Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ3REE3)

• DOT Name: Glutathione S-transferase A3 (GSTA3)
• Synonyms: EC 2.5.1.18; GST class-alpha member 3; Glutathione S-transferase A3-3
• Gene Name: GSTA3
• UniProt ID: GSTA3_HUMAN
• PDB ID: 1TDI; 2VCV
• EC Number: 2.5.1.18
• Pfam ID: PF00043 ; PF02798
• Sequence:
  MAGKPKLHYFNGRGRMEPIRWLLAAAGVEFEEKFIGSAEDLGKLRNDGSLMFQQVPMVEI
  DGMKLVQTRAILNYIASKYNLYGKDIKERALIDMYTEGMADLNEMILLLPLCRPEEKDAK
  IALIKEKTKSRYFPAFEKVLQSHGQDYLVGNKLSRADISLVELLYYVEELDSSLISNFPL
  LKALKTRISNLPTVKKFLQPGSPRKPPADAKALEEARKIFRF
• Function: Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Catalyzes isomerization reactions that contribute to the biosynthesis of steroid hormones. Efficiently catalyze obligatory double-bond isomerizations of delta(5)-androstene-3,17-dione and delta(5)-pregnene-3,20-dione, precursors to testosterone and progesterone, respectively. Has substantial activity toward aflatoxin B1-8,9-epoxide.
• 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:
  NFE2L2 regulating anti-oxidant/detoxification enzymes (R-HSA-9818027)
  Glutathione conjugation (R-HSA-156590)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Glutathione S-transferase A3 (GSTA3) increases the chemical synthesis of Progesterone.	[13]
Nevirapine	DM6HX9B	Approved	Glutathione S-transferase A3 (GSTA3) increases the glutathionylation of Nevirapine.	[14]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Investigative	Glutathione S-transferase A3 (GSTA3) increases the chemical synthesis of 4-ANDROSTENE-3-17-DIONE.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
CTK1G9578	DMI3J0F	Investigative	Glutathione S-transferase A3 (GSTA3) affects the metabolism of CTK1G9578.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Glutathione S-transferase A3 (GSTA3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutathione S-transferase A3 (GSTA3).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glutathione S-transferase A3 (GSTA3).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glutathione S-transferase A3 (GSTA3).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Glutathione S-transferase A3 (GSTA3).	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Glutathione S-transferase A3 (GSTA3).	[6]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the activity of Glutathione S-transferase A3 (GSTA3).	[7]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Glutathione S-transferase A3 (GSTA3).	[2]
Atazanavir	DMSYRBX	Approved	Atazanavir decreases the expression of Glutathione S-transferase A3 (GSTA3).	[2]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Glutathione S-transferase A3 (GSTA3).	[9]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Glutathione S-transferase A3 (GSTA3).	[10]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Glutathione S-transferase A3 (GSTA3).	[11]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of Glutathione S-transferase A3 (GSTA3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glutathione S-transferase A3 (GSTA3).	[8]

References

• [1] 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.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Butyrate interacts with benzo[a]pyrene to alter expression and activities of xenobiotic metabolizing enzymes involved in metabolism of carcinogens within colon epithelial cell models. Toxicology. 2019 Jan 15;412:1-11.
• [11] 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.
• [12] 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.
• [13] Human glutathione S-transferase A (GSTA) family genes are regulated by steroidogenic factor 1 (SF-1) and are involved in steroidogenesis. FASEB J. 2013 Aug;27(8):3198-208. doi: 10.1096/fj.12-222745. Epub 2013 May 6.
• [14] Different Reactive Metabolites of Nevirapine Require Distinct Glutathione S-Transferase Isoforms for Bioinactivation. Chem Res Toxicol. 2016 Dec 19;29(12):2136-2144. doi: 10.1021/acs.chemrestox.6b00250. Epub 2016 Nov 28.
• [15] Targeting human glutathione transferase A3-3 attenuates progesterone production in human steroidogenic cells. Biochem J. 2008 Aug 15;414(1):103-9. doi: 10.1042/BJ20080397.