Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW7UB1H)

• DOT Name: Glutathione S-transferase A2 (GSTA2)
• Synonyms: EC 2.5.1.18; GST HA subunit 2; GST class-alpha member 2; GST-gamma; GSTA2-2; GTH2
• Gene Name: GSTA2
• UniProt ID: GSTA2_HUMAN
• PDB ID: 1AGS; 2VCT; 2WJU; 4ACS
• EC Number: 2.5.1.18
• Pfam ID: PF00043 ; PF02798
• Sequence:
  MAEKPKLHYSNIRGRMESIRWLLAAAGVEFEEKFIKSAEDLDKLRNDGYLMFQQVPMVEI
  DGMKLVQTRAILNYIASKYNLYGKDIKEKALIDMYIEGIADLGEMILLLPFSQPEEQDAK
  LALIQEKTKNRYFPAFEKVLKSHGQDYLVGNKLSRADIHLVELLYYVEELDSSLISSFPL
  LKALKTRISNLPTVKKFLQPGSPRKPPMDEKSLEESRKIFRF
• Function: Catalyzes the conjugation of glutathione to a large variety of electrophilic compounds.
• Tissue Specificity: Liver.
• 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:
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  Azathioprine ADME (R-HSA-9748787)
  Glutathione conjugation (R-HSA-156590)
• BioCyc Pathway: MetaCyc:HS01846-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Azathioprine	DMMZSXQ	Approved	Glutathione S-transferase A2 (GSTA2) affects the response to substance of Azathioprine.	[16]

This DOT Affected the Regulation of Drug Effects of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Glutathione	DMAHMT9	Approved	Glutathione S-transferase A2 (GSTA2) affects the metabolism of Glutathione.	[17]
DNCB	DMDTVYC	Phase 2	Glutathione S-transferase A2 (GSTA2) decreases the metabolism of DNCB.	[19]
Mononitrophenol	DM4QO9G	Investigative	Glutathione S-transferase A2 (GSTA2) increases the metabolism of Mononitrophenol.	[19]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Investigative	Glutathione S-transferase A2 (GSTA2) decreases the metabolism of 4-ANDROSTENE-3-17-DIONE.	[19]
PGJ2	DMR2LTC	Investigative	Glutathione S-transferase A2 (GSTA2) affects the metabolism of PGJ2.	[17]
Prostaglandin A2	DMWC4X8	Investigative	Glutathione S-transferase A2 (GSTA2) affects the metabolism of Prostaglandin A2.	[17]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mefenamic acid	DMK7HFI	Approved	Glutathione S-transferase A2 (GSTA2) increases the glutathionylation of Mefenamic acid.	[18]

1 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 A2 (GSTA2).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glutathione S-transferase A2 (GSTA2).	[2]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Glutathione S-transferase A2 (GSTA2).	[3]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Glutathione S-transferase A2 (GSTA2).	[4]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Glutathione S-transferase A2 (GSTA2).	[5]
Mechlorethamine	DM0CVXA	Approved	Mechlorethamine increases the expression of Glutathione S-transferase A2 (GSTA2).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glutathione S-transferase A2 (GSTA2).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Glutathione S-transferase A2 (GSTA2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glutathione S-transferase A2 (GSTA2).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Glutathione S-transferase A2 (GSTA2).	[10]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Glutathione S-transferase A2 (GSTA2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Glutathione S-transferase A2 (GSTA2).	[12]
Bilirubin	DMI0V4O	Investigative	Bilirubin increases the expression of Glutathione S-transferase A2 (GSTA2).	[13]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of Glutathione S-transferase A2 (GSTA2).	[14]
OXYRESVERATROL	DMN7S4L	Investigative	OXYRESVERATROL increases the expression of Glutathione S-transferase A2 (GSTA2).	[15]

References

• [1] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [4] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [5] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [6] Overexpression of GSTA2 protects against cell cycle arrest and apoptosis induced by the DNA inter-strand crosslinking nitrogen mustard, mechlorethamine. J Cell Biochem. 2005 May 15;95(2):339-51. doi: 10.1002/jcb.20440.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Capturing time-dependent activation of genes and stress-response pathways using transcriptomics in iPSC-derived renal proximal tubule cells. Cell Biol Toxicol. 2023 Aug;39(4):1773-1793. doi: 10.1007/s10565-022-09783-5. Epub 2022 Dec 31.
• [9] Gene expression profiling in Caco-2 human colon cells exposed to TCDD, benzo[a]pyrene, and natural Ah receptor agonists from cruciferous vegetables and citrus fruits. Toxicol In Vitro. 2008 Mar;22(2):396-410.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response elementDegradation of Nrf2 by the 26 S proteasome. J Biol Chem. 2003 Feb 14;278(7):4536-41.
• [12] 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.
• [13] Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance. Hepatology. 2004 Oct;40(4):951-60.
• [14] Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). Toxicol Lett. 2012 Jul 7;212(1):18-28. doi: 10.1016/j.toxlet.2012.04.013. Epub 2012 May 1.
• [15] Oxyresveratrol abrogates oxidative stress by activating ERK-Nrf2 pathway in the liver. Chem Biol Interact. 2016 Feb 5;245:110-21.
• [16] Differences among allelic variants of human glutathione transferase A2-2 in the activation of azathioprine. Chem Biol Interact. 2010 Jul 30;186(2):110-7. doi: 10.1016/j.cbi.2010.04.028. Epub 2010 Apr 29.
• [17] Stereoselective conjugation of prostaglandin A2 and prostaglandin J2 with glutathione, catalyzed by the human glutathione S-transferases A1-1, A2-2, M1a-1a, and P1-1. Chem Res Toxicol. 1997 Mar;10(3):310-7. doi: 10.1021/tx9601770.
• [18] Cytochrome P450-mediated bioactivation of mefenamic acid to quinoneimine intermediates and inactivation by human glutathione S-transferases. Chem Res Toxicol. 2014 Dec 15;27(12):2071-81.
• [19] Functional polymorphism of human glutathione transferase A2. Pharmacogenetics. 2004 Feb;14(2):111-6. doi: 10.1097/00008571-200402000-00005.