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Key Event Title
Decreased protection against oxidative stress
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Oxidative stress and Developmental impairment in learning and memory||KeyEvent||Brendan Ferreri-Hanberry (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
|Oxidative stress in chronic kidney disease||KeyEvent||Brendan Ferreri-Hanberry (send email)||Under development: Not open for comment. Do not cite|
|All life stages|
Key Event Description
High levels reactive oxygen species (ROS) can be very damaging to cells and molecules within the cell. As a result, the cell has important defense mechanisms to protect itself from ROS, such as glutathione and selenoenzymes.
Glutathione (GSH) is the most abundant low molecular mass thiol compound synthesized in cells, reaching intracellular concentrations of 1–10 mM, and is the major antioxidant and redox buffer in human cells. In fact, GSH serves as a reducing agent for ROS and other unstable molecules generated by catalytic systems, including glutathione peroxidase (GPx)(Forman, 2009).
Selenium plays a crucial role in antioxidant defense, as one Se atom is absolutely required at the active site of all selenoenzymes, such as GPx and thioredoxin reductase (TrxR), in the form of selenocystein (Rayman, 2000). GPx is an antioxidant enzyme that, in the presence of tripeptide GSH, adds two electrons to reduce H2O2 and lipid peroxides to water and lipid alcohols, respectively, while simultaneously oxidizing GSH to glutathione disulfide. The GPx/GSH system is thought to be a major defense in low-level oxidative stress, and decreased GPx activity or GSH levels may lead to the absence of adequate H2O2 and lipid peroxides detoxification, which may be converted to OH-radicals and lipid peroxyl radicals, respectively, by transition metals (Fe2+) (Brigelius-Flohe, 2013). Thioredoxin reductase (TrxR) is essential for maintaining intracellular redox status. The expression of this small (12 kDa) ubiquitous thiol-active protein is induced by ROS and an elevated serum level may indicate a state of oxidative stress. In this regard, TrxR, a NADPH-dependent lipid hydroperoxide reductase, uses NADPH to maintain the levels of reduced Trx via a mechanism similar to that used by GR to maintain GSH levels, contributing to the maintenance of thiol redox homeostasis in proteins. Importantly, the inhibition of TrxR impairs the cyclical regeneration of Trx activity, as Trx remains in the oxidized state (Bjornstedt, 1995, Zhong, 2002). Other, less studied selenoproteins, such as SelP, H, K, S, R, and W selenoproteins, play a role in antioxidant defense (Pisoschi, 2015, Reeves, 2009)
How It Is Measured or Detected
- Glutathione (GSH) depletion. GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html)
- Reduction of GPx activity. The activity of GPx can be measured by a colorimetric assay, using a commercially available kit (e.g., Abcam ab102530)
- Reduction of TrxR activity. The activity of TrxR can be measured by a colorimetric assay, using a commercially available kit (e.g., Abcam ab83463)
- Reduction of Selenoprotein R activity. The methionine sulfoxide reductase activity of SelR can be measured by HPLC (Chen, 2013)
- Selenoprotein P depletion. The depletion in SelP can be measured using an ELISA (e.g., MyBiosource #MBS9301054)
- Selenoprotein W depletion. The depletion in SelW can be measured using an ELISA (e.g., MyBiosource #MBS9312544)
- Selenoprotein S depletion. The depletion in SelS can be measured using an ELISA (e.g., MyBiosource #MBS9306607)
- Selenoprotein H and K depletion. The depletion in SelH and K can be measured by western blotting (Lee, 2015, Novoselov, 2007)
Domain of Applicability
Glutathione, GPx and TrxR are present in bacteria, archea, algae, and in the majority of animals, including humans.
Evidence for Perturbation by Stressor
Bjornstedt, M., Hamberg, M., Kumar, S., Xue, J., Holmgre, A. (1995) Human thioredoxin reductase directly reduces lipid hydroperoxides by nadph and selenocysteine strongly stimulates the reaction via catalytically generated selenols. J Biol Chem 270, 11761-11764.
Brigelius-Flohe, R., Maiorino, M. (2013) Glutathione peroxidases. Biochim Biophys Acta 1830, 3289-3303.
Chen, P. et al. (2013) Direct Interaction of Selenoprotein R with Clusterin and Its Possible Role in Alzheimer's Disease. PLoS One 8, e66384.
Forman, H.J., Zhang, H., Rinna, A. (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med 30, 1-12.
Lee, J.H. et al. (2015) Selenoprotein S-dependent Selenoprotein K Binding to p97(VCP) Protein Is Essential for Endoplasmic Reticulum-associated Degradation. J Biol Chem 290, 29941-29952.
Novoselov, S.V. et al. (2007) Selenoprotein H is a nucleolar thioredoxin-like protein with a unique expression pattern. J Biol Chem 282, 11960-11968.
Pisoschi, A.M., Pop, A. (2015) The role of antioxidants in the chemistry of oxidative stress: A review. Eur J Med Chem 97, 55-74.
Rayman, M.P. (2000) The importance of selenium to human health. Lancet 356, 233-241.
Reeves, M.A., Hoffmann, P.R. (2009) The human selenoproteome: recent insights into functions and regulation. Cell Mol Life Sci 66, 2457-2478.
Zhong, L., Holmgren, A. (2002) Mammalian thioredoxin reductases as hydroperoxide reductases. Methods Enzymol 347, 236-243.