Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4UGTDO)

• DOT Name: Microsomal glutathione S-transferase 2 (MGST2)
• Synonyms: Microsomal GST-2; EC 2.5.1.18; Glutathione peroxidase MGST2; EC 1.11.1.-; Leukotriene C4 synthase MGST2; EC 4.4.1.20; Microsomal glutathione S-transferase II; Microsomal GST-II
• Gene Name: MGST2
• UniProt ID: MGST2_HUMAN
• PDB ID: 6SSR; 6SSS; 6SSU; 6SSW
• EC Number: 1.11.1.-; 2.5.1.18; 4.4.1.20
• Pfam ID: PF01124
• Sequence:
  MAGNSILLAAVSILSACQQSYFALQVGKARLKYKVTPPAVTGSPEFERVFRAQQNCVEFY
  PIFIITLWMAGWYFNQVFATCLGLVYIYGRHLYFWGYSEAAKKRITGFRLSLGILALLTL
  LGALGIANSFLDEYLDLNIAKKLRRQF
• Function: Catalyzes several different glutathione-dependent reactions. Catalyzes the glutathione-dependent reduction of lipid hydroperoxides, such as 5-HPETE. Has glutathione transferase activity, toward xenobiotic electrophiles, such as 1-chloro-2, 4-dinitrobenzene (CDNB). Catalyzes also the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4 (LTC4). Involved in oxidative DNA damage induced by ER stress and anticancer agents by activating LTC4 biosynthetic machinery in nonimmune cells.
• Tissue Specificity: Liver, spleen, skeletal muscle, heart, adrenals, pancreas, prostate, testis, fetal liver, and fetal spleen. Very low expression in lung, brain, placenta and bone marrow . Abundantly expressed in human umbilical vein endothelial cells (at protein level) .
• KEGG Pathway:
  Glutathione metabolism (hsa00480)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Drug metabolism - cytochrome P450 (hsa00982)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Platinum drug resistance (hsa01524)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - D. adducts (hsa05204)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Hepatocellular carcinoma (hsa05225)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Aflatoxin activation and detoxification (R-HSA-5423646)
  Glutathione conjugation (R-HSA-156590)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Microsomal glutathione S-transferase 2 (MGST2) affects the response to substance of DTI-015.	[22]
Melphalan	DMOLNHF	Approved	Microsomal glutathione S-transferase 2 (MGST2) decreases the response to substance of Melphalan.	[23]
Busulfan	DMXYJ9C	Approved	Microsomal glutathione S-transferase 2 (MGST2) decreases the response to substance of Busulfan.	[23]

21 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 Microsomal glutathione S-transferase 2 (MGST2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Microsomal glutathione S-transferase 2 (MGST2).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Microsomal glutathione S-transferase 2 (MGST2).	[12]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Microsomal glutathione S-transferase 2 (MGST2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[19]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[20]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Microsomal glutathione S-transferase 2 (MGST2).	[21]

References

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• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [8] 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.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] 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.
• [13] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [16] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [17] 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.
• [18] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [21] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [22] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [23] Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan. Cancer Invest. 2005;23(1):19-25.