Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOTF8DU)

• DOT Name: Glutathione S-transferase Mu 4 (GSTM4)
• Synonyms: EC 2.5.1.18; GST class-mu 4; GST-Mu2; GSTM4-4; Leukotriene C4 synthase GSTM4; EC 4.4.1.20
• Gene Name: GSTM4
• UniProt ID: GSTM4_HUMAN
• PDB ID: 4GTU
• EC Number: 2.5.1.18; 4.4.1.20
• Pfam ID: PF00043 ; PF02798
• Sequence:
  MSMTLGYWDIRGLAHAIRLLLEYTDSSYEEKKYTMGDAPDYDRSQWLNEKFKLGLDFPNL
  PYLIDGAHKITQSNAILCYIARKHNLCGETEEEKIRVDILENQAMDVSNQLARVCYSPDF
  EKLKPEYLEELPTMMQHFSQFLGKRPWFVGDKITFVDFLAYDVLDLHRIFEPNCLDAFPN
  LKDFISRFEGLEKISAYMKSSRFLPKPLYTRVAVWGNK
• Function: Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4. Can also catalyzes the transfer of a glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-docosahexaenoic acid to form maresin conjugate in tissue regeneration 1 (MCTR1), a bioactive lipid mediator that possess potent anti-inflammatory and proresolving actions.
• Tissue Specificity: Expressed in a wide variety of tissues.
• 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:
  Biosynthesis of maresin conjugates in tissue regeneration (MCTR) (R-HSA-9026762)
  Glutathione conjugation (R-HSA-156590)
• BioCyc Pathway: MetaCyc:HS09817-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Glutathione S-transferase Mu 4 (GSTM4) decreases the response to substance of Methotrexate.	[14]
Etoposide	DMNH3PG	Approved	Glutathione S-transferase Mu 4 (GSTM4) affects the response to substance of Etoposide.	[15]
Mitomycin	DMH0ZJE	Approved	Glutathione S-transferase Mu 4 (GSTM4) affects the response to substance of Mitomycin.	[15]
Artesunate	DMR27C8	Approved	Glutathione S-transferase Mu 4 (GSTM4) affects the response to substance of Artesunate.	[16]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	Glutathione S-transferase Mu 4 (GSTM4) affects the metabolism of DNCB.	[17]

13 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 Glutathione S-transferase Mu 4 (GSTM4).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[7]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the activity of Glutathione S-transferase Mu 4 (GSTM4).	[8]
Beta-carotene	DM0RXBT	Approved	Beta-carotene decreases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[1]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Glutathione S-transferase Mu 4 (GSTM4).	[13]

1 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 Glutathione S-transferase Mu 4 (GSTM4).	[3]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [6] 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.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] Simulation of interindividual differences in inactivation of reactive para-benzoquinone imine metabolites of diclofenac by glutathione S-transferases in human liver cytosol. Toxicol Lett. 2016 Jul 25;255:52-62.
• [9] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Microphysiological system modeling of ochratoxin A-associated nephrotoxicity. Toxicology. 2020 Nov;444:152582. doi: 10.1016/j.tox.2020.152582. Epub 2020 Sep 6.
• [14] The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells. PLoS One. 2013 May 13;8(5):e63276. doi: 10.1371/journal.pone.0063276. Print 2013.
• [15] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [16] Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate. In Vivo. 2005 Jan-Feb;19(1):225-32.
• [17] Isolation and analysis of the gene and cDNA for a human Mu class glutathione S-transferase, GSTM4. J Biol Chem. 1993 Aug 15;268(23):16958-65.