Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTANW3TJ)

• DOT Name: Glutathione S-transferase theta-2 (GSTT2)
• Synonyms: EC 2.5.1.18; GST class-theta-2
• Gene Name: GSTT2
• Related Disease:
  Non-small-cell lung cancer
  Usher syndrome type 1D
  Charcot marie tooth disease
  Colon cancer
  Colon carcinoma
  facioscapulohumeral muscular dystrophy
  Familial multiple trichoepithelioma
  Gastroesophageal reflux disease
  High blood pressure
  Schizophrenia
  Colorectal carcinoma
  Colorectal neoplasm
• UniProt ID: GST2_HUMAN
• PDB ID: 4MPF
• EC Number: 2.5.1.18
• Pfam ID: PF00043 ; PF02798
• Sequence:
  MGLELFLDLVSQPSRAVYIFAKKNGIPLELRTVDLVKGQHKSKEFLQINSLGKLPTLKDG
  DFILTESSAILIYLSCKYQTPDHWYPSDLQARARVHEYLGWHADCIRGTFGIPLWVQVLG
  PLIGVQVPKEKVERNRTAMDQALQWLEDKFLGDRPFLAGQQVTLADLMALEELMQPVALG
  YELFEGRPRLAAWRGRVEAFLGAELCQEAHSIILSILEQAAKKTLPTPSPEAYQAMLLRI
  ARIP
• Function: Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Has a sulfatase activity.
• Tissue Specificity: Expressed at low levels in liver. In lung, expressed at low levels in ciliated bronchiolar cells, alveolar macrophages and alveolar type II 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: Glutathione conjugation (R-HSA-156590)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Genetic Variation	[1]
Usher syndrome type 1D	DISNK779	Definitive	Genetic Variation	[2]
Charcot marie tooth disease	DIS3BT2L	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[4]
facioscapulohumeral muscular dystrophy	DISSE0H0	Strong	Biomarker	[5]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[6]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Altered Expression	[6]
High blood pressure	DISY2OHH	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[9]
Colorectal neoplasm	DISR1UCN	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Glutathione S-transferase theta-2 (GSTT2) affects the response to substance of Etoposide.	[22]
Artesunate	DMR27C8	Approved	Glutathione S-transferase theta-2 (GSTT2) affects the response to substance of Artesunate.	[23]

1 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 Glutathione S-transferase theta-2 (GSTT2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Glutathione S-transferase theta-2 (GSTT2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glutathione S-transferase theta-2 (GSTT2).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glutathione S-transferase theta-2 (GSTT2).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Glutathione S-transferase theta-2 (GSTT2).	[14]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Glutathione S-transferase theta-2 (GSTT2).	[15]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Glutathione S-transferase theta-2 (GSTT2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glutathione S-transferase theta-2 (GSTT2).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Glutathione S-transferase theta-2 (GSTT2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glutathione S-transferase theta-2 (GSTT2).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Glutathione S-transferase theta-2 (GSTT2).	[20]
Paraoxon	DMN4ZKC	Investigative	Paraoxon increases the expression of Glutathione S-transferase theta-2 (GSTT2).	[21]

References

• [1] A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of non-small cell lung cancer in smokers.Carcinogenesis. 2008 Jun;29(6):1164-9. doi: 10.1093/carcin/bgn020. Epub 2008 Feb 6.
• [2] Fine genetic and comparative mapping of the deafness mutation Ames waltzer on mouse chromosome 10.Genomics. 1998 Jun 1;50(2):260-6. doi: 10.1006/geno.1998.5298.
• [3] Analysis of neural crest cells from Charcot-Marie-Tooth disease patients demonstrates disease-relevant molecular signature.Neuroreport. 2017 Sep 6;28(13):814-821. doi: 10.1097/WNR.0000000000000831.
• [4] In vitro-fermented raw and roasted walnuts induce expression of CAT and GSTT2 genes, growth inhibition, and apoptosis in LT97 colon adenoma cells.Nutr Res. 2017 Nov;47:72-80. doi: 10.1016/j.nutres.2017.09.004. Epub 2017 Sep 18.
• [5] Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress.Neuromuscul Disord. 2003 May;13(4):322-33. doi: 10.1016/s0960-8966(02)00284-5.
• [6] Constitutively Higher Level of GSTT2 in Esophageal Tissues From African Americans Protects Cells Against DNA Damage.Gastroenterology. 2019 Apr;156(5):1404-1415. doi: 10.1053/j.gastro.2018.12.004. Epub 2018 Dec 19.
• [7] A custom rat and baboon hypertension gene array to compare experimental models.Exp Biol Med (Maywood). 2012 Jan;237(1):99-110. doi: 10.1258/ebm.2011.011188. Epub 2012 Jan 6.
• [8] Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia.Mol Psychiatry. 2010 Oct;15(10):1023-33. doi: 10.1038/mp.2009.53. Epub 2009 Jun 16.
• [9] GSTT2 promoter polymorphisms and colorectal cancer risk.BMC Cancer. 2007 Jan 25;7:16. doi: 10.1186/1471-2407-7-16.
• [10] 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.
• [11] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Human drug metabolism genes in parathion-and estrogen-treated breast cells. Int J Mol Med. 2007 Dec;20(6):875-81.
• [14] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [15] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [16] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [17] Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics. 2011 Jun 29;12:333.
• [18] 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.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Oxidative stress resulting from exposure of a human salivary gland cells to paraoxon: an in vitro model for organophosphate oral exposure. Toxicol In Vitro. 2014 Aug;28(5):715-21. doi: 10.1016/j.tiv.2014.01.009. Epub 2014 Jan 29.
• [22] 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.
• [23] 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.