Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTINT9Z4)

• DOT Name: Glutathione peroxidase 7 (GPX7)
• Synonyms: GPx-7; GSHPx-7; EC 1.11.1.9; CL683
• Gene Name: GPX7
• Related Disease:
  Advanced cancer
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Esophageal adenocarcinoma
  Huntington disease
  Minimally invasive lung adenocarcinoma
  Parkinson disease
  Amyotrophic lateral sclerosis
• UniProt ID: GPX7_HUMAN
• PDB ID: 2P31
• EC Number: 1.11.1.9
• Pfam ID: PF00255
• Sequence:
  MVAATVAAAWLLLWAAACAQQEQDFYDFKAVNIRGKLVSLEKYRGSVSLVVNVASECGFT
  DQHYRALQQLQRDLGPHHFNVLAFPCNQFGQQEPDSNKEIESFARRTYSVSFPMFSKIAV
  TGTGAHPAFKYLAQTSGKEPTWNFWKYLVAPDGKVVGAWDPTVSVEEVRPQITALVRKLI
  LLKREDL
• Function: It protects esophageal epithelia from hydrogen peroxide-induced oxidative stress. It suppresses acidic bile acid-induced reactive oxygen species (ROS) and protects against oxidative DNA damage and double-strand breaks.
• Tissue Specificity: Expressed in esophageal epithelial cells; expression is up-regulated after exposure to acidic bile acids.
• KEGG Pathway:
  Glutathione metabolism (hsa00480)
  Metabolic pathways (hsa01100)
  Thyroid hormone synthesis (hsa04918)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway: Detoxification of Reactive Oxygen Species (R-HSA-3299685)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Esophageal adenocarcinoma	DISODWFP	Strong	Altered Expression	[2]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[4]
Minimally invasive lung adenocarcinoma	DIS4W83X	Strong	Biomarker	[5]
Parkinson disease	DISQVHKL	Strong	Biomarker	[6]
Amyotrophic lateral sclerosis	DISF7HVM	Disputed	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Glutathione peroxidase 7 (GPX7).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutathione peroxidase 7 (GPX7).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutathione peroxidase 7 (GPX7).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glutathione peroxidase 7 (GPX7).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutathione peroxidase 7 (GPX7).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glutathione peroxidase 7 (GPX7).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Glutathione peroxidase 7 (GPX7).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Glutathione peroxidase 7 (GPX7).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glutathione peroxidase 7 (GPX7).	[16]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Glutathione peroxidase 7 (GPX7).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Glutathione peroxidase 7 (GPX7).	[17]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Glutathione peroxidase 7 (GPX7).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glutathione peroxidase 7 (GPX7).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Glutathione peroxidase 7 (GPX7).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Glutathione peroxidase 7 (GPX7).	[19]

References

• [1] Glutathione peroxidase 7 suppresses cancer cell growth and is hypermethylated in gastric cancer.Oncotarget. 2017 Apr 29;8(33):54345-54356. doi: 10.18632/oncotarget.17527. eCollection 2017 Aug 15.
• [2] Glutathione peroxidase 7 protects against oxidative DNA damage in oesophageal cells.Gut. 2012 Sep;61(9):1250-60. doi: 10.1136/gutjnl-2011-301078. Epub 2011 Dec 9.
• [3] Identification of a novel putative non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) essential for alleviating oxidative stress generated from polyunsaturated fatty acids in breast cancer cells.J Biol Chem. 2004 Oct 15;279(42):43522-9. doi: 10.1074/jbc.M407141200. Epub 2004 Aug 4.
• [4] Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington's disease.Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):268-72. doi: 10.1073/pnas.1417231112. Epub 2014 Dec 22.
• [5] DNA hypermethylation regulates the expression of members of the Mu-class glutathione S-transferases and glutathione peroxidases in Barrett's adenocarcinoma. Gut. 2009 Jan;58(1):5-15. doi: 10.1136/gut.2007.146290. Epub 2008 Jul 29.
• [6] Identification of Shared Genes Between Ischemic Stroke and Parkinson's Disease Using Genome-Wide Association Studies.Front Neurol. 2019 Mar 28;10:297. doi: 10.3389/fneur.2019.00297. eCollection 2019.
• [7] NPGPx-Mediated Adaptation to Oxidative Stress Protects Motor Neurons from Degeneration in Aging by Directly Modulating O-GlcNAcase.Cell Rep. 2019 Nov 19;29(8):2134-2143.e7. doi: 10.1016/j.celrep.2019.10.053.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [14] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [19] Bisphenol-A impairs cellular function and alters DNA methylation of stress pathway genes in first trimester trophoblast cells. Reprod Toxicol. 2018 Dec;82:72-79.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Microphysiological system modeling of ochratoxin A-associated nephrotoxicity. Toxicology. 2020 Nov;444:152582. doi: 10.1016/j.tox.2020.152582. Epub 2020 Sep 6.