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Event: 2131

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Conjugation, GSH

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Conjugation, GSH

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
hepatocyte

Organ term

Organ term
liver

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
glutathione binding	glutathione conjugate	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Glutathione conjugation leading to reproductive dysfunction	MolecularInitiatingEvent	Allie Always (send email)	Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Unspecific	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Glutathione, GSH (γ-L-glutamyl-L-cysteinyl-glycine) is a tripeptide synthesized in the intracellular media in a two-step process: bond between glutamic acid and cysteine by the enzyme glutamate-cystein ligase followed by the combination of the resulting dipeptide with a glycin, which is catalyzed by glutathione-synthetase (Lushchak 2012; Hellou, Ross, and Moon 2012; Aquilano, Baldelli, and Ciriolo 2014). In the oxidative stress pathway, GSH is used as substrate by different types and isoforms of enzymes, such as glutathione-reductases (GRs), glutathione-peroxidases (GPXs) and glutathione-transferases (GSTs). Conjugation with glutathione might happen spontaneously, but it is a reaction primarily catalyzed by GSTs (X. Li 2009). This class of enzymes conjugates the tripeptide with toxic chemicals (e.g. arene, oxides, unsaturated carbonyls, organic halides) in order to neutralize them, making them harmless to cells through a Michael addition reaction (Forman, Zhang, and Rinna 2009; Lushchak 2012; Aquilano, Baldelli, and Ciriolo 2014). In this case, the sulfhydryl group acts as a nucleophile and binds, for instance, to an amine group or to an atom such as Cl, as well as attacks electrophilic sites of xenobiotics (X. Li 2009). Conjugates generated from this reaction, overall, are less toxic or are excreted from cells, which causes GSH depletion (Forman, Zhang, and Rinna 2009).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Liquid chromatography–mass spectrometry (Pallante et al. 1986; Plakunov et al. 1987; Pflugmacher et al. 1998; Wiegand et al. 2001a; Dai et al. 2008; Dionisio, Gautam, and Fomsgaard 2019).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Plausible domain of applicability

Taxonomic applicability: The GSH conjugation is known to occur in eukaryotic cells.

Life stage applicability: GSH conjugation can be measured at any stage of life.

Sex applicability: GSH conjugation can be measured in both male and female species.

References

List of the literature that was cited for this KE description. More help

Lushchak, Volodymyr I. 2012. “Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions.” Journal of Amino Acids 2012 (February): 736837.

Hellou, Jocelyne, Neil W. Ross, and Thomas W. Moon. 2012. “Glutathione, Glutathione S-Transferase, and Glutathione Conjugates, Complementary Markers of Oxidative Stress in Aquatic Biota.” Environmental Science and Pollution Research International 19 (6): 2007–23.

Aquilano, Katia, Sara Baldelli, and Maria R. Ciriolo. 2014. “Glutathione: New Roles in Redox Signaling for an Old Antioxidant.” Frontiers in Pharmacology 5 (August): 196.

Forman, Henry Jay, Hongqiao Zhang, and Alessandra Rinna. 2009. “Glutathione: Overview of Its Protective Roles, Measurement, and Biosynthesis.” Molecular Aspects of Medicine 30 (1-2): 1–12.

Li, Xianchun. 2009. “Glutathione and Glutathione-S-Transferase in Detoxification Mechanisms.” In General, Applied and Systems Toxicology. Chichester, UK: John Wiley & Sons, Ltd. https://doi.org/10.1002/9780470744307.gat166.

Pallante, S. L., C. A. Lisek, D. M. Dulik, and C. Fenselau. 1986. “Glutathione Conjugates. Immobilized Enzyme Synthesis and Characterization by Fast Atom Bombardment Mass Spectrometry.” Drug Metabolism and Disposition: The Biological Fate of Chemicals 14 (3): 313–18.

Plakunov, I., T. A. Smolarek, D. L. Fischer, J. C. Wiley Jr, and W. M. Baird. 1987. “Separation by Ion-Pair High-Performance Liquid Chromatography of the Glucuronide, Sulfate and Glutathione Conjugates Formed from Benzo[a]pyrene in Cell Cultures from Rodents, Fish and Humans.” Carcinogenesis 8 (1): 59–66.

Pflugmacher, S., C. Wiegand, A. Oberemm, K. A. Beattie, E. Krause, G. A. Codd, and C. E. Steinberg. 1998. “Identification of an Enzymatically Formed Glutathione Conjugate of the Cyanobacterial Hepatotoxin Microcystin-LR: The First Step of Detoxication.” Biochimica et Biophysica Acta 1425 (3): 527–33.

Wiegand, C., E. Krause, C. Steinberg, and S. Pflugmacher. 2001a. “Toxicokinetics of Atrazine in Embryos of the Zebrafish (Danio Rerio).” Ecotoxicology and Environmental Safety 49 (3): 199–205.

Dai, Ming, Ping Xie, Gaodao Liang, Jun Chen, and Hehua Lei. 2008. “Simultaneous Determination of Microcystin-LR and Its Glutathione Conjugate in Fish Tissues by Liquid Chromatography-Tandem Mass Spectrometry.” Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 862 (1-2): 43–50.

Dionisio, Giuseppe, Maheswor Gautam, and Inge Sindbjerg Fomsgaard. 2019. “Identification of Azoxystrobin Glutathione Conjugate Metabolites in Maize Roots by LC-MS.” Molecules 24 (13). https://doi.org/10.3390/molecules24132473.