Glutathione (γ-L-Glutamyl-L-cysteinylglycine) is a small tripeptide molecule composed of three dietary amino acids; L-glutamate, L-cysteine, and glycine.[1] This tripeptide is popularly 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.[2] Glutathione also has a role in conjugating some compounds in the body and priming them for elimination, which has been interpreted as a detoxificative role[3] and also used as validation for its dietary supplementation.

1.2. Sources and Structure

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.[4]Dietary glutathione content, however, does not correlate with systemic glutathione activity.[4]

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 glutathione or its precursor (N-Acetylcysteine). Dietary glutathione does not correlate with overall glutathione activity.

1.3. Biological Significance.

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.[1]

Glutathione 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).[5] 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[6]and enhancing its actions can enhance glutathione activity and its antioxidant effects.[7] A deficiency of GCS results in both a depletion in glutathione as well as a cellular glutathione-S-transferase activity.[8] Due to glutathione itself exerting a negative regulatory role on this enzyme (in both bacterial[9] and rat cells;[10] latter being homologous to human[11]) 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.[12] This enzyme is present in yeast and bacteria although they share little homology with rat and human variants,[13][14] and the rat variant has around 88% homology with the human variant.[15] The enzyme appears to requite Cys-422 to function in humans[16] and its function can be inhibited in experiments with Methionine SulfOximine (MSO).[17]

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;[18] due to this, supplementation of N-acetylcysteine is sometimes used to increase glutathione synthesis (after N-acetylcysteine gets deacetylated to form L-cysteine, however).[18]

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.[19]

Oxidized glutathione (GSSG) can be converted back into GSH via the NADPH-dependent glutathione disulfide reductase enzyme,[12] and the activity of this enzyme seems to be in part controlled by glutathione itself.[20] The activity of this enzyme appears to be a major determinant of the overall GSH/GSSG ratio.[12]

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 anti-oxidative 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 anti-oxidative effect.[21]

GST enzymes are divided into eight distinct classes in mammals of alpha (α),[22] mu (μ),[23] pi (π),[24]theta (θ),[25] zeta (ζ),[26] sigma (σ),[27] omega (ω),[27] and the mitochondrial kappa (κ)[28][29] divided into two superfamilies of soluble GSTs located in the cytosol (with the exception of kappa)[27] and microsomal GSTs collectively known as Membrane-Associated Proteins in Eicosanoid and Glutathione metabolism (MAPEG) which are associated with cellular membranes.[30]

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.[31] These enzymes are selenium-dependent enzymes and a reduction in their activity in the body mediates the adverse effects of selenium deficiency.[31][32]

Glutathine S-transferase (GST) and glutathione peroxidase (GPx) enzymes mediate many of the anti-oxidative actions of glutathione. and in general this process modifies [34][33]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)the proteins actions and is involved in regulating transcription[35] and both protein folding and degradation.[36] 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.

2 Pharmacology

2.1. Absorption

Glutathione, due to being a small peptide molecule, is subject to hydrolysis (digestion) in the small intestines usually by γ-glutamyltransferase in the brush border of the jejunum[37] where the enzyme predominates.[38] There may also be hydrolysis post-absorption since infusions of glutathione are mostly degraded into its constituent amino acids and increase serum L-cysteine.[39]

There appears to be a transporter for glutathione absorption in human intestinal cells[40] and increases in serum[41] and tissue[42] glutathione have been noted with orally supplemented glutathione in rats, but overall glutathione activity in the human does not correlate with dietary glutathione.[4]

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.

2.2. Serum

Oral ingestion of 3g glutathione (0.15mM/kg) solution in otherwise healthy subjects has failed to increase circulating glutathione concentrations over the course of the next 270 minutes relative to baseline[43] and infusions of glutathione have noted that the increase in serum L-cysteine is approximately equivalent to the amount of L-cysteine within glutathione[39][44] 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[45] 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;[46] 250mg was less effective at six months relative to 1,000mg.[46]

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

2.3. Cellular Kinetics

Glutathione is synthesized intracellularly, and while it can be effluxed from a cell it tends to be hydrolyzed to its constituent amino acids to then be taken back up by cells and resynthesized intracellularly into glutathione.[18]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[47]) for extracellular transport, and upon reaching another tissue the γ-glutamylamino acid dipeptide is cleaved by γ-glutamyl cyclotransferaseto free the amino acid and produce the cyclic form of glutamic acid (5-oxoproline) which is converted into glutamine by 5-oxoprolinase.[48][18]

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[49]and the half-life has been noted to be around 14.1+/-9.2 minutes.[44] The cells that have been noted to be able to absorb intact glutathione include hepatocytes (HepG2[50]), intestinal mucosal cells,[51]and retinal cells.[52][53]

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.

2.4. Phase II Enzyme Interactions

Glutathione can be conjugated to other molecules by select Phase II Enzymes; while this process is classically referred to as a detoxification process as this conjugation 'tags' the molecule for removal by the liver and kidneys[54] in some cases glutathione conjugation serves to bioactive the target molecule.[55] This process applies to both xenobiotics (things originating from outside the body) as well as some endogenous molecules like steroids[56] and prostaglandins.[57]

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.[58] 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.[54][55]

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.

3 Cardiovascular Health

3.1. Cardiac Tissue

In rats subject to treadmill training, oral supplementation of 5g/kg glutathione for 17 days prior to ischemia-reperfusion (IR), supplementation was protective; glutathione reduced the IR-induced increases in left ventricular systolic pressure and also increased contractility (+dP/dt) more than glutathione alone and training alone (the latter of which was not protective).[59]

4 Inflammation and Immunology

4.1. Virological Interactions

Macrophages from people with HIV appear to have higher concentrations of GSSG (relative to reduced glutathione) than do macrophages from noninfected controls.[60] This was thought to be related to a reduced expression of glutamine-cysteine ligase (GCLC) seen with HIV infection in macrophages.[60]

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.[60] The difference in potency persisted when assessing lipid peroxidation (via malondialdehyde assay) and in reducing the intracellular growth of M. tuberculosis.[60]

The immune system works best if the lymph cells have sufficient glutathione. The cloning of T-cells consumes large quantities of cysteine. Macrophages (white blood cells), which are only present in sufficient quantities when there is sufficient glutathione, provide the cysteine for the T-cell cloning. Glutathione regulates the binding, internalization, degradation and T-cell proliferation by increasing the number of binding cellular receptors. More
Enhancement of Immune Functionequates to more T-cells being produced. Cellular GSH also affects the growth and replication of T-cells through growth stimulating cytokines.receptors
The role of glutathione in the humoral response is that it protects
Enhancement of Humoral Immune Functioncells taking part in the humoral response. A quick synopsis of the humoral immune response: “humoral” means circulating in the bloodstream. This is an immune response (chiefly against bacterial invasion) that is mediated by B cells and involves the transformation of B cells into plasma cells that produce and secrete antibodies to a specific antigen. The process in a nutshell: Macrophages engulf and digest the invading pathogen. The digested pieces activate helper T cells which in turn activate the proliferation of B cells that are programed for the specific invading pathogenthe

5 Interactions with Oxidation

5.1. Superoxide

Superoxide (O2-), produced when a single electron is abstracted by an oxygen molecule (O2) or as the byproduct of metabolic reactions,[61] is a free radical with which both N-acetylcysteine[62] and glutathione[63][64] 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-)[65] and since O2 is ubiquitously required in metabolic reactions.[61]

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 sequestration of O2- tends to be handled by the superoxide dismutase (SOD) enzymes which convert O2- into hydrogen peroxide (H2O2).[66][67]

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 anti-oxidative potential indirectly reducing superoxide.

5.2. Hydrogen Peroxide

The superoxide radical is converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD), and once this occurs the enzyme glutathione peroxidase (GPx) is able to reduce it to H2O via utilization of two glutathione tripeptides (and formation of GSSG afterward).[68] H2O2 may also be produced as a byproduct in aerobic metabolic reactions.[61][69]

The antioxidant enzyme catalase also removes H2O2 by decomposing it into water and oxygen.[70] Catalase and GPx act cooperatively, as H2O2 can inactivate catalase at high concentrations[71][72]and this inactivation appears to be protected against by GPx.[73]

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).

5.3. Hydroxyl

The hydroxyl radical (OH•, the neutral form of hydroxide which is OH-) is a potent radical produced when O2- reacts with iron via a Fenton reaction, and unlike O2- and H2O2 which are mild and reversible oxidants OH• is an irreversible modifier of protein structures.[74] Hydroxyl is thought to mediate many of the more adverse effects of elevated H2O2 concentrations in a cell such as the subsequent DNA damage.[75][76]

6 Peripheral Organ Systems

6.1. Intestines

Inflammatory bowel diseases, including ulcerative colitis[77] and Crohn's disease.[78], are characterized by increases in oxidative stress and simultaneous reductions in oxidative defenses such as glutathione concentrations.[79] As glutathione is the major nonenzymatic antioxidant in gastrointestinal tissue[80] and since measures that preserve glutathione tend to reduce inflammation and oxidative stress in animal models of these disease states[81] 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.[82]

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.[83]

6.2. Male Sex Organs

Male infertility is a state characterized by excessive oxidative stress which suggests a possible therapeutic role of antioxidants in general.[84] 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).[85][86]

Glutathione's therapeutic effect was confirmed in one study using 600mg glutathione as an intramuscular injection which yielded improved sperm motility.[87] This specific benefit (improved motility) has also been noted in vitro with N-acetylcysteine[88] and with 600mg NAC daily in infertile men over the course of three months.[89]

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.

7 Longevity and Life Extension

7.1. Rationale

Glutathione content is reduced in cells during the aging process even in the absence of disease,[90][91][92] resulting in a more oxidative state.[93] 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[94]) with no alterations in its metabolism by γ-glutamyltranspeptidase or restoration into an antioxidant by glutathione reductase,[94] 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.[95] This decrease could be associated with a reduction in whole-body protein turnover seen in aging,[96][97] which would decrease pools of glycine and cysteine for use in glutathione synthesis.[95] 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,[95] 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.[95]

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[98] or just the sulfur-containing amino acids found in dietary protein.[99]

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.

8 Nutrient-Nutrient Interactions

8.1. Alpha-lipoic acid

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.[109] 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.[110]

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.[18] 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,[111] which is the substrate needed for the rate-limiting step in glutathione synthesis.[18] Furthermore, GSSG (the oxidized form of glutathione) can be directly reduced back into GSH via reduced alpha-lipoic acid[112] 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[18][113][112][114] and appears to occur in vivo with 16mg/kg ALA in rats.[113]

Alpha-lipoic acid can reduce oxidized glutathione, thereby enhancing and preserving glutathione's actions in a cell.

8.2. Citrulline

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 bloodstream. L-citrulline is a byproduct of NO synthesis that can be converted back into arginine through the arginine-citrulline cycle. [115] For this reason, L-citrulline is a more efficient way to increase blood L-arginine.[116]

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.[116] 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.[116]

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 bloodstream due to the presence of glutathione.

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