Drug Information

Drug (ID: DG00029) and It's Reported Resistant Information

• Name: Glutathione
• Synonyms: Glutathione; 70-18-8; Glutathion; Isethion; Tathion; Glutathione-SH; Glutinal; reduced glutathione; Neuthion; Deltathione; Copren; L-Glutathione reduced; Glutide; Tathione; Triptide; Ledac; Glutatione; GSH; Glutatiol; Panaron; gamma-L-Glutamyl-L-cysteinylglycine; Glutathione SH; L-Glutatione; Glutathione (reduced); Agifutol S; L-gamma-glutamyl-L-cysteinylglycine; gamma-L-glutamyl-L-cysteinyl-glycine; 5-L-Glutamyl-L-cysteinylglycine; Glutathione [JAN]; glutathione red; gamma-L-Glutamylcysteinylglycine; red. glutathione
• Indication:
  In total 1 Indication(s)
  Human immunodeficiency virus disease [ICD-11: 1C60-1C62]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Bladder cancer [ICD-11: 2C94]; [2]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Astrocytoma [ICD-11: 2F36]; [3]
• Target: Enzyme unspecific (Enz); NOUNIPROTAC; [1]
• Formula: C10H17N3O6S
• IsoSMILES: C(CC(=O)N[C@@H](CS)C(=O)NCC(=O)O)[C@@H](C(=O)O)N
• InChI: 1S/C10H17N3O6S/c11-5(10(18)19)1-2-7(14)13-6(4-20)9(17)12-3-8(15)16/h5-6,20H,1-4,11H2,(H,12,17)(H,13,14)(H,15,16)(H,18,19)/t5-,6-/m0/s1
• InChIKey: RWSXRVCMGQZWBV-WDSKDSINSA-N
• PubChem CID: 124886
• ChEBI ID: CHEBI:16856
• TTD Drug ID: D02HFD
• VARIDT ID: DR00039
• INTEDE ID: DR2036
• DrugBank ID: DB00143

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Bladder cancer [ICD-11: 2C94]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder carcinoma [ICD-11: 2C94.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: SABC immunohistochemistry assay
• Mechanism Description: In the 119 cases of bladder carcinoma, the positive rate of HIF-1alpha was 57.9%, the positive rate of GST-Pi was 67.2%. Co-expression of HIF-1alpha and GST-Pi is a object index for judging differentiation and chemoresistance of bladder cancer. GTS-Pi catalyzes the combination of glutathione and drugs to form gh-x, which makes it easier to excrete cells and cause drug resistance of cancer.

Astrocytoma [ICD-11: 2F36]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Chloroquine resistance transporter (CRT) [3]

• Molecule Alteration: Missense mutation; p.K76T
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum C-1Dd2; 5833
• In Vitro Model: Plasmodium falciparum C2GC03; 5833
• In Vitro Model: Plasmodium falciparum C3Dd2; 5833
• In Vitro Model: Plasmodium falciparum C67G8; 5833
• In Vitro Model: Plasmodium falciparum GC03; 5833
• In Vitro Model: Plasmodium falciparum T76k-1Dd2; 5833
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: [3H]-hypoxanthine assay
• Mechanism Description: The k76T mutation in PfCRT generates structural changes that are sufficient to allow GSH transport, but not CQ transport. mutant pfcrt allows enhanced transport of GSH into the parasite's DV. The elevated levels of GSH in the DV reduce the level of free heme available for CQ binding, which mediates the lower susceptibility to CQ in the PfCRT mutant parasites.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Gamma-glutamylcysteine synthetase (GGCS) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium berghei ANkA 2.34; 5823
• In Vitro Model: Plasmodium berghei pbggcs-ko; 5821
• In Vitro Model: Plasmodium berghei pbggcs-oe; 5821
• In Vivo Model: Swiss albino CD-1 female mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: In vivo drug suppressive test assay
• Mechanism Description: To analyze the role of GSH levels in CQ and ART resistance, we generated transgenic Plasmodium berghei parasites either deficient in or overexpressing the gamma-glutamylcysteine synthetase gene (pbggcs) encoding the rate-limiting enzyme in GSH biosynthesis. These lines produce either lower (pbggcs-ko) or higher (pbggcs-oe) levels of GSH than wild type parasites. Recrudescence assays after the parasites have been exposed to a sub-lethal dose of ART showed that parasites with low levels of GSH are more sensitive to ART tre.

References

• Ref 1: Implications of Glutathione Levels in the Plasmodium berghei Response to Chloroquine and Artemisinin. PLoS One. 2015 May 26;10(5):e0128212. doi: 10.1371/journal.pone.0128212. eCollection 2015.
• Ref 2: [Expression and significance of GST-Pi and HIF-1alpha in bladder carcinoma]. Ai Zheng. 2006 Feb;25(2):190-3.
• Ref 3: Glutathione transport: a new role for PfCRT in chloroquine resistance. Antioxid Redox Signal. 2013 Sep 1;19(7):683-95. doi: 10.1089/ars.2012.4625. Epub 2012 Dec 20.