Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT4P8DE)

• DTT Name: Glutathione S-transferase A1 (GSTA1)
• Synonyms: GTH1; GSTA1-1; GST-epsilon; GST class-alpha member 1; GST HA subunit 1; Androst-5-ene-3,17-dione isomerase; 13-hydroperoxyoctadecadienoate peroxidase
• Gene Name: GSTA1
• DTT Type: Literature-reported target; [1]
• UniProt ID: GSTA1_HUMAN
• TTD ID: T17221
• EC Number: EC 2.5.1.18
• Sequence:
  MAEKPKLHYFNARGRMESTRWLLAAAGVEFEEKFIKSAEDLDKLRNDGYLMFQQVPMVEI
  DGMKLVQTRAILNYIASKYNLYGKDIKERALIDMYIEGIADLGEMILLLPVCPPEEKDAK
  LALIKEKIKNRYFPAFEKVLKSHGQDYLVGNKLSRADIHLVELLYYVEELDSSLISSFPL
  LKALKTRISNLPTVKKFLQPGSPRKPPMDEKSLEEARKIFRF
• Function: Glutathione S-transferase that catalyzes the nucleophilic attack of the sulfur atom of glutathione on the electrophilic groups of a wide range of exogenous and endogenous compounds (Probable). Involved in the formation of glutathione conjugates of both prostaglandin A2 (PGA2) and prostaglandin J2 (PGJ2). It also catalyzes the isomerization of D5-androstene-3,17-dione (AD) into D4-androstene-3,17-dione and may therefore play an important role in hormone biosynthesis. Through its glutathione-dependent peroxidase activity toward the fatty acid hydroperoxide (13S)-hydroperoxy-(9Z,11E)-octadecadienoate/13-HPODE it is also involved in the metabolism of oxidized linoleic acid.
• 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 - DNA adducts (hsa05204)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Hepatocellular carcinoma (hsa05225)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Heme degradation (R-HSA-189483)
  Azathioprine ADME (R-HSA-9748787)
  Nuclear events mediated by NFE2L2 (R-HSA-9759194)
  Glutathione conjugation (R-HSA-156590)
• BioCyc Pathway: MetaCyc:G66-32542-MON

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Glutathione S-transferase alpha-1 (GSTA1) DME Info
• Gene Name: GSTA1

16 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[2]
Amyl nitrite	DMJKO05	Angina pectoris	BA40	Approved	[3]
Artemisinin	DMOY7W3	Malaria	1F40-1F45	Approved	[4]
Busulfan	DMXYJ9C	Chronic myelogenous leukaemia	2A20.0	Approved	[5]
Cisplatin	DMRHGI9	Adenocarcinoma	2D40	Approved	[6]
Clofibrate	DMPC1J7	Dysbetalipoproteinemia	5C80.2	Approved	[7]
DTI-015	DMXZRW0	Brain cancer	2A00	Approved	[8]
Ethacrynic acid	DM60QMR	Edema	MG29	Approved	[9]
Fosfomycin	DMVGPMX	Bacterial infection	1A00-1C4Z	Approved	[10]
Isosorbide Dinitrate	DMBI4JG	Anal fissure	DB50.0	Approved	[11]
Melphalan	DMOLNHF	Hematologic disease	3C0Z	Approved	[12]
Phenytoin	DMNOKBV	Epilepsy	8A60-8A68	Approved	[13]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[14]
Tacrine	DM51FY6	Alzheimer disease	8A20	Approved	[15]
Thiotepa	DMIZKOP	Breast cancer	2C60-2C65	Approved	[16]
Trabectedin	DMG3Y89	Leiomyosarcoma	2B58	Approved	[17]

2 Clinical Trial Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Selinexor	DMBD4K3	Multiple myeloma	2A83	Phase 3	[18]
PEITC	DMOMN31	Prostate cancer	2C82.0	Phase 2	[19]

References

• [1] Glutathione S-transferase A1 (GSTA1) as a marker of acetaminophen-induced hepatocyte injury in vitro. Toxicol Mech Methods. 2017 Jul;27(6):401-407.
• [2] Retinoid X receptor alpha regulates the expression of glutathione s-transferase genes and modulates acetaminophen-glutathione conjugation in mouse liver. Mol Pharmacol. 2005 Dec;68(6):1590-6.
• [3] Subunit specificity and organ distribution of glutathione transferase-catalysed S-nitrosoglutathione formation from alkyl nitrites in the rat. Biochem Pharmacol. 1997 Jan 10;53(1):117-20.
• [4] Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.
• [5] Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004 Sep 1;104(5):1574-7.
• [6] Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin. Mol Cancer Ther. 2008 Oct;7(10):3247-55.
• [7] Characterization and formation of the glutathione conjugate of clofibric acid. Drug Metab Dispos. 1995 Jan;23(1):119-23.
• [8] Expression of glutathione S-transferase T1 (GSTT1) in human brain tumours. Histol Histopathol. 2006 Nov;21(11):1199-207.
• [9] Purification and biochemical properties of glutathione S-transferase from Lactuca sativa. J Biochem Mol Biol. 2005 Mar 31;38(2):232-7.
• [10] Formation of an adduct between fosfomycin and glutathione: a new mechanism of antibiotic resistance in bacteria. Antimicrob Agents Chemother. 1988 Oct;32(10):1552-6.
• [11] Nitroglycerin and isosorbide dinitrate stimulation of glutathione disulfide efflux from perfused rat liver. Biochem Pharmacol. 1989 Nov 1;38(21):3807-10.
• [12] Metabolism of melphalan by rat liver microsomal glutathione S-transferase. Chem Biol Interact. 2005 Apr 15;152(2-3):101-6.
• [13] Comparison of basal glutathione S-transferase activities and of the influence of phenobarbital, butylated hydroxy-anisole or 5,5'-diphenylhydantoin on enzyme activity in male rodents. Comp Biochem Physiol C. 1987;88(1):91-3.
• [14] Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. J Biol Chem. 2001 Aug 31;276(35):33061-5.
• [15] Combined glutathione-S-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity. Clin Pharmacol Ther. 2000 Apr;67(4):432-7.
• [16] Differential catalytic efficiency of allelic variants of human glutathione S-transferase Pi in catalyzing the glutathione conjugation of thiotepa. Arch Biochem Biophys. 1999 Jun 1;366(1):89-94.
• [17] In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis, Trabectidin), a novel marine anti-cancer drug. Invest New Drugs. 2006 Jan;24(1):3-14.
• [18] FDA label of Selinexor. The 2020 official website of the U.S. Food and Drug Administration.
• [19] Pharmacokinetics and pharmacodynamics of phenethyl isothiocyanate: implications in breast cancer prevention. AAPS J. 2014 Jul;16(4):705-13.