Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE9A5XQ)

• DOT Name: Thioredoxin, mitochondrial
• Synonyms: MTRX; Mt-Trx; Thioredoxin-2
• Gene Name: TXN2
• Related Disease:
  Obsolete combined oxidative phosphorylation defect type 29
  Combined oxidative phosphorylation deficiency 29
• UniProt ID: THIOM_HUMAN
• PDB ID: 1UVZ; 1W4V; 1W89
• Pfam ID: PF00085
• Sequence:
  MAQRLLLRRFLASVISRKPSQGQWPPLTSRALQTPQCSPGGLTVTPNPARTIYTTRISLT
  TFNIQDGPDFQDRVVNSETPVVVDFHAQWCGPCKILGPRLEKMVAKQHGKVVMAKVDIDD
  HTDLAIEYEVSAVPTVLAMKNGDVVDKFVGIKDEDQLEAFLKKLIG
• Function: Important for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability. Possesses a dithiol-reducing activity.
• Tissue Specificity: Widely expressed in adult (at protein level) and fetal tissues.
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  Parkinson disease (hsa05012)
  Salmonella infection (hsa05132)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Detoxification of Reactive Oxygen Species (R-HSA-3299685)
  Degradation of cysteine and homocysteine (R-HSA-1614558)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete combined oxidative phosphorylation defect type 29	DISWZZ5G	Supportive	Autosomal recessive	[1]
Combined oxidative phosphorylation deficiency 29	DIS3U4PY	Limited	Unknown	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Thioredoxin, mitochondrial decreases the response to substance of Etoposide.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Thioredoxin, mitochondrial.	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Thioredoxin, mitochondrial.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Thioredoxin, mitochondrial.	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Thioredoxin, mitochondrial.	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Thioredoxin, mitochondrial.	[7]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Thioredoxin, mitochondrial.	[12]
Abexinostat	DM91LGU	Phase 3	Abexinostat decreases the expression of Thioredoxin, mitochondrial.	[13]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Thioredoxin, mitochondrial.	[14]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram increases the expression of Thioredoxin, mitochondrial.	[14]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Thioredoxin, mitochondrial.	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Thioredoxin, mitochondrial.	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Thioredoxin, mitochondrial.	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Thioredoxin, mitochondrial.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Thioredoxin, mitochondrial.	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the oxidation of Thioredoxin, mitochondrial.	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the oxidation of Thioredoxin, mitochondrial.	[10]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the oxidation of Thioredoxin, mitochondrial.	[11]
Triapine	DM7XZY5	Phase 2	Triapine increases the oxidation of Thioredoxin, mitochondrial.	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Thioredoxin, mitochondrial.	[17]
Paraquat	DMR8O3X	Investigative	Paraquat increases the oxidation of Thioredoxin, mitochondrial.	[20]
acrolein	DMAMCSR	Investigative	acrolein increases the oxidation of Thioredoxin, mitochondrial.	[21]
Diamide	DMOCQ9J	Investigative	Diamide increases the oxidation of Thioredoxin, mitochondrial.	[9]

References

• [1] Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration. Brain. 2016 Feb;139(Pt 2):346-54. doi: 10.1093/brain/awv350. Epub 2015 Dec 1.
• [2] The absence of mitochondrial thioredoxin 2 causes massive apoptosis, exencephaly, and early embryonic lethality in homozygous mice. Mol Cell Biol. 2003 Feb;23(3):916-22. doi: 10.1128/MCB.23.3.916-922.2003.
• [3] 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.
• [4] 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.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Mitochondrial Thioredoxin System as a Modulator of Cyclophilin D Redox State. Sci Rep. 2016 Mar 15;6:23071. doi: 10.1038/srep23071.
• [10] Protection against oxidant-induced apoptosis by mitochondrial thioredoxin in SH-SY5Y neuroblastoma cells. Toxicol Appl Pharmacol. 2006 Oct 15;216(2):256-62. doi: 10.1016/j.taap.2006.05.006. Epub 2006 May 20.
• [11] The mitochondrial superoxide/thioredoxin-2/Ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes. Toxicol Sci. 2008 Feb;101(2):341-9. doi: 10.1093/toxsci/kfm273. Epub 2007 Nov 1.
• [12] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [13] PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells. Clin Cancer Res. 2009 May 15;15(10):3354-65. doi: 10.1158/1078-0432.CCR-08-2365. Epub 2009 May 5.
• [14] Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci. 2010 Sep;117(1):81-9.
• [15] The iron-chelating drug triapine causes pronounced mitochondrial thiol redox stress. Toxicol Lett. 2011 Mar 5;201(2):130-6. doi: 10.1016/j.toxlet.2010.12.017. Epub 2010 Dec 31.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] 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.
• [18] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [19] 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.
• [20] Maneb and paraquat-mediated neurotoxicity: involvement of peroxiredoxin/thioredoxin system. Toxicol Sci. 2011 Jun;121(2):368-75. doi: 10.1093/toxsci/kfr058. Epub 2011 Mar 14.
• [21] Acrolein oxidizes the cytosolic and mitochondrial thioredoxins in human endothelial cells. Toxicology. 2008 Jan 14;243(1-2):164-76. doi: 10.1016/j.tox.2007.10.004. Epub 2007 Oct 10.
• [22] Human mitochondrial thioredoxin. Involvement in mitochondrial membrane potential and cell death. J Biol Chem. 2002 Sep 6;277(36):33249-57. doi: 10.1074/jbc.M203036200. Epub 2002 Jun 21.