Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYK80JA)

• DOT Name: Glutathione S-transferase 3, mitochondrial (MGST3)
• Synonyms: GST-3; EC 2.5.1.-; Glutathione peroxidase MGST3; EC 1.11.1.-; LTC4 synthase MGST3; EC 4.4.1.20
• Gene Name: MGST3
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: MGST3_HUMAN
• EC Number: 1.11.1.-; 2.5.1.-; 4.4.1.20
• Pfam ID: PF01124
• Sequence:
  MAVLSKEYGFVLLTGAASFIMVAHLAINVSKARKKYKVEYPIMYSTDPENGHIFNCIQRA
  HQNTLEVYPPFLFFLAVGGVYHPRIASGLGLAWIVGRVLYAYGYYTGEPSKRSRGALGSI
  ALLGLVGTTVCSAFQHLGWVKSGLGSGPKCCH
• Function: Displays both glutathione S-transferase and glutathione peroxidase activities toward oxyeicosanoids, as part of cellular detoxification as well as synthesis of bioactive metabolites. Catalyzes conjugate addition of reduced glutathione to the alpha, beta-unsaturated C=C carbonyl group of eisosanoids such as leukotriene A4 and 15-deoxy-Delta12,14-prostaglandin J2 to form GSH adducts relevant to the inflammatory response. Catalyzes glutathione-dependent reduction of eicosanoid peroxides to yield the corresponding eicosanoid hydroxides.
• Tissue Specificity: Predominantly expressed in heart, skeletal muscle, and adrenal cortex. Also found in brain, placenta, liver, kidney, pancreas, thyroid, testis and ovary. Almost absent in lung, thymus and peripheral blood leukocytes. Expressed in mast cells.
• 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Artesunate	DMR27C8	Approved	Glutathione S-transferase 3, mitochondrial (MGST3) affects the response to substance of Artesunate.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Glutathione S-transferase 3, mitochondrial (MGST3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glutathione S-transferase 3, mitochondrial (MGST3).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Glutathione S-transferase 3, mitochondrial (MGST3).	[17]

17 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 3, mitochondrial (MGST3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[13]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[20]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Glutathione S-transferase 3, mitochondrial (MGST3).	[21]

References

• [1] Evaluation of the microsomal glutathione S-transferase 3 (MGST3) locus on 1q23 as a Type 2 diabetes susceptibility gene in Pima Indians.Hum Genet. 2003 Sep;113(4):353-8. doi: 10.1007/s00439-003-0980-y. Epub 2003 Jul 26.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] 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.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] 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.
• [8] 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.
• [9] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [10] 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.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [13] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [14] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] 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.
• [19] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.
• [22] 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.