Research Breakdown on Glutathione
Glutathione (γ-L-Glutamyl-L-cysteinylglycine) is a small tripeptide molecule composed of three dietary amino acids; L-glutamate, L-cysteine, and glycine. This tripeptide is popularily known as an antioxidant due to the system that it belongs to (the glutathione system) using this tripeptide as the substrate to regulate most oxidative processes in the cell. Glutathione also has a role in conjugating some compounds in the body and priming them for elimination, which has been interpretated as a detoxificative role and also used as validation for its dietary supplementation.
Beyond being an endogenous antioxidant, glutathione is present in the food supply via most foods. One study sample had a mean daily intake of 34.8mg, but a wide range of 13-109.9mg. Over half of dietary glutathione came from fruits and vegetables, with less than quarter from meat sources. Dietary glutathione content, however, does not correlate with systemic glutathione activity.
Glutathione is present in the human diet in food products, although the doses consumed in even the most prolific diets is significantly smaller than can be achieved through supplementation with glutathine or its precursor (N-Acetylcysteine). Dietary glutathine does not correlate with overall glutathine activity.
Glutathione is a tripeptide (L-glutamic acid, L-cysteine, and glycine) that is known as the most prominent nonenzymatic antioxidant in the human body, and is a substrate for a system of enzymes involved in regulating glutathione metabolism.
Glutathoine is an intermediate in the 'glutathione system' which regulates oxidation.
An enzyme known as γ-GlutamylCysteine Synthetase (GCS) is a glutamate-cysteine ligase which is involved in synthesizing glutathione, specifically catalyzing the first reaction of combining glutamate and cysteine to form a dipeptide known as γ-glutamylcysteine (hence the name of the enzyme). This enzyme is a target of certain pharmacological interventions assessing the actions of glutathione in a cell, as it can be inhibited with Buthionine SulfOximine (BSO) resulting in a depletion of active GSH and enhancing its actions can enhance glutathione activity and its antioxidant effects. A deficiency of GCS results in both a depletion in glutathione as well as a cellular glutathione-S-transferase activity. Due to glutathione itself exerting a negative regulatory role on this enzyme (in both bacterial and rat cells; latter being homologous to human) an excess of glutathione production from overactivity seems unlikely.
The second enzyme involved in the synthesis of glutathione is glutathione synthetase, which takes the γ-glutamylcysteine created in the previous enzymatic reaction and attaches glycine into it, forming the tripeptide known as glutathione. This enzyme is present in yeast and bacteria although they share little homology with rat and human variants, and the rat variant has around 88% homology with the human variant. The enzyme appears to requite Cys-422 to function in humans and its function can be inhibited in experiments with Methionine SulfOximine (MSO).
The rate-limiting step of glutathione synthesis does not appear to be the activity of either enzyme under normal conditions, but rather the provision of one of the amino acids (L-cysteine) making up the tripeptide; due to this, supplementation of N-acetylcysteine is sometimes used to increase glutathione synthesis (after N-acetylcysteine gets deacetylated to form L-cysteine, however).
The synthesis of glutathione in the body involves two enzymes, the first of which binds L-cysteine and glutamic acid to one another in a gamma configuration (producing γ-glutamylcysteine), and the second enzyme adds a glycine molecule onto it to ultimately form glutathione.
Glutathione itself (GSH) is present in both a reduced form known as reduced glutathione (GSH) prior to exerting antioxidant effects and an oxidized form (GSSG) after it exerts antioxidant effects on targets; the two form a ratio known as the GSH/GSSG ratio where the former normally constitutes 98% of total glutathione and alterations in the ratio signify changes in cellular oxidative balance.
Oxidized glutathione (GSSG) can be converted back into GSH via the NADPH-dependent glutathione disulfide reductase enzyme, and the activity of this enzyme seems to be in part controlled by glutathione itself. The activity of this enzyme appears to be a major determinent of the overall GSH/GSSG ratio.
Glutathione exists in two forms: a reduced form (GSH) and an oxidized form (GSSG). The ratio of rGSH to GSSH is indicative of the overall oxidative state of a cell, with increasing oxidized forms (GSSG) relative to the reduced form (GSH) suggestive of a more oxidative state.
The antioxidant enzymes that utilize glutathione to exert antioxidative effects are known as glutathione S-transferases (GSTs), and work by priming the glutathione molecule to donate an electron pair (known as a nucleophilic attack) and allowing this attack to reach targets that are able to accept the electrons (electrophilic targets) resulting in a transfer of electrons; this transfer itself is the antioxidative effect.
GST enzymes are divided into eight distinct classes in mammals of alpha (α), mu (μ), pi (π), theta (θ), zeta (ζ), sigma (σ), omega (ω), and the mitochondrial kappa (κ) divided into two superfamilies of soluble GSTs located in the cytosol (with the exception of kappa) and microsomal GSTs collectively known as Membrane-Associated Proteins in Eicosanoid and Glutathione metabolism (MAPEG) which are associated with cellular membranes.
Another group of enzymes are the glutathione peroxidase (GPx) enzymes which use glutathione tripeptides to reduce lipid peroxidation and hydrogen peroxide into water, with differing efficacy and targets depending on which of the eight isomers is being investigated. These enzymes are selenium-dependent enzymes and a reduction in their activity in the body mediates the adverse effects of selenium deficiency.
Glutathine S-transferase (GST) and gluathione peroxidase (GPx) enzymes mediate many of the antioxidative actions of glutathione.
Beyond the usage of glutathione as substrate by its enzymes to exert antioxidant effects, it can directly modify L-cysteine residues on proteins in a process known as S-glutathionylation (or S-glutathiolation) and in general this process modifies the proteins actions and is involved in regulating transcription and both protein folding and degradation. While vital pathways, the relevance of this information of oral supplementation of either glutathione of N-acetylcysteine is unknown.
Glutathione itself can modify protein function via a process known as S-glutathionylation, which is independent of its classical antioxidant effects. where the enzyme predominates. There may also be hydrolysis post-absorption, since infusions of glutathione are mostly degraded into its constituent amino acids and increase serum L-cysteine. There appears to be a transporter for glutathione absorption in human intestinal cells and increases in serum and tissue glutathione have been noted with orally supplemented glutathione in rats, but overall glutathione activity in the human does not correlate with dietary glutathione.
Dietary or orally-ingested glutathione can be hydrolyzed into its constituent amino acids in the intestines and in serum, although there is a possibility of some of the glutathione making it into circulation via absorption from the intestines. and infusions of glutathione have noted that the increase in serum L-cysteine is approximately equivalent to the amount of L-cysteine within glutathione suggesting degradation of glutathione in serum. While one study has found oral supplementation of 1,000mg glutathione over four weeks failing to increase red blood cell stores of glutathione in otherwise healthy humans another study (funded by a the producer of the tested supplement, Setria®, but no conflicts of interest declared) using the same dose or a lesser 250mg dose over six months noted increases in red blood cell glutathione reaching 30-35% at peak; 250mg was less effective at six months relative to 1,000mg.
Glutathione is not stable in the blood, and whether via oral or intravenous administration, glutathione will be readily degraded into L-cysteine or other sulfur containing molecules. It is still possible for oral glutathione to increase bodily glutathione stores though, although this likely requires its degradation into L-cysteine for absorption γ-glutamyl transpeptidase cleaves the γ-glutamyl bond in glutathione producing a cysteine-glycine dipeptide and γ-glutamyl moiety which is bound to another amino acid (usually cystine, a product of two L-cysteine molecules) for extracellular transport, and upon reaching another tissue the γ-glutamylamino acid dipeptide is cleaved by γ-glutamyl cyclotransferase to free the amino acid and produce the cyclic form of glutamic acid (5-oxoproline) which is converted into glutamine by 5-oxoprolinase. Glutathione as the tripeptide, when effluxed from a cell, cannot be absorbed back into most cells intact. This leads to a basal glutathione content in serum, of which the normal range is 3.8–5.5μM and the half-life has been noted to be around 14.1+/-9.2 minutes. The cells that have been noted to be able to absorb intact glutathione include hepatocytes (HepG2), intestinal mucosal cells, and retinal cells.
Glutathione can be exported from the cells where it is synthesized, and it exists in its intact form to some degree in the blood. Most cells, however, must break it down in order to absorb it. in some cases glutathione conjugation serves to bioactive the target molecule. This process applies to both xenobiotics (things originating from outside the body) as well as some endogenous molecules like steroids and prostaglandins. These enzymes are the glutathione S-transferases (GSTs), and the conjugation reaction is similar to an antioxidation reaction where the glutathione performs a nucleophilic attack (donating a pair of electrons) to electrophilic targets in the conjugation process. After conjugation, it is either ejected immediately from the liver into the intestines (thus forming a fecal metabolite) or it travels to the kidneys to ultimately be excreted in the urine as an aceylated L-cysteine conjugate known as mercapturic acid.
Glutathione is used by glutathione S-transferase (GST) enzymes to conjugate targets. This conjugation modifies the target's structure, and while in most cases this serves a detoxifying role by aiding in the removal of the target from the body, it is implicated in a few instances of enhancing the target's actions/toxicity. This was thought to be related to a reduced expression of glutamine-cysteine ligase (GCLC) seen with HIV infection in macrophages. Macrophages isolated from patients with HIV on stable antiretroviral therapy and incubated with M. tuberculosis and 5-10μM glutathione resulted in an increase in reduced glutathione (53-93% in HIV+ and 80-83% in HIV- controls) which was only matched with N-acetylcysteine at 10mM. The difference in potency persisted when assessing lipid peroxidation (via malondialdehyde assay) and in reducing the intracellular growth of M. tuberculosis. is a free radical with which both N-acetylcysteine and glutathione are able to directly and nonenzymatically react, although the rate constants for such reactions are poor (and so they are low potency antioxidants in this case). The formation of superoxide is a common first stage in oxidant production since O2 is able to transverse membranes easily (similar to H2O2 but not O2-) and since O2 is ubiquitously required in metabolic reactions. The enzymes that utilize glutathione to exert enzymatic antioxidant effects (the peroxidases and S-transferases) also do not appear to have potent antioxidant effects on this radical, and endogenous sequesteration of O2- tends to be handled by the superoxide dismutase (SOD) enzymes which convert O2- into hydrogen peroxide (H2O2).
Superoxide (O2-) is one of the basic free radicals that can exert oxidative effects in the cell, and is usually handled by the enzyme superoxide dismutase, which converts it into hydrogen peroxide for glutathione to then reduce; glutathione and its enzymes do not have much antioxidative potential in directly reducing superoxide. H2O2 may also be produced as a byproduct in aerobic metabolic reactions. The antioxidant enzyme catalase also removes H2O2 by decomposing it into into water and oxygen. Catalase and GPx act cooperatively, as H2O2 can inactivate catalase at high concentrations and this inactivation appears to be protected against by GPx.
Glutathione, utilized by the GPx enzymes, has a role alongside catalase in reducing potential buildups of the oxidant known as hydrogen peroxide (H2O2). These enzymes can reduce the hydrogen peroxide back into water (or water and oxygen in the case of catalase). Hydroxyl is thought to mediate many of the more adverse effects of elevated H2O2 concentrations in a cell such as the subsequent DNA damage. and Crohn's disease., are characterized by increases in oxidative stress and simultaneous reductions in oxidative defenses such as glutathione concentrations. As glutathione is the major nonenzymatic antioxidant in gastrointestinal tissue and since measures that preserve glutathione tend to reduce inflammation and oxidative stress in animal models of these disease states glutathione has been investigated as a therapeutic agent. In rats, an injection of glutathione (200mg/kg) an hour before induction of colitis via trinitrobenzensulphonic acid (TNBS) appeared to exert protective effects relative to saline, whereas 50mg/kg glutathione (injections) daily for eight weeks after colitis was induced was noted to nearly ablate the alterations in lipid peroxidation and inflammation. In humans on mesalamine therapy and then given additional 800mg of N-acetylcysteine (which can restore glutathione levels) or placebo, the protective effect with combination therapy was both mild and failed to reach statistical significance. In particular, a glutathione peroxidase deficiency (via selenium deficiency, since the enzyme requires it) appears to result in defective motility and morphology by affecting the midpiece of the spermatozoon (the section between its head and tail). Glutathione's therapeutic effect was confirmed in one study using 600mg glutathione as intramuscular injection which yielded improved sperm motility. This specific benefit (improved motility) has also been noted in vitro with N-acetylcysteine and with 600mg NAC daily in infertile men over the course of three months.
Injections of glutathione may improve male fertility by improving the morphology and motility of sperm. This effect has also been noted in preliminary studies using oral supplementation of N-acetylcysteine; no studies on oral supplementation of glutathione have been conducted to date. resulting in a more oxidative state. At least in aging rats, the cause for this appears to be related to reduced synthetic capacities of the second step of glutathione anabolism (catalyzed by glutathione synthetase) with no alterations in its metabolism by γ-glutamyltranspeptidase or restoration into an antioxidant by glutathione reductase, although this mechanism has not been explored in humans. It has been established, however, that the glutathione synthesis rate (fractional and absolute) in elderly humans is lower relative to youthful controls. This decrease could be associated with a reduction in whole-body protein turnover seen in aging, which would decrease pools of glycine and cysteine for use in glutathione synthesis. Indeed, red blood cell glutathione levels, as well as its constituent amino acids L-cysteine and glycine (not glutamate), have been noted to be reduced in the elderly relative to youth, and oral supplementation of N-acetylcysteine (100mg/kg of L-cysteine) and glycine (100mg/kg) was noted to restore glutathione concentrations by 94.6% within two weeks restoring levels and the synthesis rates of glutathione to those seen in youth. Insufficient dietary intake of protein may also account for reduced glutathione levels, however, as reduced glutathione synthesis and turnover can be induced in healthy non-elderly adults by limiting dietary protein or just the sulfur-containing amino acids found in dietary protein.
Glutathione appears to be reduced in the elderly when compared to youthful controls, even if there are no apparent disease states. Orally ingesting precursor amino acids of glutathione (L-cysteine and glycine) can restore glutathione levels to those seen in youthful controls fairly rapidly. Such proposed mechanisms include chelation of tyrosinase's copper site, interference with the cellular transfer of tyrosinase to premelanosomes, causing the increased synthesis of the lighter red/yellow phaeomelanin and less eumelanin, or scavenging peroxides from ultraviolet radiation, which induce tyrosinase activity. There have been a handful of trials that assessed the effects of glutathione on skin pigmentation and may provide insights. They are discussed below. In a randomized, double-blind, placebo-controlled trial, 60 participants (23 with Fitzpatrick scale phototype of II, 26 with III, 10 with IV and 1 with V) were allocated to take 500 mg of glutathione or placebo daily for 4 weeks. Some areas of the body were frequently exposed to the sun, and some were protected from the sun. Melanin index was reduced more in the glutathione group than the placebo group, but the differences weren't statistically significant except for the right side of the face and the left forearm (2 out of 6 areas). There was a possible role of sun exposure in reducing sun-induced melanin synthesis, but it was difficult to determine with confidence. The study provided some weak evidence for a sun-independent effect as well, with effects seen in sun-protected areas. There was a modest, statistically significant difference in the number of UV spots (placebo group increased, glutathione group didn't see increases or saw smaller increases), and a small nonsignificant increase in evenness and reduction in pore size in the glutathione group. In another randomized, double-blind, placebo-controlled trial, 30 female participants with Fitzpatrick scale type III (6 participants) or IV (24 participants) were allocated to use a lotion containing 2% glutathione or a placebo lotion (0.5 g spread evenly on half of the face) for 10 weeks. Participants were advised to avoid sun exposure. The glutathione group saw a statistically significant reduction in Melanin Index compared with the placebo lotion that continued each week for the entire 10 weeks of the study. There was a small increase in skin moisture compared with placebo that was statistically significant at weeks 8 and 9. Wrinkles increase slightly in both groups at week 6 and afterward, but the glutathione group returned to baseline at week 10, while the placebo group didn't, the difference being statistically significant at 10 weeks. Skin smoothness was also significantly improved after week 6 in the glutathione group. In an open-label, uncontrolled trial, 34 healthy women with Fitzpatrick scale ratings of 4 or 5 were given 500 mg of glutathione in lozenge form for 8 weeks. There was a designated sun-exposed area (extensor surface of the right wrist) and a sun-protected area (mid-sternum). There were statistically significant reductions in Melanin Index for both sun-exposed and sun-protected areas relative to baseline In a randomized, double-blind, placebo-controlled trial 60 healthy participants, almost all with Fitzpatrick scale type IV skin pigmentation, were allocated into equal groups to take 250 mg of reduced glutathione, 250 mg of oxidized glutathione, or placebo for 12 weeks. The glutathione groups both tended to have lower Melanin Index scores than the placebo group at the end of the trial for all spots on the face and arms, both sun-exposed and sun-protected, but the differences weren't statistically significant. There was a significant reduction in the sun-exposed right arm area in participants aged >40, but not for the other areas. There were some significant reductions in wrinkles and increases in moisture content and elasticity, but they were inconsistent across body parts, though generally favoring glutathione. There were no notable differences in adverse events between groups.
Overall, glutathione seems to have an inherent, mild, skin-lightening effect in people with dark skin that's independent of UV-exposure in the short-term, while it's not yet clear the extent to which it causes lightening when used for more than a few months. It's currently not possible to determine the extent of the role of its antioxidant effects in reducing melanin synthesis in response to UV radiation, though there is some suggestive evidence that it does this too. High doses may inherently impair melanin synthesis or lead to the greater synthesis of phaeomelanin (lighter) and less synthesis of eumelanin, which may reduce photoprotection. There may be some modest improvements in measures of skin quality such as wrinkles, moisture, and elasticity, but much more research is needed. and reduced mineral-chelating proteins such as ceruloplasma and transferrin (leading to more free minerals, which is known to contribute to oxidative stress),  suggesting that the overall bodily state of autistic children is more prooxidative than antioxidative. Plasma glutathione and the reduced form thereof are low in autistic children relative to control and oxidized glutathione is higher. There are no alterations in the activity of glutathione reductase between autistic children and controls although glutathione peroxidase has mixed evidence (suppressed and elevated both being noted) and the GSSG:GSH ratio (usually indicative of the activity of glutathione reductase) is also elevated, indicative of more oxidation, compared to controls.
Autism, overall, is a state characterized by excessive oxidative stress relative to controls without autism. As glutathione is the major antioxidant system in the body, the perturbations in whole-body antioxidant status extends to the glutathione system, which appears to be less active in autistic children relative to controls.One study in autistic children using either oral (lipid soluble glutathione at 50-200mg per 30lbs bodyweight twice daily in increasing doses) or transdermal (135-405mg in three divided doses in increasing doses) glutathione supplementation noted insignificant increases in total glutathione in both therapies and an increase in reduced glutathione in the serum of the oral group; while the study measured baseline autistic severity, the measurement was not repeated post-treatment.Alpha-lipoic acid (ALA) is an antioxidant thiol produced in mitochondria from octanoic acid and used as both a REDOX antioxidant (having both an oxidized and reduced form) and mitochondrial enzymatic cofactor. Although it shares similarities with glutathione in being a sulfur-containing antioxidant, unlike glutathione it can be absorbed intact from the intestines and may influence the body as a dietary supplement. ALA appears to have a role in promoting the synthesis of glutathione. Glutathione cannot be transferred between cells intact; instead, L-cystine is transported between cells to provide L-cysteine for glutathione synthesis. Since L-cystine is an oxidative product of L-cysteine (two oxidized L-cysteine molecules bound together) ALA can reduce L-cystine into two L-cysteine amino acids, and thereby increase glutathione synthesis by liberating its precursor, which is the substrate needed for the rate-limiting step in glutathione synthesis. Furthermore, GSSG (the oxidized form of glutathione) can be directly reduced back into GSH via reduced alpha-lipoic acid which in turn becomes its oxidized form (dihydrolipoic acid). This general supportive role of ALA in glutathione activity has been noted in variety of cell lines and appears to occur in vivo with 16mg/kg ALA in rats.
Alpha-lipoic acid can reduce oxidized glutathione, thereby enhancing and preserving glutathione's actions in a cell.L-citrulline is an amino acid that often is used to increase nitric oxide (NO) levels, a potent vasodilator and popular target with pre-workout supplementation. To form NO, L-arginine is combined with oxygen by the nitric oxide synthase (NOS) enzyme. The problem with L-arginine is that after oral ingestion, a significant amount is broken down in the liver before it ever gets to the blood stream. L-citrulline is a byproduct of NO synthesis that can be converted back into arginine through the arginine-citrulline cycle.  For this reason, L-citrulline is a more efficient way to increase blood L-arginine. To examine whether glutathione may potentiate NO signaling, 200 mg/day glutathione alongside-2 g/day L-citrulline was tested in a human randomized, controlled trial. Although increased cGMP levels were observed but did not reach statistical significance, the citrulline and glutathione combo did increase nitrate and nitrite levels more than citrulline alone. Since nitrate and nitrite are substrates for NO synthesis and markers for increased activity of the NO pathway, this indicated that L-citrulline and glutathione supplementation could promote NO production to a greater extent than L-citrulline alone.
Taking glutathione alongside citrulline may potentiate nitric oxide (NO) signaling. The mechanism by which this occurs is not yet clear, but may involve prolonged life of NO in the blood stream due to the presence of glutathione.
- Wu G1, et al. Glutathione metabolism and its implications for health. J Nutr. (2004)
- Filomeni G1, Rotilio G, Ciriolo MR. Cell signalling and the glutathione redox system. Biochem Pharmacol. (2002)
- Dickinson DA1, Forman HJ. Cellular glutathione and thiols metabolism. Biochem Pharmacol. (2002)
- Flagg EW1, et al. Dietary glutathione intake in humans and the relationship between intake and plasma total glutathione level. Nutr Cancer. (1994)
- Griffith OW1, Mulcahy RT. The enzymes of glutathione synthesis: gamma-glutamylcysteine synthetase. Adv Enzymol Relat Areas Mol Biol. (1999)
- Reliene R1, Schiestl RH. Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice. Carcinogenesis. (2006)
- Das GC1, et al. Enhanced gamma-glutamylcysteine synthetase activity decreases drug-induced oxidative stress levels and cytotoxicity. Mol Carcinog. (2006)
- Beutler E, Gelbart T, Pegelow C. Erythrocyte glutathione synthetase deficiency leads not only to glutathione but also to glutathione-S-transferase deficiency. J Clin Invest. (1986)
- Richman PG, Meister A. Regulation of gamma-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione. J Biol Chem. (1975)
- Huang CS1, Moore WR, Meister A. On the active site thiol of gamma-glutamylcysteine synthetase: relationships to catalysis, inhibition, and regulation. Proc Natl Acad Sci U S A. (1988)
- Gipp JJ1, Chang C, Mulcahy RT. Cloning and nucleotide sequence of a full-length cDNA for human liver gamma-glutamylcysteine synthetase. Biochem Biophys Res Commun. (1992)
- Anderson ME. Glutathione: an overview of biosynthesis and modulation. Chem Biol Interact. (1998)
- Mutoh N1, et al. Cloning and sequencing of the gene encoding the large subunit of glutathione synthetase of Schizosaccharomyces pombe. Biochem Biophys Res Commun. (1991)
- Yamaguchi H1, et al. Three-dimensional structure of the glutathione synthetase from Escherichia coli B at 2.0 A resolution. J Mol Biol. (1993)
- Gali RR1, Board PG. Sequencing and expression of a cDNA for human glutathione synthetase. Biochem J. (1995)
- Gali RR1, Board PG. Identification of an essential cysteine residue in human glutathione synthase. Biochem J. (1997)
- Griffith OW, Meister A. Differential inhibition of glutamine and gamma-glutamylcysteine synthetases by alpha-alkyl analogs of methionine sulfoximine that induce convulsions. J Biol Chem. (1978)
- Meister A. Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol Ther. (1991)
- Owen JB, Butterfield DA. Measurement of oxidized/reduced glutathione ratio. Methods Mol Biol. (2010)
- Chung PM1, Cappel RE, Gilbert HF. Inhibition of glutathione disulfide reductase by glutathione. Arch Biochem Biophys. (1991)
- Hayes JD1, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol. (2005)
- Eichholzer M1, et al. Effects of selenium status, dietary glucosinolate intake and serum glutathione S-transferase α activity on the risk of benign prostatic hyperplasia. BJU Int. (2012)
- Huenchuguala S1, et al. Glutathione transferase mu 2 protects glioblastoma cells against aminochrome toxicity by preventing autophagy and lysosome dysfunction. Autophagy. (2014)
- Lee WH1, Joshi P, Wen R. Glutathione S-Transferase Pi Isoform (GSTP1) Expression in Murine Retina Increases with Developmental Maturity. Adv Exp Med Biol. (2014)
- Landi S. Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat Res. (2000)
- Board PG1, et al. Zeta, a novel class of glutathione transferases in a range of species from plants to humans. Biochem J. (1997)
- Hayes JD1, Strange RC. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. (2000)
- Pemble SE1, Wardle AF, Taylor JB. Glutathione S-transferase class Kappa: characterization by the cloning of rat mitochondrial GST and identification of a human homologue. Biochem J. (1996)
- Robinson A1, et al. Modelling and bioinformatics studies of the human Kappa-class glutathione transferase predict a novel third glutathione transferase family with similarity to prokaryotic 2-hydroxychromene-2-carboxylate isomerases. Biochem J. (2004)
- Jakobsson PJ1, et al. Common structural features of MAPEG -- a widespread superfamily of membrane associated proteins with highly divergent functions in eicosanoid and glutathione metabolism. Protein Sci. (1999)
- Brigelius-Flohé R1, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta. (2013)
- Brigelius-Flohé R. Glutathione peroxidases and redox-regulated transcription factors. Biol Chem. (2006)
- Klatt P1, Lamas S. Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem. (2000)
- Hill BG1, Bhatnagar A. Role of glutathiolation in preservation, restoration and regulation of protein function. IUBMB Life. (2007)
- Irihimovitch V1, Shapira M. Glutathione redox potential modulated by reactive oxygen species regulates translation of Rubisco large subunit in the chloroplast. J Biol Chem. (2000)
- Lockwood TD. Redox control of protein degradation. Antioxid Redox Signal. (2000)
- Hagen TM1, et al. Fate of dietary glutathione: disposition in the gastrointestinal tract. Am J Physiol. (1990)
- Garvey TQ 3rd, Hyman PE, Isselbacher KJ. gamma-glutamyl transpeptidase of rat intestine: localization and possible role in amino acid transport. Gastroenterology. (1976)
- Fukagawa NK1, Ajami AM, Young VR. Plasma methionine and cysteine kinetics in response to an intravenous glutathione infusion in adult humans. Am J Physiol. (1996)
- Iantomasi T1, et al. Glutathione transport system in human small intestine epithelial cells. Biochim Biophys Acta. (1997)
- Hagen TM1, et al. Bioavailability of dietary glutathione: effect on plasma concentration. Am J Physiol. (1990)
- Aw TY1, Wierzbicka G, Jones DP. Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact. (1991)
- Witschi A1, et al. The systemic availability of oral glutathione. Eur J Clin Pharmacol. (1992)
- Aebi S1, Assereto R, Lauterburg BH. High-dose intravenous glutathione in man. Pharmacokinetics and effects on cyst(e)ine in plasma and urine. Eur J Clin Invest. (1991)
- Allen J1, Bradley RD. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J Altern Complement Med. (2011)
- Richie JP Jr1, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr. (2014)
- Thompson GA, Meister A. Hydrolysis and transfer reactions catalyzed by gamma-glutamyl transpeptidase; evidence for separate substrate sites and for high affinity of L-cystine. Biochem Biophys Res Commun. (1976)
- Orlowski M, Meister A. The gamma-glutamyl cycle: a possible transport system for amino acids. Proc Natl Acad Sci U S A. (1970)
- Kern JK1, et al. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. (2011)
- Sze G1, et al. Bidirectional membrane transport of intact glutathione in Hep G2 cells. Am J Physiol. (1993)
- Benard O1, Balasubramanian KA. Effect of oxidant exposure on thiol status in the intestinal mucosa. Biochem Pharmacol. (1993)
- Lu SC1, et al. Bidirectional glutathione transport by cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. (1995)
- Kannan R1, et al. Identification of a novel, sodium-dependent, reduced glutathione transporter in the rat lens epithelium. Invest Ophthalmol Vis Sci. (1996)
- Pastore A1, et al. Analysis of glutathione: implication in redox and detoxification. Clin Chim Acta. (2003)
- van Bladeren PJ. Glutathione conjugation as a bioactivation reaction. Chem Biol Interact. (2000)
- Barycki JJ1, Colman RF. Identification of the nonsubstrate steroid binding site of rat liver glutathione S-transferase, isozyme 1-1, by the steroid affinity label, 3beta-(iodoacetoxy)dehydroisoandrosterone. Arch Biochem Biophys. (1997)
- Bogaards JJ1, Venekamp JC, van Bladeren PJ. Stereoselective conjugation of prostaglandin A2 and prostaglandin J2 with glutathione, catalyzed by the human glutathione S-transferases A1-1, A2-2, M1a-1a, and P1-1. Chem Res Toxicol. (1997)
- Eaton DL1, Bammler TK. Concise review of the glutathione S-transferases and their significance to toxicology. Toxicol Sci. (1999)
- Ramires PR1, Ji LL. Glutathione supplementation and training increases myocardial resistance to ischemia-reperfusion in vivo. Am J Physiol Heart Circ Physiol. (2001)
- Morris D1, et al. Glutathione supplementation improves macrophage functions in HIV. J Interferon Cytokine Res. (2013)
- Imlay JA. Cellular defenses against superoxide and hydrogen peroxide. Annu Rev Biochem. (2008)
- Benrahmoune M1, Thérond P, Abedinzadeh Z. The reaction of superoxide radical with N-acetylcysteine. Free Radic Biol Med. (2000)
- Winterbourn CC1, Metodiewa D. The reaction of superoxide with reduced glutathione. Arch Biochem Biophys. (1994)
- Cardey B1, Foley S, Enescu M. Mechanism of thiol oxidation by the superoxide radical. J Phys Chem A. (2007)
- Ligeza A1, et al. Oxygen permeability of thylakoid membranes: electron paramagnetic resonance spin labeling study. Biochim Biophys Acta. (1998)
- Abreu IA1, Cabelli DE. Superoxide dismutases-a review of the metal-associated mechanistic variations. Biochim Biophys Acta. (2010)
- Hassan HM, Fridovich I. Chemistry and biochemistry of superoxide dismutases. Eur J Rheumatol Inflamm. (1981)
- Margis R1, et al. Glutathione peroxidase family - an evolutionary overview. FEBS J. (2008)
- Messner KR1, Imlay JA. The identification of primary sites of superoxide and hydrogen peroxide formation in the aerobic respiratory chain and sulfite reductase complex of Escherichia coli. J Biol Chem. (1999)
- Bai J1, Cederbaum AI. Mitochondrial catalase and oxidative injury. Biol Signals Recept. (2001)
- Lardinois OM1, Mestdagh MM, Rouxhet PG. Reversible inhibition and irreversible inactivation of catalase in presence of hydrogen peroxide. Biochim Biophys Acta. (1996)
- Ghadermarzi M1, Moosavi-Movahedi AA. Determination of the kinetic parameters for the "suicide substrate" inactivation of bovine liver catalase by hydrogen peroxide. J Enzyme Inhib. (1996)
- Baud O1, et al. Glutathione peroxidase-catalase cooperativity is required for resistance to hydrogen peroxide by mature rat oligodendrocytes. J Neurosci. (2004)
- Sauer H1, Wartenberg M, Hescheler J. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem. (2001)
- Henle ES1, et al. Sequence-specific DNA cleavage by Fe2+-mediated fenton reactions has possible biological implications. J Biol Chem. (1999)
- Imlay JA1, Chin SM, Linn S. Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science. (1988)
- Holmes EW1, et al. Glutathione content of colonic mucosa: evidence for oxidative damage in active ulcerative colitis. Dig Dis Sci. (1998)
- Iantomasi T1, et al. Glutathione metabolism in Crohn's disease. Biochem Med Metab Biol. (1994)
- Lih-Brody L1, et al. Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Dig Dis Sci. (1996)
- Loguercio C1, Di Pierro M. The role of glutathione in the gastrointestinal tract: a review. Ital J Gastroenterol Hepatol. (1999)
- Ardite E1, et al. Replenishment of glutathione levels improves mucosal function in experimental acute colitis. Lab Invest. (2000)
- Loguercio C1, et al. Glutathione supplementation improves oxidative damage in experimental colitis. Dig Liver Dis. (2003)
- Guijarro LG1, et al. N-acetyl-L-cysteine combined with mesalamine in the treatment of ulcerative colitis: randomized, placebo-controlled pilot study. World J Gastroenterol. (2008)
- Mora-Esteves C1, Shin D. Nutrient supplementation: improving male fertility fourfold. Semin Reprod Med. (2013)
- Hansen JC1, Deguchi Y. Selenium and fertility in animals and man--a review. Acta Vet Scand. (1996)
- Ursini F1, et al. Dual function of the selenoprotein PHGPx during sperm maturation. Science. (1999)
- Lenzi A1, et al. Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility. Hum Reprod. (1993)
- Oeda T1, et al. Scavenging effect of N-acetyl-L-cysteine against reactive oxygen species in human semen: a possible therapeutic modality for male factor infertility. Andrologia. (1997)
- Ciftci H1, et al. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status. Urology. (2009)
- Lang CA1, et al. Low blood glutathione levels in healthy aging adults. J Lab Clin Med. (1992)
- Matsubara LS1, Machado PE. Age-related changes of glutathione content, glutathione reductase and glutathione peroxidase activity of human erythrocytes. Braz J Med Biol Res. (1991)
- Erden-Inal M1, Sunal E, Kanbak G. Age-related changes in the glutathione redox system. Cell Biochem Funct. (2002)
- Rebrin I1, Sohal RS. Pro-oxidant shift in glutathione redox state during aging. Adv Drug Deliv Rev. (2008)
- Liu RM1, Dickinson DA. Decreased synthetic capacity underlies the age-associated decline in glutathione content in Fisher 344 rats. Antioxid Redox Signal. (2003)
- Sekhar RV1, et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr. (2011)
- Morais JA1, et al. Whole-body protein turnover in the healthy elderly. Am J Clin Nutr. (1997)
- Fereday A1, et al. Protein requirements and ageing: metabolic demand and efficiency of utilization. Br J Nutr. (1997)
- Jackson AA1, et al. Synthesis of erythrocyte glutathione in healthy adults consuming the safe amount of dietary protein. Am J Clin Nutr. (2004)
- Lyons J1, et al. Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proc Natl Acad Sci U S A. (2000)
- Sonthalia S, Daulatabad D, Sarkar R. Glutathione as a skin whitening agent: Facts, myths, evidence and controversies. Indian J Dermatol Venereol Leprol. (2016)
- Dilokthornsakul W, Dhippayom T, Dilokthornsakul P. The clinical effect of glutathione on skin color and other related skin conditions: A systematic review. J Cosmet Dermatol. (2019)
- Arjinpathana N, Asawanonda P. Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study. J Dermatolog Treat. (2012)
- Watanabe F, et al. Skin-whitening and skin-condition-improving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial in healthy women. Clin Cosmet Investig Dermatol. (2014)
- Weschawalit S, et al. Glutathione and its antiaging and antimelanogenic effects. Clin Cosmet Investig Dermatol. (2017)
- Chauhan A1, et al. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Life Sci. (2004)
- Chauhan A1, Chauhan V. Oxidative stress in autism. Pathophysiology. (2006)
- Ghanizadeh A1, et al. Glutathione-related factors and oxidative stress in autism, a review. Curr Med Chem. (2012)
- Al-Yafee YA1, et al. Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia. BMC Neurol. (2011)
- Geier DA1, et al. A prospective study of transsulfuration biomarkers in autistic disorders. Neurochem Res. (2009)
- Adams JB1, et al. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab (Lond). (2011)
- James SJ1, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. (2004)
- Yorbik O1, et al. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot Essent Fatty Acids. (2002)
- Al-Gadani Y1, et al. Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem. (2009)
- Scott BC1, et al. Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic Res. (1994)
- Shay KP1, et al. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta. (2009)
- Han D1, et al. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors. (1997)
- Bast A1, Haenen GR. Interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation. Biochim Biophys Acta. (1988)
- Busse E1, et al. Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Arzneimittelforschung. (1992)
- Suh JH1, et al. (R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis. Arch Biochem Biophys. (2004)
- Wu GY, Brosnan JT. Macrophages can convert citrulline into arginine. Biochem J. (1992)
- McKinley-Barnard S, et al. Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis. J Int Soc Sports Nutr. (2015)