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Glutathione

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GENERAL FEATURES

Name: Glutathione
Generic Names/
Synonyms:
L-g-glutamyl-L- cysteinylglycine[1]
g-glutamyl-cysteinyl-glycine[2],[3]
Trade Names: RayGelTM (reduced glutathione and anthocyanins; Integrative Therapies, Portland, OR)[4]
IUPAC name: (2S)-2-amino-4-{[(1R)-1-[(carboxymethyl)carbamoyl]-2-sulfanylethyl]carbamoyl}butanoic acid[5]
2-amino-5-{[2-carboxymethyl)-amino]-1-(mercaptomethyl)-2-oxoethyl]-amino}-5-oxopentanoic acid) [6],[7],[8]
Molecular Weight: 307 g/mol[9]
307.3235 g/mol [7]
Structure: [10],[11],[12],[8]
Functional Group/
chemical
constitution:
It is a tri-peptide composed of non-essential amino acids(g-glutamyl-cysteinyl-glycine)[2],[13]
γ-glutamyl linkage and sulphydryl group (–SH)[1]
sulphydryl group (–SH)[14]
has both amide and amine groups[3]
Chemical Nature: Intracellular thiol antioxidant[13],[15]
Found in cells as reduced (GSH) and oxidized form(GSSG)[1], also as mixed disulfide with protein and non-protein sulfhydryls, thiol esters of GSH[11]
nucleophilic[16]
It is water soluble in nature and has melting point of 383°F/195°C. [7]
GSH acts as electron carriers[8]
GSH has a net charge of- 1 at neutral pH[17]
It has approximate net charge of -1 at pH 7[42]
Synthesis: Although synthesized naturally in all tissues[10], synthesized more in liver[18],[10]
Synthesized intracellularly by γ-glutamylcysteine synthetase and GSH synthetase, requiring ATP[2],[11]
Functions: Chief nonprotein intracellular sulfhydryl[11]
Acts as a cofactor for Glutaredoxins[19]
glutathione is a coenzyme for several reactions.[20], it conjugates with foreign compounds, drugs [21]
Glutathione appaers to be a storage form and a transport form of amino acid 'cysteine' [21] Maintains intracellular redox status through reduced glutathione(GSH)/oxidized glutathione(GSSG) system and glutaredoxin system, functions directly or indirectly in many important phenomema including synthesis of protein and DNA, transport, enzyme activity, metabolism and cell protection[22]
Endogenous glutathione takes part in cellular antioxic and defensive function
non-antioxidant functions involve modulation of cell proliferation and immune response
prooxidant reactions induced by GSH catabolsim appeared to modulate cellular signal transduction chains such as cell surface receptors, protein phosphatase activities. [15],[23]
GSH in lens maintains protein thiols in the reduced state, preventing the formation of high molecular weight protein aggregates, protect membrane -SH groups that are important in cation transport and permeability, detoxifies hydrogen peroxide and other organoperoxides in aqueous humor of eye[24]
the GSH oxidation-reduction cycle helps maintain structural and functional viability in spite of endogenous production of reactive oxygen intermediates in many cell types[11]
Glutathione is involved in the disposal of peroxides by brain cells and in the protection against reactive oxygen species.[25]
plays role in metal homeostasis and signal transduction under metal stress[26]
major protective role against the reactive drug intermediates generated by bioreduction is provided by the ubiquitous glutathione redox cycle. glutathione redox cycle has a vital role in the cellular response to bio-reduction and activation of various classes of compounds. The regulatory role of glutathione is very evident in the utilization of reducing equivalents [27]
The metabolic role of glutathione was investigated with emphasis on oxidative transitions associated with hydroperoxide and drug metabolism. Hydroperoxide reduction is catalyzed by the GSH peroxidases (Se dependent or non-Se dependent) and leads to the formation of glutathione disulfide. Intracellularly, a steady state is maintained (a) by the activity of GSSG reductase operating at the expense of NADPH, and (b) by an efflux of GSSG from the cell.[28]
plasma glutathione plays role in the interorgan relationships in glutathione turnover[28]
Actions
& Indications:
Pharmcological Action-
Amino thiol radioprotector[29]
antioxidant[30],[6]
Therapeutic indications:
Preclinical study-
Increase in glutathione in brain is suggested to be promising therpy for Alzheimer's disease[2]
The prior administration of glutathione (GSH) partially prevented carbon tetrachloride (CCl4)-induced liver necrosis in rats in vivo[31]
early and delayed treatment with GSH prevented peroxynitrite-mediated acetaminophen hepatotoxicity in mice[32]
Exogenous GSH protected rat small-intestinal epithelial cells against oxidative chemical injury induced by t-butyl hydroperoxide[33]
exogenous GSH is could be a promising for the treatment of anemia in most hemodialyzed patients[34]
It has been suggested to be a candidate as an adjunctive in management of periodontitis[7]
Derivates/
Analogues/
Complex:
Monoethyl (MEE) and diethyl (DEE) esters of glutathione (GSH) exhibited some protection of normal and buthionine sulfoximine (BSO) pretreated cells against X-irradiation[35]
y-glutamylcysteinylglycyl monomethyl (or monoethyl) ester is speculated to offer protection against radiation[36]
Administration of the glutathione monoester prevented the marked decline of mitochondrial glutathione produced by buthionine sulfoximine in skeletal muscle and increased the level of glutathione in heart mitochondria of mice[37]
monoethyl ester of glutathione was found to protect human lymphoid cells of the CEM line against the lethal effects of irradiation, when given prior to radiation[38].
Notes: Blood glutathione(glutathione redox ratio in blood) can be used as an index of radiation-induced oxidative stress, as reported in a study with mice and human[39]
glutathione diethyl ester is highly effective as a delivery agent for glutathione monoester, and thus for glutathione, in human cells, hence suggested to have significant practical application[40]
dominant apoptosis resistance is found to be dependent, at least in part, on intracellular GSH levels in leukemia cells[41]
oxidised glutathione , glutathione sulphinic acid γ-glutamylalanylglycine , γ-glutamylserylglycine, and hydrogen peroxide have been found to form in the 60Co γ radiolysis of aerated reduced glutathione solutions at pH values between 1-7.3[14]
concentration of GSH during the treatment of locally advanced cervical cancer is suggested be important for the prediction of the efficacy of the treatment(neoadjuvant chemotherapy followed by concurrent chemoradiation) in a clinical study[43]
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18. Chapter 107: Detoxificaton by Salguero ML; In: Integrative Medicine, second edition, by Rakel D, Saunders, Elsevier, Philadelphoa 2007, page no. 1130.
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19. Chatterjee A, Reduced Glutathione: A Radioprotector or a Modulator of DNA-Repair Activity? Nutrients 2013; 5(2): 525-542.
http://dx.doi.org/10.3390/nu5020525
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22. Chapter 3: Radioenhancement by targeting cellular redox pathways and/or by incorporation of High-Z material in to target:section 3.4 Radiosensitization by targeting the GSH/GSSG system; In : Radiosensitizers and Radiochemotherapy in the Treatment of Cancer by Lehnert S, CRC Press, Taylor and Fancis group, Florida, page no. 88.
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43. Daukantienė L et al, The significance of reduced glutathione and glutathione S-transferase during chemoradiotherapy of locally advanced cervical cancer. Medicina. 2014;50(4):222–229.
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