Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZQQC3T)

• DOT Name: Thioredoxin reductase 2, mitochondrial
• Synonyms: EC 1.8.1.9; Selenoprotein Z; SelZ; TR-beta; Thioredoxin reductase TR3
• Gene Name: TXNRD2
• Related Disease:
  Familial glucocorticoid deficiency
  Obsolete familial isolated dilated cardiomyopathy
  Dilated cardiomyopathy
  Glucocorticoid deficiency 5
• UniProt ID: TRXR2_HUMAN
• EC Number: 1.8.1.9
• Pfam ID: PF07992 ; PF02852
• Sequence:
  MAAMAVALRGLGGRFRWRTQAVAGGVRGAARGAAAGQRDYDLLVVGGGSGGLACAKEAAQ
  LGRKVAVVDYVEPSPQGTRWGLGGTCVNVGCIPKKLMHQAALLGGLIQDAPNYGWEVAQP
  VPHDWRKMAEAVQNHVKSLNWGHRVQLQDRKVKYFNIKASFVDEHTVCGVAKGGKEILLS
  ADHIIIATGGRPRYPTHIEGALEYGITSDDIFWLKESPGKTLVVGASYVALECAGFLTGI
  GLDTTIMMRSIPLRGFDQQMSSMVIEHMASHGTRFLRGCAPSRVRRLPDGQLQVTWEDST
  TGKEDTGTFDTVLWAIGRVPDTRSLNLEKAGVDTSPDTQKILVDSREATSVPHIYAIGDV
  VEGRPELTPIAIMAGRLLVQRLFGGSSDLMDYDNVPTTVFTPLEYGCVGLSEEEAVARHG
  QEHVEVYHAHYKPLEFTVAGRDASQCYVKMVCLREPPQLVLGLHFLGPNAGEVTQGFALG
  IKCGASYAQVMRTVGIHPTCSEEVVKLRISKRSGLDPTVTGCUG
• Function: Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis. Maintains thioredoxin in a reduced state. May play a role in redox-regulated cell signaling.
• Tissue Specificity: Highly expressed in the prostate, ovary, liver, testis, uterus, colon and small intestine. Intermediate levels in brain, skeletal muscle, heart and spleen. Low levels in placenta, pancreas, thymus and peripheral blood leukocytes. According to PubMed:10608886, high levels in kidney, whereas according to PubMed:9923614, levels are low. High expression is observed in the adrenal cortex .
• KEGG Pathway:
  Selenocompound metabolism (hsa00450)
  Pathways in cancer (hsa05200)
  Hepatocellular carcinoma (hsa05225)
• Reactome Pathway: Detoxification of Reactive Oxygen Species (R-HSA-3299685)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial glucocorticoid deficiency	DISG7TB4	Supportive	Autosomal recessive	[1]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[2]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[3]
Glucocorticoid deficiency 5	DISER9UK	Limited	Unknown	[4]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Avastin+/-Tarceva	DMA86FL	Phase 3	Thioredoxin reductase 2, mitochondrial increases the reduction of Avastin+/-Tarceva.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Thioredoxin reductase 2, mitochondrial.	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Thioredoxin reductase 2, mitochondrial.	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Thioredoxin reductase 2, mitochondrial.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Thioredoxin reductase 2, mitochondrial.	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Thioredoxin reductase 2, mitochondrial.	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Thioredoxin reductase 2, mitochondrial.	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Thioredoxin reductase 2, mitochondrial.	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Thioredoxin reductase 2, mitochondrial.	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Thioredoxin reductase 2, mitochondrial.	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Thioredoxin reductase 2, mitochondrial.	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Thioredoxin reductase 2, mitochondrial.	[13]
Selenium	DM25CGV	Approved	Selenium increases the activity of Thioredoxin reductase 2, mitochondrial.	[14]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Thioredoxin reductase 2, mitochondrial.	[15]
Mechlorethamine	DM0CVXA	Approved	Mechlorethamine decreases the activity of Thioredoxin reductase 2, mitochondrial.	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Thioredoxin reductase 2, mitochondrial.	[17]
Abexinostat	DM91LGU	Phase 3	Abexinostat decreases the expression of Thioredoxin reductase 2, mitochondrial.	[18]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Thioredoxin reductase 2, mitochondrial.	[19]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram increases the expression of Thioredoxin reductase 2, mitochondrial.	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Thioredoxin reductase 2, mitochondrial.	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Thioredoxin reductase 2, mitochondrial.	[22]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Thioredoxin reductase 2, mitochondrial.	[19]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Thioredoxin reductase 2, mitochondrial.	[24]
Wogonin	DMGCF51	Investigative	Wogonin decreases the expression of Thioredoxin reductase 2, mitochondrial.	[25]

References

• [1] Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. 2014 Aug;99(8):E1556-63. doi: 10.1210/jc.2013-3844. Epub 2014 Mar 6.
• [2] Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. Eur Heart J. 2011 May;32(9):1121-33. doi: 10.1093/eurheartj/ehq507. Epub 2011 Jan 18.
• [3] 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.
• [4] Autozygome and high throughput confirmation of disease genes candidacy. Genet Med. 2019 Mar;21(3):736-742. doi: 10.1038/s41436-018-0138-x. Epub 2018 Sep 21.
• [5] 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.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] 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.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [14] Overexpression of enzymatically active human cytosolic and mitochondrial thioredoxin reductase in HEK-293 cells. Effect on cell growth and differentiation. J Biol Chem. 2004 Dec 24;279(52):54510-7. doi: 10.1074/jbc.M408494200. Epub 2004 Oct 7.
• [15] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [16] Cross-linking of thioredoxin reductase by the sulfur mustard analogue mechlorethamine (methylbis(2-chloroethyl)amine) in human lung epithelial cells and rat lung: selective inhibition of disulfide reduction but not redox cycling. Chem Res Toxicol. 2014 Jan 21;27(1):61-75. doi: 10.1021/tx400329a. Epub 2013 Dec 9.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci. 2010 Sep;117(1):81-9.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [25] Wogonin induces cellular senescence in breast cancer via suppressing TXNRD2 expression. Arch Toxicol. 2020 Oct;94(10):3433-3447. doi: 10.1007/s00204-020-02842-y. Epub 2020 Jul 15.
• [26] Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: Implications for development of specific inhibitors. Free Radic Biol Med. 2011 Mar 15;50(6):689-99.