosis
  Diabetic kidney disease
  High blood pressure
  Hyperglycemia
  Renal cell carcinoma
  Breast cancer
  Breast carcinoma
  Myocardial ischemia
• UniProt ID: SRXN1_HUMAN
• PDB ID: 1XW3; 1XW4; 1YZS; 2B6F; 2RII; 3CYI; 3HY2; 7LJ1
• EC Number: 1.8.98.2
• Sequence:
  MGLRAGGTLGRAGAGRGAPEGPGPSGGAQGGSIHSGRIAAVHNVPLSVLIRPLPSVLDPA
  KVQSLVDTIREDPDSVPPIDVLWIKGAQGGDYFYSFGGCHRYAAYQQLQRETIPAKLVQS
  TLSDLRVYLGASTPDLQ
• Function: Contributes to oxidative stress resistance by reducing cysteine-sulfinic acid formed under exposure to oxidants in the peroxiredoxins PRDX1, PRDX2, PRDX3 and PRDX4. Does not act on PRDX5 or PRDX6. May catalyze the reduction in a multi-step process by acting both as a specific phosphotransferase and a thioltransferase.
• Tissue Specificity: Widely expressed with highest levels in kidney, lung, spleen and thymus.
• Reactome Pathway: NFE2L2 regulating anti-oxidant/detoxification enzymes (R-HSA-9818027)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[3]
Cerebrovascular disease	DISAB237	Strong	Genetic Variation	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[6]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[7]
High blood pressure	DISY2OHH	Strong	Biomarker	[4]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[7]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[8]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[8]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[9]

58 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 Sulfiredoxin-1 (SRXN1).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sulfiredoxin-1 (SRXN1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sulfiredoxin-1 (SRXN1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sulfiredoxin-1 (SRXN1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sulfiredoxin-1 (SRXN1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sulfiredoxin-1 (SRXN1).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sulfiredoxin-1 (SRXN1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sulfiredoxin-1 (SRXN1).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sulfiredoxin-1 (SRXN1).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sulfiredoxin-1 (SRXN1).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sulfiredoxin-1 (SRXN1).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Sulfiredoxin-1 (SRXN1).	[20]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Sulfiredoxin-1 (SRXN1).	[21]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Sulfiredoxin-1 (SRXN1).	[22]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Sulfiredoxin-1 (SRXN1).	[23]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Sulfiredoxin-1 (SRXN1).	[24]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Sulfiredoxin-1 (SRXN1).	[25]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Sulfiredoxin-1 (SRXN1).	[26]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of Sulfiredoxin-1 (SRXN1).	[27]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Sulfiredoxin-1 (SRXN1).	[28]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Sulfiredoxin-1 (SRXN1).	[29]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Sulfiredoxin-1 (SRXN1).	[29]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Sulfiredoxin-1 (SRXN1).	[29]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Sulfiredoxin-1 (SRXN1).	[29]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Sulfiredoxin-1 (SRXN1).	[29]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Sulfiredoxin-1 (SRXN1).	[30]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the expression of Sulfiredoxin-1 (SRXN1).	[17]
Ampicillin	DMHWE7P	Approved	Ampicillin decreases the expression of Sulfiredoxin-1 (SRXN1).	[31]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the expression of Sulfiredoxin-1 (SRXN1).	[32]
Benzoic acid	DMKB9FI	Approved	Benzoic acid increases the expression of Sulfiredoxin-1 (SRXN1).	[28]
Ethacrynic acid	DM60QMR	Approved	Ethacrynic acid increases the expression of Sulfiredoxin-1 (SRXN1).	[33]
Flucloxacillin	DMNUWST	Approved	Flucloxacillin increases the expression of Sulfiredoxin-1 (SRXN1).	[32]
Amoxicillin	DMUYNEI	Approved	Amoxicillin increases the expression of Sulfiredoxin-1 (SRXN1).	[32]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sulfiredoxin-1 (SRXN1).	[34]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sulfiredoxin-1 (SRXN1).	[35]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Sulfiredoxin-1 (SRXN1).	[33]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Sulfiredoxin-1 (SRXN1).	[33]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sulfiredoxin-1 (SRXN1).	[36]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Sulfiredoxin-1 (SRXN1).	[30]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Sulfiredoxin-1 (SRXN1).	[28]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram increases the expression of Sulfiredoxin-1 (SRXN1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sulfiredoxin-1 (SRXN1).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sulfiredoxin-1 (SRXN1).	[37]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sulfiredoxin-1 (SRXN1).	[38]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sulfiredoxin-1 (SRXN1).	[39]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Sulfiredoxin-1 (SRXN1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sulfiredoxin-1 (SRXN1).	[40]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sulfiredoxin-1 (SRXN1).	[41]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Sulfiredoxin-1 (SRXN1).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Sulfiredoxin-1 (SRXN1).	[33]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Sulfiredoxin-1 (SRXN1).	[42]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Sulfiredoxin-1 (SRXN1).	[43]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Sulfiredoxin-1 (SRXN1).	[31]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Sulfiredoxin-1 (SRXN1).	[44]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol decreases the expression of Sulfiredoxin-1 (SRXN1).	[33]
methyl salicylate	DMKCG8H	Investigative	methyl salicylate increases the expression of Sulfiredoxin-1 (SRXN1).	[28]
2-Propanol, Isopropanol	DML5O0H	Investigative	2-Propanol, Isopropanol increases the expression of Sulfiredoxin-1 (SRXN1).	[28]
Hydroxybenzo(a)pyrene	DM9H5EN	Investigative	Hydroxybenzo(a)pyrene increases the expression of Sulfiredoxin-1 (SRXN1).	[45]

References

• [1] Maesopsin 4-O-beta-D-glucoside, a natural compound isolated from the leaves of Artocarpus tonkinensis, inhibits proliferation and up-regulates HMOX1, SRXN1 and BCAS3 in acute myeloid leukemia.J Chemother. 2011 Jun;23(3):150-7. doi: 10.1179/joc.2011.23.3.150.
• [2] Sulfiredoxin May Promote Cervical Cancer Metastasis via Wnt/-Catenin Signaling Pathway.Int J Mol Sci. 2017 Apr 27;18(5):917. doi: 10.3390/ijms18050917.
• [3] Neuroprotective effects of sulfiredoxin-1 during cerebral ischemia/reperfusion oxidative stress injury in rats.Brain Res Bull. 2017 Jun;132:99-108. doi: 10.1016/j.brainresbull.2017.05.012. Epub 2017 May 24.
• [4] Genetic Polymorphisms of Transcription Factor NRF2 and of its Host Gene Sulfiredoxin (SRXN1) are Associated with Cerebrovascular Disease in a Finnish Cohort, the TAMRISK Study.Int J Med Sci. 2016 Apr 10;13(5):325-9. doi: 10.7150/ijms.14849. eCollection 2016.
• [5] Identification and characterization of human leukocyte antigen class I ligands in renal cell carcinoma cells.Proteomics. 2011 Jun;11(12):2528-41. doi: 10.1002/pmic.201000486. Epub 2011 May 18.
• [6] Sulphiredoxin plays peroxiredoxin-dependent and -independent roles via the HOG signalling pathway in Cryptococcus neoformans and contributes to fungal virulence.Mol Microbiol. 2013 Nov;90(3):630-648. doi: 10.1111/mmi.12388. Epub 2013 Oct 3.
• [7] Sulfiredoxin-1 alleviates high glucose-induced podocyte injury though promoting Nrf2/ARE signaling via inactivation of GSK-3.Biochem Biophys Res Commun. 2019 Sep 3;516(4):1137-1144. doi: 10.1016/j.bbrc.2019.06.157. Epub 2019 Jul 6.
• [8] Genetic polymorphisms and protein expression of NRF2 and Sulfiredoxin predict survival outcomes in breast cancer.Cancer Res. 2012 Nov 1;72(21):5537-46. doi: 10.1158/0008-5472.CAN-12-1474. Epub 2012 Sep 10.
• [9] Sulfiredoxin-1 enhances cardiac progenitor cell survival against oxidative stress via the upregulation of the ERK/NRF2 signal pathway.Free Radic Biol Med. 2018 Aug 1;123:8-19. doi: 10.1016/j.freeradbiomed.2018.05.060. Epub 2018 May 14.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [16] 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.
• [17] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [20] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [21] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [22] Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol. 2020 Jan;28:101321. doi: 10.1016/j.redox.2019.101321. Epub 2019 Sep 5.
• [23] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [24] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [25] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [26] Comprehensive Landscape of Nrf2 and p53 Pathway Activation Dynamics by Oxidative Stress and DNA Damage. Chem Res Toxicol. 2017 Apr 17;30(4):923-933. doi: 10.1021/acs.chemrestox.6b00322. Epub 2016 Dec 16.
• [27] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [28] Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci. 2010 Sep;117(1):81-9.
• [29] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [30] Oxidative stress mechanisms do not discriminate between genotoxic and nongenotoxic liver carcinogens. Chem Res Toxicol. 2015 Aug 17;28(8):1636-46.
• [31] 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.
• [32] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [33] Mapping the dynamics of Nrf2 antioxidant and NFB inflammatory responses by soft electrophilic chemicals in human liver cells defines the transition from adaptive to adverse responses. Toxicol In Vitro. 2022 Oct;84:105419. doi: 10.1016/j.tiv.2022.105419. Epub 2022 Jun 17.
• [34] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [35] 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.
• [36] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [37] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [38] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [39] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [40] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [41] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [42] In vitro blood brain barrier exposure to mycotoxins and carotenoids pumpkin extract alters mitochondrial gene expression and oxidative stress. Food Chem Toxicol. 2021 Jul;153:112261. doi: 10.1016/j.fct.2021.112261. Epub 2021 May 17.
• [43] 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.
• [44] The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth. Free Radic Biol Med. 2009 Jan 15;46(2):220-31.
• [45] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.