ListMoto - Glutathione

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(GSH) is an important antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione
is capable of preventing damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides, and heavy metals.[2] It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and the amine group of cysteine, and the carboxyl group of cysteine is attached by normal peptide linkage to a glycine. Thiol
groups are reducing agents, existing at a concentration around 5 mM in animal cells. Glutathione
reduces disulfide bonds formed within cytoplasmic proteins to cysteines by serving as an electron donor. In the process, glutathione is converted to its oxidized form, glutathione disulfide (GSSG), also called L-(–)-glutathione. Once oxidized, glutathione can be reduced back by glutathione reductase, using NADPH
as an electron donor.[3] The ratio of reduced glutathione to oxidized glutathione within cells is often used as a measure of cellular oxidative stress.[4][5]


1 Biosynthesis 2 Function

2.1 Function in animals 2.2 Function in plants

3 Bioavailability
and supplementation 4 Methods to determine glutathione

4.1 Small-molecule-based glutathione probes

4.1.1 Ellman's reagent
Ellman's reagent
and monobromobimane 4.1.2 Monochlorobimane 4.1.3 5-Chloromethylfluorescein diacetate (CMFDA) 4.1.4 ThiolQuant Green 4.1.5 RealThiol

4.2 Protein-based glutathione probes

5 Other biological implications

5.1 Lead 5.2 Cancer 5.3 Cystic fibrosis 5.4 Alzheimer's disease (AD)

6 Uses

6.1 Winemaking 6.2 Cosmetics

7 Importance of gamma-glutamylcysteine as a precursor for glutathione synthesis 8 See also 9 References 10 Further reading 11 External links

Biosynthesis[edit] The biosynthesis pathway for glutathione is found in some bacteria, such as cyanobacteria and proteobacteria, but is missing in many other bacteria. Most eukaryotes, including humans, synthesize glutathione, but some do not, such as Leguminosae, Entamoeba, and Giardia. The only archaea that make glutathione are halobacteria.[6][7] Glutathione
is not an essential nutrient for humans, since it can be synthesized in the body from the amino acids L-cysteine, L-glutamic acid, and glycine; it does not have to be present as a supplement in the diet. The sulfhydryl group (SH) of cysteine serves as a proton donor and is responsible for its biological activity. Cysteine
is the rate-limiting factor in cellular glutathione biosynthesis, since this amino acid is relatively rare in foods. Cells make glutathione in two adenosine triphosphate-dependent steps:

First, gamma-glutamylcysteine is synthesized from L-glutamate and cysteine via the enzyme gamma-glutamylcysteine synthetase (glutamate cysteine ligase, GCL). This reaction is the rate-limiting step in glutathione synthesis.[8] Second, glycine is added to the C-terminal of gamma-glutamylcysteine via the enzyme glutathione synthetase.

Animal glutamate cysteine ligase (GCL) is a heterodimeric enzyme composed of a catalytic and a modulatory subunit. The catalytic subunit is necessary and sufficient for all GCL enzymatic activity, whereas the modulatory subunit increases the catalytic efficiency of the enzyme. Mice lacking the catalytic subunit (i.e., lacking all de novo GSH synthesis) die before birth.[9] Mice lacking the modulatory subunit demonstrate no obvious phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.[10][11][12] While all animal cells are capable of synthesizing glutathione, glutathione synthesis in the liver has been shown to be essential. GCLC knockout mice die within a month of birth due to the absence of hepatic GSH synthesis.[13][14] Major transport into the blood stream is driven by an electrochemical gradient, specifically through the transport proteins RcGshT and RsGshT.[15] Similarly, glutathione S-conjugates, synthesized hepatically, feature preferential secretion into bile.[14][16] The plant glutamate cysteine ligase (GCL) is a redox-sensitive homodimeric enzyme, conserved in the plant kingdom.[17] In an oxidizing environment, intermolecular disulfide bridges are formed and the enzyme switches to the dimeric active state. The midpoint potential of the critical cysteine pair is -318 mV. In addition to the redox-dependent control, the plant GCL enzyme is feedback inhibited by glutathione.[18] GCL is exclusively located in plastids, and glutathione synthetase (GS) is dual-targeted to plastids and cytosol, thus GSH and gamma-glutamylcysteine are exported from the plastids.[19] Both glutathione biosynthesis enzymes are essential in plants; knock-outs of GCL and GS are lethal to embryo and seedling.[20] Function[edit] Glutathione
exists in both reduced (GSH) and oxidized (GSSG) states. In the reduced state, the thiol group of cysteine is able to donate a reducing equivalent (H++ e−) to other molecules, such as reactive oxygen species to neutralize them, or to protein cysteines to maintain their reduced forms. With donating an electron, glutathione itself becomes reactive and readily reacts with another reactive glutathione to form glutathione disulfide (GSSG). Such a reaction is probable due to the relatively high concentration of glutathione in cells (up to 7 mM in the liver).[21] Generally, interactions between GSH and other molecules with higher relative electrophilicity deplete GSH levels within the cell. An exception to this case involves the sensitivity of GSH to the electrophilic compound's relative concentration. In high concentrations, the organic molecule diethyl maleate fully depleted GSH levels in cells. However, in low concentrations, a minor decrease in cellular GSH levels was followed by a two-fold increase.[22][23] GSH can be regenerated from GSSG by the enzyme glutathione reductase (GSR):[3] NADPH
reduces FAD present in GSR to produce a transient FADH-anion. This anion then quickly breaks a disulfide bond (Cys58 – Cys63) and leads to Cys63's nucleophilically attacking the nearest sulfide unit in the GSSG molecule (promoted by His467), which creates a mixed disulfide bond (GS-Cys58) and a GS-anion. His467 of GSR then protonates the GS-anion to form the first GSH. Next, Cys63 nucleophilically attacks the sulfide of Cys58, releasing a GS-anion, which, in turn, picks up a solvent proton and is released from the enzyme, thereby creating the second GSH. So, for every GSSG and NADPH, two reduced GSH molecules are gained, which can again act as antioxidants scavenging reactive oxygen species in the cell. In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH) and less than 10% exists in the disulfide form (GSSG). An increased GSSG-to-GSH ratio is considered indicative of oxidative stress.[24] Glutathione
has multiple functions:

It maintains levels of reduced glutaredoxin and glutathione peroxidase.[25] It is one of the major endogenous antioxidants produced by the cells, participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as vitamins C and E in their reduced (active) forms.[26][27][28] Regulation of the nitric oxide cycle is critical for life, but can be problematic if unregulated.[29] Glutathione
enhances the function of citrulline as part of the nitric oxide cycle. It is used in metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Thus, every system in the body can be affected by the state of the glutathione system, especially the immune system, the nervous system, the gastrointestinal system, and the lungs.[citation needed] It has a vital function in iron metabolism. Yeast cells depleted of GSH or containing toxic levels of GSH show an intense iron starvation-like response and impairment of the activity of extramitochondrial ISC enzymes thus inhibiting oxidative endoplasmic reticulum folding, followed by death.[30] It has roles in progression of the cell cycle, including cell death.[5] GSH levels regulate redox changes to nuclear proteins necessary for the initiation of cell differentiation. Differences in GSH levels also determine the expressed mode of cell death, being either apoptosis or cell necrosis. Manageably low levels result in the systematic breakage of the cell whereas excessively low levels result in rapid cell death.[31]

Function in animals[edit] GSH is known as a substrate in conjugation reactions, which is catalyzed by glutathione S-transferase enzymes in cytosol, microsomes, and mitochondria. However, GSH is also capable of participating in nonenzymatic conjugation with some chemicals. In the case of N-acetyl-p-benzoquinone imine (NAPQI), the reactive cytochrome P450-reactive metabolite formed by paracetamol (acetaminophen), which becomes toxic when GSH is depleted by an overdose of acetaminophen, glutathione is an essential antidote to overdose. Glutathione
conjugates to NAPQI
and helps to detoxify it. In this capacity, it protects cellular protein thiol groups, which would otherwise become covalently modified; when all GSH has been spent, NAPQI
begins to react with the cellular proteins, killing the cells in the process. The preferred treatment for an overdose of this painkiller is the administration (usually in atomized form) of N-acetyl-L-cysteine (often as a preparation called Mucomyst[32]), which is processed by cells to L-cysteine and used in the de novo synthesis of GSH. Glutathione
(GSH) participates in leukotriene synthesis and is a cofactor for the enzyme glutathione peroxidase. It is also important as a hydrophilic molecule that is added to lipophilic toxins and waste in the liver during biotransformation before they can become part of the bile. Glutathione
is also needed for the detoxification of methylglyoxal, a toxin produced as a byproduct of metabolism. This detoxification reaction is carried out by the glyoxalase system. Glyoxalase I
Glyoxalase I
(EC catalyzes the conversion of methylglyoxal and reduced glutathione to S-D-lactoyl-glutathione. Glyoxalase II (EC catalyzes the hydrolysis of S-D-lactoyl-glutathione to glutathione and D-lactic acid. Glutathione, along with oxidized glutathione (GSSG) and S-nitrosoglutathione
(GSNO), have been found to bind to the glutamate recognition site of the NMDA and AMPA
receptors (via their γ-glutamyl moieties), and may be endogenous neuromodulators.[33][34][35] At millimolar concentrations, they may also modulate the redox state of the NMDA receptor
NMDA receptor
complex.[34] Glutathione
has been found to bind to and activate ionotropic receptors that are different from any other excitatory amino acid receptor, and which may constitute glutathione receptors, potentially making it a neurotransmitter.[36] Glutathione is also able to activate the purinergic P2X7 receptor from Müller glia, inducing acute calcium transient signals and GABA release from both retinal neurons and glial cells.[37][38] Function in plants[edit] In plants, glutathione is crucial for biotic and abiotic stress management. It is a pivotal component of the glutathione-ascorbate cycle, a system that reduces poisonous hydrogen peroxide.[39] It is the precursor of phytochelatins, glutathione oligomers that chelate heavy metals such as cadmium.[40] Glutathione
is required for efficient defence against plant pathogens such as Pseudomonas syringae and Phytophthora
brassicae.[41] Adenylyl-sulfate reductase, an enzyme of the sulfur assimilation pathway, uses glutathione as an electron donor. Other enzymes using glutathione as a substrate are glutaredoxins. These small oxidoreductases are involved in flower development, salicylic acid, and plant defence signalling.[42] Bioavailability
and supplementation[edit] Systemic bioavailability of orally consumed glutathione is poor because the molecule, a tripeptide, is the substrate of proteases (peptidases) of the alimentary canal, and due to the absence of a specific carrier of glutathione at the level of cell membrane.[43][44] Because direct supplementation of glutathione is not always successful, supply of the raw nutritional materials used to generate GSH, such as cysteine and glycine, may be more effective at increasing glutathione levels. Other antioxidants such as ascorbic acid (vitamin C) may also work synergistically with glutathione, preventing depletion of either. The glutathione-ascorbate cycle, which works to detoxify hydrogen peroxide (H2O2), is one very specific example of this phenomenon. Additionally, compounds such as N-acetylcysteine[45] (NAC) and alpha lipoic acid[46] (ALA, not to be confused with the unrelated alpha-linolenic acid) are both capable of helping to regenerate glutathione levels. NAC in particular is commonly used to treat overdose of acetaminophen, a type of potentially fatal poisoning which is harmful in part due to severe depletion of glutathione levels. Calcitriol
(1,25-dihydroxyvitamin D3), the active metabolite of vitamin D3, after being synthesized from calcifediol in the kidney, increases glutathione levels in the brain and appears to be a catalyst for glutathione production.[47] It takes about ten days for the body to process vitamin D3 into calcitriol.[48] S-adenosylmethionine (SAMe), a cosubstrate involved in methyl group transfer, has also been shown to increase cellular glutathione content in persons suffering from a disease-related glutathione deficiency.[49][50][51] Low glutathione is commonly observed in wasting and negative nitrogen balance, as seen in cancer, HIV/AIDS, sepsis, trauma, burns, and athletic overtraining. Low levels are also observed in periods of starvation. These effects are hypothesized to be influenced by the higher glycolytic activity associated with cachexia, which result from reduced levels of oxidative phosphorylation.[52][53] Methods to determine glutathione[edit] Small-molecule-based glutathione probes[edit] Ellman's reagent
Ellman's reagent
and monobromobimane[edit] Reduced glutathione may be visualized using Ellman's reagent
Ellman's reagent
or bimane derivatives such as monobromobimane. The monobromobimane method is more sensitive. In this procedure, cells are lysed and thiols extracted using a HCl buffer. The thiols are then reduced with dithiothreitol and labelled by monobromobimane. Monobromobimane becomes fluorescent after binding to GSH. The thiols are then separated by HPLC and the fluorescence quantified with a fluorescence detector. Monochlorobimane[edit] Monochlorobimane can be used to quantify glutathione in vivo. The quantification is done by confocal laser scanning microscopy after application of the dye to living cells.[54] This quantification process relies on measuring the rates of fluorescence changes and is limited to plant cells. 5-Chloromethylfluorescein diacetate (CMFDA)[edit] CMFDA was initially used as a cell tracker. Unfortunately, it has also been mistakenly used as a glutathione probe. Unlike monochlorobimane, whose fluorescence increases upon reacting with glutathione, the fluorescence increase of CMFDA is due to the hydrolysis of the acetate groups inside cells. Although CMFDA may react with glutathione in cells, the fluorescence increase does not reflect the reaction. Therefore, studies using CMFDA as a glutathione probe should be revisited and re-interpreted.[55][56] ThiolQuant Green[edit] The major limitation of these bimane-based probes and many other reported probes is that these probes are based on irreversible chemical reactions with glutathione, which renders these probes incapable of monitoring the real-time glutathione dynamics. Recently, the first reversible reaction based fluorescent probe-ThiolQuant Green (TQG)-for glutathione was reported.[57] ThiolQuant Green can not only perform high resolution measurements of glutathione levels in single cells using a confocal microscope, but also be applied in flow cytometry to perform bulk measurements. RealThiol[edit] The Real Thiol
(RT) probe is the second-generation reversible reaction-based GSH probe developed by the Wang group. A few key features of RealThiol: 1) it has a much faster forward and backward reaction kinetics compared to ThiolQuant Green, which enables real-time monitoring of GSH dynamics in live cells; 2) only micromolar to sub-micromolar Real Thiol
is needed for staining in cell-based experiments, which induces minimal perturbation to GSH level in cells; 3) a high-quantum-yield coumarin fluorophore was implemented so that background noise can be minimized; and 4) equilibrium constant of the reaction between Real Thiol
and GSH has been fine-tuned to respond to physiologically relevant concentration of GSH.[58] Real Thiol
can be used to perform measurements of glutathione levels in single cells using a high-resolution confocal microscope, as well as be applied in flow cytometry to perform bulk measurements in high throughput manner. Organelle-targeted RT probe has also been developed. A mitochondria targeted version, MitoRT, was reported and demonstrated in monitoring the dynamic of mitochondrial glutathione both on confocoal microscope and FACS based analysis.[59] Protein-based glutathione probes[edit] Another approach, which allows measurement of the glutathione redox potential at a high spatial and temporal resolution in living cells, is based on redox imaging using the redox-sensitive green fluorescent protein (roGFP)[60] or redox-sensitive yellow fluorescent protein (rxYFP)[61] GSSG because its very low physiological concentration is difficult to measure accurately unless the procedure is carefully executed and monitored and the occurrence of interfering compounds is properly addressed. GSSG concentration ranges from 10 to 50 μM in all solid tissues, and from 2 to 5 μM in blood (13–33 nmol per gram Hb). GSH-to-GSSG ratio ranges from 100 to 700.[62] Other biological implications[edit] Lead[edit] The sulphur-rich aspect of glutathione results in it forming relatively strong complexes with lead(II).[63] Cancer[edit] Once a tumor has been established, elevated levels of glutathione may act to protect cancerous cells by conferring resistance to chemotherapeutic drugs.[64] The antineoplastic mustard drug canfosfamide was modelled on the structure of glutathione. Cystic fibrosis[edit] Several studies have been completed on the effectiveness of introducing inhaled glutathione to people with cystic fibrosis with mixed results.[65][66] Alzheimer's disease (AD)[edit] Whilst extracellular amyloid beta (Aβ) plaques, neurofibrillary tangles (NFT), inflammation in the form of reactive astrocytes and microglia, and neuronal loss are all consistent pathological features of AD, a mechanistic link between these factors is yet to be clarified. Although the majority of past research has focused on fibrillar Aβ, soluble oligomeric Aβ species are now considered to be of major pathological importance in AD. Up-regulation of GSH may be protective against the oxidative and neurotoxic effects of oligomeric Aβ. Uses[edit] Winemaking[edit] The content of glutathione in must, the first raw form of wine, determines the browning, or caramelizing effect, during the production of white wine by trapping the caffeoyltartaric acid quinones generated by enzymic oxidation as grape reaction product.[67] Its concentration in wine can be determined by UPLC-MRM mass spectrometry.[68] Cosmetics[edit] Glutathione
plays an important role in preventing oxidative damage to the skin.[69] In addition to its many recognized biological functions, glutathione has also been associated with skin lightening ability.[70] The role of glutathione as a skin whitener was discovered as a side effect of large doses of glutathione.[71] Glutathione
utilizes different mechanisms to exert its action as a skin whitening agent at various levels of melanogenesis. It inhibits melanin synthesis by means of stopping the neurotransmitter precursor L-DOPA's ability to interact with tyrosinase in the process of melanin production.[72] Glutathione
inhibits the actual production as well as agglutination of melanin by interrupting the function of L-DOPA. Another study found that glutathione inhibits melanin formation by direct inactivation of the enzyme tyrosinase by binding and chelating copper within the enzyme's active site.[73] Glutathione's antioxidant property allows it to inhibit melanin synthesis by quenching of free radicals and peroxides that contribute to tyrosinase activation and melanin formation.[74] Its antioxidant property also protects the skin from UV radiation and other environmental as well as internal stressors that generate free radicals that cause skin damage and hyperpigmentation.[75] In most mammals, melanin formation consists of eumelanin (brown-black pigment) and pheomelanin ( yellow-red pigment) as either mixtures or co-polymers.[76] Increase in glutathione level may induce the pigment cell to produce pheomelanin instead of eumelanin pigments.[77] A research by Te-Sheng Chang found lowest levels of reduced glutathione to be associated with eumelanin type pigmentation, whereas the highest ones were associated with the pheomelanin.[70] As a result, it is reasonable to assume that depletion of glutathione would result in eumelanin formation. Prota [78] observed that decreased glutathione concentration led to the conversion of L-Dopaquinone
to Dopachrome, increasing the formation of brown-black pigment (eumelanin). Importance of gamma-glutamylcysteine as a precursor for glutathione synthesis[edit] Gamma-glutamylcysteine
(GGC) is the immediate precursor to GSH. GGC supplementation would circumvent feedback inhibitory control of GCL by the end product GSH. Accordingly, a method of elevating GSH levels with the notable advantage of bypassing negative feedback inhibition has been described. Because of this, GGC has been the focus of therapeutic efforts since Puri and Meister 1983. The first documented use of GGC in brains appears to be Pileblad and Magnusson, 1992. Astroglia cells are capable of utilising GGC.[79] Direct delivery of the GSH precursor GGC to brain has been reported to effectively replenish levels of GSH in the brain.[80] Most of the work done on GGC has been preclinical, based on in vivo animal models, or in vitro brain cultures. In order for the therapeutic value of GGC elevation against AD to be vindicated, two empirical hurdles have to be cleared. The first is to demonstrate that delivery of GGC into the brain can indeed increase GSH.[80] The second is to demonstrate that the increase in GGC can indeed reduce oxidative stress in the brain,[81] a condition frequently linked with cognitive decline. See also[edit]

Reductive stress Glutathione synthetase
Glutathione synthetase
deficiency Ophthalmic acid roGFP, a tool to measure the cellular glutathione redox potential Glutathione-ascorbate cycle Bacterial glutathione transferase Thioredoxin, a cysteine-containing small proteins with very similar functions as reducing agents Glutaredoxin, an antioxidant protein that uses reduced glutathione as a cofactor and is reduced nonenzymatically by it Bacillithiol Mycothiol Gamma-L-Glutamyl-L-cysteine


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induces GABA release through P2X7R activation on Müller glia". Neurogenesis. 4 (1): e1283188. doi:10.1080/23262133.2017.1283188. PMC 5305167 . PMID 28229088.  ^ Noctor G, Foyer CH (June 1998). "ASCORBATE AND GLUTATHIONE: Keeping Active Oxygen Under Control". Annual Review of Plant Physiology and Plant Molecular Biology. 49 (1): 249–279. doi:10.1146/annurev.arplant.49.1.249. PMID 15012235.  ^ Ha SB, Smith AP, Howden R, Dietrich WM, Bugg S, O'Connell MJ, Goldsbrough PB, Cobbett CS (June 1999). "Phytochelatin synthase genes from Arabidopsis and the yeast Schizosaccharomyces pombe". The Plant Cell. 11 (6): 1153–64. doi:10.1105/tpc.11.6.1153. PMC 144235 . PMID 10368185.  ^ Parisy V, Poinssot B, Owsianowski L, Buchala A, Glazebrook J, Mauch F (January 2007). "Identification of PAD2 as a gamma-glutamylcysteine synthetase highlights the importance of glutathione in disease resistance of Arabidopsis". The Plant Journal. 49 (1): 159–72. doi:10.1111/j.1365-313X.2006.02938.x. PMID 17144898.  ^ Rouhier N, Lemaire SD, Jacquot JP (2008). "The role of glutathione in photosynthetic organisms: emerging functions for glutaredoxins and glutathionylation". Annual Review of Plant Biology. 59 (1): 143–66. doi:10.1146/annurev.arplant.59.032607.092811. PMID 18444899.  ^ Allen J, Bradley RD (September 2011). "Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers". Journal of Alternative and Complementary Medicine. 17 (9): 827–33. doi:10.1089/acm.2010.0716. PMC 3162377 . PMID 21875351.  ^ Witschi A, Reddy S, Stofer B, Lauterburg BH (1992). "The systemic availability of oral glutathione". European Journal of Clinical Pharmacology. 43 (6): 667–9. doi:10.1007/bf02284971. PMID 1362956.  ^ " Acetylcysteine
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loading dose guideline for vitamin D-deficient adults". European Journal of Endocrinology. 162 (4): 805–11. doi:10.1530/EJE-09-0932. PMID 20139241.  ^ Lieber CS (November 2002). "S-adenosyl-L-methionine: its role in the treatment of liver disorders". The American Journal of Clinical Nutrition. 76 (5): 1183S–7S. PMID 12418503.  ^ Vendemiale G, Altomare E, Trizio T, Le Grazie C, Di Padova C, Salerno MT, Carrieri V, Albano O (May 1989). "Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease". Scandinavian Journal of Gastroenterology. 24 (4): 407–15. doi:10.3109/00365528909093067. PMID 2781235.  ^ Loguercio C, Nardi G, Argenzio F, Aurilio C, Petrone E, Grella A, Del Vecchio Blanco C, Coltorti M (September 1994). "Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease". Alcohol and Alcoholism. 29 (5): 597–604. doi:10.1093/oxfordjournals.alcalc.a045589. PMID 7811344.  ^ Dröge W, Holm E (November 1997). "Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction". FASEB Journal. 11 (13): 1077–89. PMID 9367343.  ^ Tateishi N, Higashi T, Shinya S, Naruse A, Sakamoto Y (January 1974). "Studies on the regulation of glutathione level in rat liver". Journal of Biochemistry. 75 (1): 93–103. doi:10.1093/oxfordjournals.jbchem.a130387. PMID 4151174.  ^ Meyer AJ, May MJ, Fricker M (July 2001). "Quantitative in vivo measurement of glutathione in Arabidopsis cells". The Plant Journal. 27 (1): 67–78. doi:10.1046/j.1365-313x.2001.01071.x. PMID 11489184.  ^ Sebastià J, Cristòfol R, Martín M, Rodríguez-Farré E, Sanfeliu C (January 2003). "Evaluation of fluorescent dyes for measuring intracellular glutathione content in primary cultures of human neurons and neuroblastoma SH-SY5Y". Cytometry. Part A. 51 (1): 16–25. doi:10.1002/cyto.a.10003. PMID 12500301.  ^ Lantz RC, Lemus R, Lange RW, Karol MH (April 2001). "Rapid reduction of intracellular glutathione in human bronchial epithelial cells exposed to occupational levels of toluene diisocyanate". Toxicological Sciences. 60 (2): 348–55. doi:10.1093/toxsci/60.2.348. PMID 11248147.  ^ Jiang X, Yu Y, Chen J, Zhao M, Chen H, Song X, Matzuk AJ, Carroll SL, Tan X, Sizovs A, Cheng N, Wang MC, Wang J (March 2015). "Quantitative imaging of glutathione in live cells using a reversible reaction-based ratiometric fluorescent probe". ACS Chemical Biology. 10 (3): 864–74. doi:10.1021/cb500986w. PMC 4371605 . PMID 25531746.  ^ Jiang X, Chen J, Bajić A, Zhang C, Song X, Carroll SL, Cai ZL, Tang M, Xue M, Cheng N, Schaaf CP, Li F, MacKenzie KR, Ferreon AC, Xia F, Wang MC, Maletić-Savatić M, Wang J (July 2017). "Quantitative imaging of glutathione". Nature Communications. 8: 16087. doi:10.1038/ncomms16087. PMC 5511354 . PMID 28703127.  ^ Chen J, Jiang X, Zhang C, MacKenzie KR, Stossi F, Palzkill T, Wang MC, Wang J (2017). "Reversible Reaction-Based Fluorescent Probe for Real-Time Imaging of Glutathione
Dynamics in Mitochondria". ACS Sensors. 2 (9): 1257–1261. doi:10.1021/acssensors.7b00425. PMC 5771714 . PMID 28809477.  ^ Meyer AJ, Brach T, Marty L, Kreye S, Rouhier N, Jacquot JP, Hell R (December 2007). "Redox-sensitive GFP in Arabidopsis thaliana is a quantitative biosensor for the redox potential of the cellular glutathione redox buffer". The Plant Journal. 52 (5): 973–86. doi:10.1111/j.1365-313X.2007.03280.x. PMID 17892447.  ^ Maulucci G, Labate V, Mele M, Panieri E, Arcovito G, Galeotti T, Østergaard H, Winther JR, De Spirito M, Pani G (October 2008). "High-resolution imaging of redox signaling in live cells through an oxidation-sensitive yellow fluorescent protein". Science Signaling. 1 (43): pl3. doi:10.1126/scisignal.143pl3. PMID 18957692.  ^ Giustarini D, Dalle-Donne I, Milzani A, Fanti P, Rossi R (September 2013). "Analysis of GSH and GSSG after derivatization with N-ethylmaleimide". Nature Protocols. 8 (9): 1660–9. doi:10.1038/nprot.2013.095. PMID 23928499.  ^ Farkas E, Buglyó P (2017). "Chapter 8. Lead(II) Complexes of Amino Acids, Peptides, and Other Related Ligands of Biological Interest". In Astrid S, Helmut S, Sigel RK. Lead: Its Effects on Environment and Health. Metal Ions in Life Sciences. 17. de Gruyter. pp. 201–240. doi:10.1515/9783110434330-008.  ^ Balendiran GK, Dabur R, Fraser D (2004). "The role of glutathione in cancer". Cell Biochemistry and Function. 22 (6): 343–52. doi:10.1002/cbf.1149. PMID 15386533.  ^ Visca A, Bishop CT, Hilton SC, Hudson VM. "Improvement in clinical markers in CF patients using a reduced glutathione regimen: an uncontrolled, observational study. J Cyst Fibros 2008 ^ Bishop C, Hudson VM, Hilton SC, Wilde C (January 2005). "A pilot study of the effect of inhaled buffered reduced glutathione on the clinical status of patients with cystic fibrosis". Chest. 127 (1): 308–17. doi:10.1378/chest.127.1.308. PMID 15653998.  ^ Rigaud J, Cheynier V, Souquet J, Moutounet M (1991). "Influence of must composition on phenolic oxidation kinetics". Journal of the Science of Food and Agriculture. 57 (1): 55–63. doi:10.1002/jsfa.2740570107.  ^ Vallverdú-Queralt A, Verbaere A, Meudec E, Cheynier V, Sommerer N (January 2015). "Straightforward method to quantify GSH, GSSG, GRP, and hydroxycinnamic acids in wines by UPLC-MRM-MS". Journal of Agricultural and Food Chemistry. 63 (1): 142–9. doi:10.1021/jf504383g. PMID 25457918.  ^ Jansen AH, Russell BJ, Chernick V (October 1975). "Respiratory effects of H+ and dinitrophenol injections into the brain stem subarachnoid space of fetal lambs". Canadian Journal of Physiology and Pharmacology. 53 (5): 726–33. doi:10.1139/y75-101. PMID 134.  ^ a b Libíková H, Pogády J, Wiedermann V, Breier S (November 1975). "Search for herpetic antibodies in the cerebrospinal fluid in senile dementia and mental retardation". Acta Virologica. 19 (6): 493–5. PMC 2443094 . PMID 1996.  ^ Prasad S, Srivastava S, Singh M, Shukla Y (2009). "Clastogenic effects of glyphosate in bone marrow cells of swiss albino mice". Journal of Toxicology. 2009: 308985. doi:10.1155/2009/308985. PMC 2809416 . PMID 20107585.  ^ Matsuki M, Watanabe T, Ogasawara A, Mikami T, Matsumoto T (August 2008). "[Inhibitory mechanism of melanin synthesis by glutathione]". Yakugaku Zasshi. 128 (8): 1203–7. doi:10.1248/yakushi.128.1203. PMID 18670186.  ^ Scott DM, Mazurkiewicz M, Leeman P (January 1976). "The long-term monitoring of ventilation rhythms of the polychaetous annelid Nereis virens sars". Comparative Biochemistry and Physiology. A, Comparative Physiology. 53 (1): 65–8. doi:10.1016/s0300-9629(76)80012-6. PMID 187.  ^ Karg E, Odh G, Wittbjer A, Rosengren E, Rorsman H (February 1993). " Hydrogen peroxide
Hydrogen peroxide
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Further reading[edit]

Bilinsky LM, Reed MC, Nijhout HF (July 2015). "The role of skeletal muscle in liver glutathione metabolism during acetaminophen overdose". Journal of Theoretical Biology. 376: 118–33. doi:10.1016/j.jtbi.2015.04.006. PMC 4431659 . PMID 25890031. Lay summary – ALN Magazine (24 June 2015).  Drevet JR (May 2006). "The antioxidant glutathione peroxidase family and spermatozoa: a complex story". Molecular and Cellular Endocrinology. 250 (1–2): 70–9. doi:10.1016/j.mce.2005.12.027. PMID 16427183.  Wu G, Fang YZ, Yang S, Lupton JR, Turner ND (March 2004). "Glutathione metabolism and its implications for health". The Journal of Nutrition. 134 (3): 489–92. PMID 14988435. 

External links[edit]

bound to proteins in the PDB Risk Factors

v t e


Food antioxidants

6-Hydroxymelatonin Acetyl-L-carnitine (ALCAR) Alpha-lipoic acid (ALA) Ascorbic acid
Ascorbic acid
(vitamin C) Carotenoids (vitamin A) Curcumin Edaravone Polyphenols Glutathione Hydroxytyrosol L-carnitine Ladostigil Melatonin Mofegiline N- Acetylcysteine
(NAC) N-Acetylserotonin
(NAS) Oleocanthal Oleuropein Rasagiline Resveratrol Selegiline Selenium Tocopherols (vitamin E) Tocotrienols (vitamin E) Tyrosol Ubiquinone (coenzyme Q) Uric acid

Fuel antioxidants

Butylated hydroxytoluene 2,6-Di-tert-butylphenol 1,2-Diaminopropane 2,4-Dimethyl-6-tert-butylphenol Ethylenediamine


Folin method ORAC TEAC FRAP

v t e

Antidotes (V03AB)

Nervous system

Nerve agent
Nerve agent
/ Organophosphate poisoning

Atropine# Biperiden Diazepam# Oximes

Obidoxime Pralidoxime

see also: Cholinesterase

Barbiturate overdose

Bemegride Ethamivan

Benzodiazepine overdose

Cyprodenate Flumazenil

GHB overdose

Physostigmine SCH-50911

Opioid overdose

Diprenorphine Doxapram Nalmefene Nalorphine Naloxone# Naltrexone

Reversal of neuromuscular blockade


Circulatory system

Beta blocker


Digoxin toxicity

Digoxin Immune Fab




Arsenic poisoning

Dimercaprol# Succimer

Cyanide poisoning

4-Dimethylaminophenol Hydroxocobalamin nitrite

Amyl nitrite Sodium nitrite#

Sodium thiosulfate#

Hydrofluoric acid


/ Ethylene glycol poisoning

Primary alcohols: Ethanol Fomepizole

toxicity (Acetaminophen)

Acetylcysteine# Glutathione Methionine#

Toxic metals (cadmium

lead mercury thallium)

Dimercaprol# Edetates Prussian blue#



Potassium iodide

Methylthioninium chloride# oxidizing agent

Potassium permanganate



sulfate Ipecacuanha

Syrup of ipecac

#WHO-EM ‡Withdrawn from market Clinical trials:

†Phase III §Never to phase III

v t e


Active forms


(B3) Coenzyme A
Coenzyme A
(B5) PLP / P5P (B6) Biotin
(B7) THFA / H4FA, DHFA / H2FA, MTHF (B9) AdoCbl, MeCbl (B12) Ascorbic acid
Ascorbic acid
(C) Phylloquinone
(K1), Menaquinone (K2) Coenzyme F420


ATP CTP SAMe PAPS GSH Coenzyme B Cofactor F430 Coenzyme M Coenzyme Q Heme
/ Haem (A, B, C, O) Lipoic Acid Methanofuran Molybdopterin/ Molybdenum
cofactor PQQ THB / BH4 THMPT / H4MPT

metal ions

Ca2+ Cu2+ Fe2+, Fe3+ Mg2+ Mn2+ Mo Ni2+ Zn2+

Base forms

vitamins: see vitamins

v t e


Amino acid-derived

Major excitatory/inhibitory systems: Glutamate
system: Agmatine Aspartic acid
Aspartic acid
(aspartate) Cycloserine Glutamic acid
Glutamic acid
(glutamate) Glutathione Glycine GSNO GSSG Kynurenic acid NAA NAAG Proline Serine; GABA system: GABA GABOB GHB; Glycine
system: α-Alanine β-Alanine Glycine Hypotaurine Proline Sarcosine Serine Taurine; GHB system: GHB T-HCA (GHC)

Biogenic amines: Monoamines: 6-OHM Dopamine Epinephrine
(adrenaline) NAS (normelatonin) Norepinephrine
(noradrenaline) Serotonin
(5-HT); Trace amines: 3-Iodothyronamine N-Methylphenethylamine N-Methyltryptamine m-Octopamine p-Octopamine Phenylethanolamine Phenethylamine Synephrine Tryptamine m-Tyramine p-Tyramine; Others: Histamine

Neuropeptides: See here instead.


Endocannabinoids: 2-AG 2-AGE (noladin ether) 2-ALPI 2-OG AA-5-HT Anandamide
(AEA) DEA LPI NADA NAGly OEA Oleamide PEA RVD-Hpα SEA Virodhamine

Neurosteroids: See here instead.


Nucleosides: Adenosine
system: Adenosine ADP AMP ATP


Cholinergic system: Acetylcholine


Gasotransmitters: Carbon monoxide
Carbon monoxide
(CO) Hydrogen sulfide
Hydrogen sulfide
(H2S) Nitric oxide
Nitric oxide
(NO); Candidates: Acetaldehyde Ammonia
(NH3) Carbonyl sulfide
Carbonyl sulfide
(COS) Nitrous oxide
Nitrous oxide
(N2O) Sulfur dioxide
Sulfur dioxide

receptor modulators

v t e

Ionotropic glutamate receptor
Ionotropic glutamate receptor


Agonists: Main site agonists: 5-Fluorowillardiine Acromelic acid (acromelate) AMPA BOAA Domoic acid Glutamate Ibotenic acid Proline Quisqualic acid Willardiine; Positive allosteric modulators: Aniracetam Cyclothiazide CX-516 CX-546 CX-614 Farampator
(CX-691, ORG-24448) CX-717 CX-1739 CX-1942 Diazoxide Hydrochlorothiazide
(HCTZ) IDRA-21 LY-392098 LY-395153 LY-404187 LY-451646 LY-503430 Mibampator
(LY-451395) Nooglutyl ORG-26576 Oxiracetam PEPA PF-04958242 Piracetam Pramiracetam S-18986 Tulrampator
(S-47445, CX-1632)

Antagonists: ACEA-1011 ATPO Becampanel Caroverine CNQX Dasolampanel DNQX Fanapanel
(MPQX) GAMS Kaitocephalin Kynurenic acid Kynurenine Licostinel
(ACEA-1021) NBQX PNQX Selurampanel Tezampanel Theanine Topiramate YM90K Zonampanel; Negative allosteric modulators: Barbiturates
(e.g., pentobarbital, sodium thiopental) Cyclopropane Enflurane Ethanol (alcohol) Evans blue GYKI-52466 GYKI-53655 Halothane Irampanel Isoflurane Perampanel Pregnenolone sulfate Sevoflurane Talampanel; Unknown/unsorted antagonists: Minocycline


Agonists: Main site agonists: 5-Bromowillardiine 5-Iodowillardiine Acromelic acid (acromelate) AMPA ATPA Domoic acid Glutamate Ibotenic acid Kainic acid LY-339434 Proline Quisqualic acid SYM-2081; Positive allosteric modulators: Cyclothiazide Diazoxide Enflurane Halothane Isoflurane

Antagonists: ACEA-1011 CNQX Dasolampanel DNQX GAMS Kaitocephalin Kynurenic acid Licostinel
(ACEA-1021) LY-382884 NBQX NS102 Selurampanel Tezampanel Theanine Topiramate UBP-302; Negative allosteric modulators: Barbiturates
(e.g., pentobarbital, sodium thiopental) Enflurane Ethanol (alcohol) Evans blue NS-3763 Pregnenolone sulfate


Agonists: Main site agonists: AMAA Aspartate Glutamate Homocysteic acid
Homocysteic acid
(L-HCA) Homoquinolinic acid Ibotenic acid NMDA Proline Quinolinic acid Tetrazolylglycine Theanine; Glycine
site agonists: β-Fluoro-D-alanine ACBD ACC (ACPC) ACPD AK-51 Apimostinel
(NRX-1074) B6B21 CCG D-Alanine D-Cycloserine D-Serine DHPG Dimethylglycine Glycine HA-966 L-687414 L-Alanine L-Serine Milacemide Neboglamine
(nebostinel) Rapastinel
(GLYX-13) Sarcosine; Polyamine site agonists: Neomycin Spermidine Spermine; Other positive allosteric modulators: 24S-Hydroxycholesterol DHEA (prasterone) DHEA sulfate
DHEA sulfate
(prasterone sulfate) Epipregnanolone sulfate Pregnenolone sulfate SAGE-201 SAGE-301 SAGE-718

Antagonists: Competitive antagonists: AP5
(APV) AP7 CGP-37849 CGP-39551 CGP-39653 CGP-40116 CGS-19755 CPP Kaitocephalin LY-233053 LY-235959 LY-274614 MDL-100453 Midafotel
(d-CPPene) NPC-12626 NPC-17742 PBPD PEAQX Perzinfotel PPDA SDZ-220581 Selfotel; Glycine
site antagonists: 4-Cl-KYN (AV-101) 5,7-DCKA 7-CKA ACC ACEA-1011 ACEA-1328 Apimostinel
(NRX-1074) AV-101 Carisoprodol CGP-39653 CNQX D-Cycloserine DNQX Felbamate Gavestinel GV-196771 Harkoseride Kynurenic acid Kynurenine L-689560 L-701324 Licostinel
(ACEA-1021) LU-73068 MDL-105519 Meprobamate MRZ 2/576 PNQX Rapastinel
(GLYX-13) ZD-9379; Polyamine site antagonists: Arcaine Co 101676 Diaminopropane Diethylenetriamine Huperzine A Putrescine; Uncompetitive pore blockers (mostly dizocilpine site): 2-MDP 3-HO-PCP 3-MeO-PCE 3-MeO-PCMo 3-MeO-PCP 4-MeO-PCP 8A-PDHQ 18-MC α-Endopsychosin Alaproclate Alazocine
(SKF-10047) Amantadine Aptiganel Argiotoxin-636 Arketamine ARL-12495 ARL-15896-AR ARL-16247 Budipine Coronaridine Delucemine
(NPS-1506) Dexoxadrol Dextrallorphan Dextromethadone Dextromethorphan Dextrorphan Dieticyclidine Diphenidine Dizocilpine Ephenidine Esketamine Etoxadrol Eticyclidine Fluorolintane Gacyclidine Ibogaine Ibogamine Indantadol Ketamine Ketobemidone Lanicemine Levomethadone Levomethorphan Levomilnacipran Levorphanol Loperamide Memantine Methadone Methorphan Methoxetamine Methoxphenidine Milnacipran Morphanol NEFA Neramexane Nitromemantine Noribogaine Norketamine Orphenadrine PCPr PD-137889 Pethidine
(meperidine) Phencyclamine Phencyclidine Propoxyphene Remacemide Rhynchophylline Rimantadine Rolicyclidine Sabeluzole Tabernanthine Tenocyclidine Tiletamine Tramadol; Ifenprodil (NR2B) site antagonists: Besonprodil Buphenine
(nylidrin) CO-101244 (PD-174494) Eliprodil Haloperidol Isoxsuprine Radiprodil (RGH-896) Rislenemdaz
(CERC-301, MK-0657) Ro 8-4304 Ro 25-6981 Safaprodil Traxoprodil
(CP-101606); NR2A-selective antagonists: MPX-004 MPX-007 TCN-201 TCN-213; Cations: Hydrogen Magnesium Zinc; Alcohols/volatile anesthetics/related: Benzene Butane Chloroform Cyclopropane Desflurane Diethyl ether Enflurane Ethanol (alcohol) Halothane Hexanol Isoflurane Methoxyflurane Nitrous oxide Octanol Sevoflurane Toluene Trichloroethane Trichloroethanol Trichloroethylene Urethane Xenon Xylene; Unknown/unsorted antagonists: ARR-15896 Bumetanide Caroverine Conantokin D-αAA Dexanabinol Flufenamic acid Flupirtine FPL-12495 FR-115427 Furosemide Hodgkinsine Ipenoxazone (MLV-6976) MDL-27266 Metaphit Minocycline MPEP Niflumic acid Pentamidine Pentamidine
isethionate Piretanide Psychotridine Transcrocetin

See also: Receptor/signaling modulators Metabotropic glutamate receptor
Metabotropic glutamate receptor
modulators Glutamate
metabolism/transport modulators

v t e

Metabotropic glutamate receptor
Metabotropic glutamate receptor

Group I


Agonists: ACPD DHPG Glutamate Ibotenic acid Quisqualic acid Ro01-6128 Ro67-4853 Ro67-7476 VU-71 Theanine

Antagonists: BAY 36-7620 CPCCOEt Cyclothiazide LY-367,385 LY-456,236 MCPG NPS-2390


Agonists: ACPD ADX-47273 CDPPB CHPG DFB DHPG Glutamate Ibotenic acid Quisqualic acid VU-1545

Antagonists: CTEP DMeOB LY-344,545 Mavoglurant MCPG NPS-2390 Remeglurant SIB-1757 SIB-1893; Negative allosteric modulators: Basimglurant Dipraglurant Fenobam GRN-529 MPEP MTEP Raseglurant

Group II


Agonists: BINA CBiPES DCG-IV Eglumegad Glutamate Ibotenic acid LY-379,268 LY-404,039
(pomaglumetad) LY-487,379 LY-566,332 MGS-0028 Pomaglumetad methionil (LY-2140023) Talaglumetad; Positive allosteric modulators: JNJ-40411813

Antagonists: APICA CECXG EGLU HYDIA LY-307,452 LY-341,495 MCPG MGS-0039 PCCG-4; Negative allosteric modulators: Decoglurant RO4491533


Agonists: CBiPES DCG-IV Eglumegad Glutamate Ibotenic acid LY-379,268 LY-404,039
(pomaglumetad) LY-487,379 MGS-0028 Pomaglumetad methionil (LY-2140023) Talaglumetad

Antagonists: APICA CECXG EGLU HYDIA LY-307,452 LY-341,495 MCPG MGS-0039; Negative allosteric modulators: Decoglurant RO4491533

Group III


Agonists: Glutamate L-AP4 PHCCC VU-001,171 VU-0155,041; Positive allosteric modulators: Foliglurax MPEP

Antagonists: CPPG MAP4 MPPG MSOP MTPG UBP-1112


Agonists: Glutamate L-AP4

Antagonists: CPPG MAP4 MPPG MSOP MTPG UBP-1112


Agonists: AMN082 Glutamate L-AP4



Agonists: DCPG Glutamate L-AP4

Antagonists: CPPG MAP4 MPPG MSOP MTPG UBP-1112

See also: Receptor/signaling modulators • Ionotropic glutamate receptor modulators • Glutamate
metabolism/transport modulators

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