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- Methionine-Adequate Cysteine-Free Diet Does Not Limit Erythrocyte Glutathione Synthesis in Young Healthy Adult Men
So it was on healthy people and very short, I doubt they would be able to sustain this for long without compromising nutrition over the times.
As it was commented above, I suspect that depleting yourself of antioxidants is not the best alternative. When all required nutrients are given, the body will have enough reagents to push on whatever direction is ideal. There are also other means to generate oxidative stress that won't leave the body starved.
I don't understand why Chris recommends straight glutathione instead of cysteine, it's possible that he's actually getting paid to share that (for real). Even when it's absorbed intact, which is not often the case, most tissues require reassembling of the molecule.
- Glutathione - Scientific Review on Usage, Dosage, Side Effects
- Acetylcysteine - Wikipedia
- Glutathione synthesis (Chris)
"Cysteine is unstable extracellularly where it readily autoxidizes to cystine, which is taken up by some cells and is rapidly reduced to cysteine intracellularly [47]."
"GS[ynth(et)ase] has received relatively little attention in the field of GSH biosynthesis. GS is composed of two identical subunits and is not subject to feedback inhibition by GSH [48]. GS deficiency in humans can result in dramatic metabolic consequences because the accumulated γ-glutamylcysteine is converted to 5-oxoproline, which can cause severe metabolic acidosis, hemolytic anemia and central nervous system damage [137,138]."
Source: the internet.
"There is accumulating data that reduced GSH levels occur in many human diseases and they contribute to worsening of the condition [4]. While oxidative injury plays a dominant role in GSH depletion in many of these disorders, some are causally related to reduced expression of GSH synthetic enzymes [13]."
"Endotoxemia lowers GSH levels in the liver [156,157], peritoneal macrophages and lymphocytes [158]. Septic patients have lower blood GSH:GSSG ratios [159]. Exogenous GSH treatment suppressed LPS-induced systemic inflammatory response and reduced mortality [160]. GSH level is an important variable that determines susceptibility to LPS-induced injury in multiple tissues [157,160,161]. This may be related to GSH’s ability to influence toll like receptor 4 (TLR4) signaling. Specifically, LPS-induced mortality and TNFα secretion were higher when GSH level was reduced [162]. The fall in GSH is multifactorial. In liver, increased GSH efflux and increased oxidative stress both contribute [153,156]."
- The Consequences Of Cheese As A Main Source Of Protein
- Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study.
- https://chrismasterjohnphd.com/2017/01/13/manage-glutathione-status/
NAC is 75% cysteine and the standard dose of supplements is 600 mg, providing 850 kg. But then there's the bioavaialisbity issues which might be different from foods.
- An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly
- A Review on Various Uses of N-Acetyl Cysteine
"The goal of this study was to determine whether GSH synthesis would increase following supplementation of the level of total SAA (TSAA) intake that supported maximum protein synthesis. This was determined by measuring erythrocyte GSH fractional and absolute synthesis rates (ASR) as well as erythrocyte GSH concentration in healthy adult men fed a diet providing 1 g/kg protein in the presence of the mean population requirement for TSAA (as methionine only) of 14 mg·kg−1·d−1 and a varying additional cysteine intake."
"Cysteine intake did not affect erythrocyte GSH concentration":
"This is the first study, to our knowledge, to report on the erythrocyte GSH kinetics in healthy adult male in response to varying cysteine intake levels in the presence of adequate protein and energy intakes and the mean methionine requirement of 14 mg·kg−1·d−1. These results suggest that in the presence of an adequate protein intake of 1 g·kg−1·d−1 and the mean methionine requirement of 14 mg·kg−1·d−1 (19,21), further increases in the SAA intake in the form of cysteine did not affect erythrocyte GSH metabolism (Fig. 2). The GSH synthesis rates and concentrations in the current study were similar to those in previous studies of GSH kinetics in healthy adults (6,7)."
"The inability to measure GSH kinetics in liver or muscle due to practical and ethical considerations is a potential limitation of in vivo studies with healthy subjects. However, erythrocyte GSH kinetics has been shown to respond to dietary changes in disease (10,11), malnutrition (8), and even to small decreases in protein intake (7), demonstrating that erythrocyte GSH is a sensitive pool from which to detect changes in GSH metabolism. At a protein intake of 0.75 g·kg−1·d−1, set by WHO as the safe intake (26), Jackson et al. (7) showed decreased erythrocyte GHS synthesis when compared with a habitual protein intake of 1.13 g·kg−1·d−1. In fact, this higher protein requirement was recently confirmed by our group, showing that a safe intake of protein is closer to 1 g·kg−1·d−1 (27). In addition, cysteine supplementation at only 15 mg·kg−1·d−1 produced significantly increased GSH synthesis in symptom-free HIV individuals (10), suggesting that at the cysteine intakes used in the current study, significant changes in GSH metabolism should have been observed had they occurred."
"Although we did not observe changes in GSH metabolism in response to feeding graded intakes of cysteine to healthy adults receiving the previously derived mean methionine (TSAA) requirement (Fig. 2), we observed a significant linear increase in urinary sulfate production in response to graded cysteine intakes (Fig. 3)."
"The precise mechanisms governing all aspects of SAA metabolism are not yet completely understood. However, the increases in urinary sulfate excretion in the current study can be partly explained by work conducted by Stipanuk et al (13). Because excess cysteine is considered toxic, the liver regulates cysteine concentration within a small range and maintains a plasma concentration within a 2.5-fold range (13). Cysteine concentration has been found to be the key regulator of it own metabolism (4,5,15,28–30). When protein and/or SAA intake is low, γ-glutamylcysteine synthetase, the rate-limiting enzyme for GSH synthesis is upregulated, resulting in a greater partitioning of SAA toward GSH synthesis. On the other hand, when protein and/or SAA intake is increased, cysteine dioxygenase the enzyme that catalyzes cysteine to sulfate and taurine, is upregulated, resulting in greater partitioning of cysteine toward sulfate production. Thus, increasing urinary sulfate observed in the present study appears to be due to increased partitioning of dietary cysteine toward catabolism in response to graded intakes of cysteine."
"However, a closer look at the pattern of the isotope results reveals a similar rate of erythrocyte GSH synthesis at cysteine intakes of 0, 20, 30, and 40 mg·kg−1·d−1, with an almost 45% increase from 0 at a cysteine intake of 10 mg·kg−1·d−1. This increase in GSH synthesis, although not significant (P = 0.49), may be of biological importance, especially because other investigators have shown significant results at lower changes in synthesis rates (6,7). The observed similar GSH synthesis rates at cysteine intakes of 20 mg·kg−1·d−1 and above to that observed at a 0 cysteine intake suggest a return to baseline at the higher cysteine intakes. This is supported by previous data that show that increasing the level of protein (soy and casein), as well as the SAA methionine and cysteine, in the diets of rats or the addition of SAA to the culture medium of primary rat hepatocyte results in increased cysteine dioxygenase and decreased γ-glutamylcysteine activity (5,28,29). In healthy humans, a deficient protein and or SAA intake has been shown to significantly decrease GSH synthesis (6,7). Although no comparison studies of graded protein or SAA intake have been published, supplemental cysteine has been found to restore GSH synthesis to that of controls in diseased individuals (8,10)."
"Cysteine intake did not affect erythrocyte GSH concentration":
"This is the first study, to our knowledge, to report on the erythrocyte GSH kinetics in healthy adult male in response to varying cysteine intake levels in the presence of adequate protein and energy intakes and the mean methionine requirement of 14 mg·kg−1·d−1. These results suggest that in the presence of an adequate protein intake of 1 g·kg−1·d−1 and the mean methionine requirement of 14 mg·kg−1·d−1 (19,21), further increases in the SAA intake in the form of cysteine did not affect erythrocyte GSH metabolism (Fig. 2). The GSH synthesis rates and concentrations in the current study were similar to those in previous studies of GSH kinetics in healthy adults (6,7)."
"The inability to measure GSH kinetics in liver or muscle due to practical and ethical considerations is a potential limitation of in vivo studies with healthy subjects. However, erythrocyte GSH kinetics has been shown to respond to dietary changes in disease (10,11), malnutrition (8), and even to small decreases in protein intake (7), demonstrating that erythrocyte GSH is a sensitive pool from which to detect changes in GSH metabolism. At a protein intake of 0.75 g·kg−1·d−1, set by WHO as the safe intake (26), Jackson et al. (7) showed decreased erythrocyte GHS synthesis when compared with a habitual protein intake of 1.13 g·kg−1·d−1. In fact, this higher protein requirement was recently confirmed by our group, showing that a safe intake of protein is closer to 1 g·kg−1·d−1 (27). In addition, cysteine supplementation at only 15 mg·kg−1·d−1 produced significantly increased GSH synthesis in symptom-free HIV individuals (10), suggesting that at the cysteine intakes used in the current study, significant changes in GSH metabolism should have been observed had they occurred."
"Although we did not observe changes in GSH metabolism in response to feeding graded intakes of cysteine to healthy adults receiving the previously derived mean methionine (TSAA) requirement (Fig. 2), we observed a significant linear increase in urinary sulfate production in response to graded cysteine intakes (Fig. 3)."
"The precise mechanisms governing all aspects of SAA metabolism are not yet completely understood. However, the increases in urinary sulfate excretion in the current study can be partly explained by work conducted by Stipanuk et al (13). Because excess cysteine is considered toxic, the liver regulates cysteine concentration within a small range and maintains a plasma concentration within a 2.5-fold range (13). Cysteine concentration has been found to be the key regulator of it own metabolism (4,5,15,28–30). When protein and/or SAA intake is low, γ-glutamylcysteine synthetase, the rate-limiting enzyme for GSH synthesis is upregulated, resulting in a greater partitioning of SAA toward GSH synthesis. On the other hand, when protein and/or SAA intake is increased, cysteine dioxygenase the enzyme that catalyzes cysteine to sulfate and taurine, is upregulated, resulting in greater partitioning of cysteine toward sulfate production. Thus, increasing urinary sulfate observed in the present study appears to be due to increased partitioning of dietary cysteine toward catabolism in response to graded intakes of cysteine."
"However, a closer look at the pattern of the isotope results reveals a similar rate of erythrocyte GSH synthesis at cysteine intakes of 0, 20, 30, and 40 mg·kg−1·d−1, with an almost 45% increase from 0 at a cysteine intake of 10 mg·kg−1·d−1. This increase in GSH synthesis, although not significant (P = 0.49), may be of biological importance, especially because other investigators have shown significant results at lower changes in synthesis rates (6,7). The observed similar GSH synthesis rates at cysteine intakes of 20 mg·kg−1·d−1 and above to that observed at a 0 cysteine intake suggest a return to baseline at the higher cysteine intakes. This is supported by previous data that show that increasing the level of protein (soy and casein), as well as the SAA methionine and cysteine, in the diets of rats or the addition of SAA to the culture medium of primary rat hepatocyte results in increased cysteine dioxygenase and decreased γ-glutamylcysteine activity (5,28,29). In healthy humans, a deficient protein and or SAA intake has been shown to significantly decrease GSH synthesis (6,7). Although no comparison studies of graded protein or SAA intake have been published, supplemental cysteine has been found to restore GSH synthesis to that of controls in diseased individuals (8,10)."
So it was on healthy people and very short, I doubt they would be able to sustain this for long without compromising nutrition over the times.
As it was commented above, I suspect that depleting yourself of antioxidants is not the best alternative. When all required nutrients are given, the body will have enough reagents to push on whatever direction is ideal. There are also other means to generate oxidative stress that won't leave the body starved.
I don't understand why Chris recommends straight glutathione instead of cysteine, it's possible that he's actually getting paid to share that (for real). Even when it's absorbed intact, which is not often the case, most tissues require reassembling of the molecule.
- Glutathione - Scientific Review on Usage, Dosage, Side Effects
"There may be some absorption of glutathione intact from the intestines, but it cannot enter cells intact. It must be metabolized to form L-cystine (two molecules of L-cysteine bound together) before being taken up."
"In effect, glutathione is an indirect and expensive way to provide dietary L-cysteine. Dietary protein itself, including L-cysteine rich sources such as Whey Protein, are effective but inefficient ways to increase L-cysteine intake in the diet and N-Acetylcysteine is both more efficient and cheaper than glutathione."
"Although oral glutathione supplementation does not efficiently increase intracellular glutathione levels for the above reasons, it can be absorbed intact into the blood stream. Since increased glutathione levels in the blood have been shown to slow the breakdown of nitric oxide, glutathione supplementation may be useful to augment nitric oxide boosters such as L-Citrulline or L-Arginine."
"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]"
"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]" "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]"
"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]"
"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 determinent of the overall GSH/GSSG ratio.[12]"
"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 [again,] overall glutathione activity in the human does not correlate with dietary glutathione.[4]"
"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]"
"The superoxide radical is converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD), and once this occurs the enzyme glutathione peroxidase (GPx) [involves selenium] is able to reduce it to H2O via utilization of two glutathione tripeptides (and formation of GSSG afterwards).[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 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]"
"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]"
"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]"
"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. [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] "
"In effect, glutathione is an indirect and expensive way to provide dietary L-cysteine. Dietary protein itself, including L-cysteine rich sources such as Whey Protein, are effective but inefficient ways to increase L-cysteine intake in the diet and N-Acetylcysteine is both more efficient and cheaper than glutathione."
"Although oral glutathione supplementation does not efficiently increase intracellular glutathione levels for the above reasons, it can be absorbed intact into the blood stream. Since increased glutathione levels in the blood have been shown to slow the breakdown of nitric oxide, glutathione supplementation may be useful to augment nitric oxide boosters such as L-Citrulline or L-Arginine."
"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]"
"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]" "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]"
"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]"
"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 determinent of the overall GSH/GSSG ratio.[12]"
"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 [again,] overall glutathione activity in the human does not correlate with dietary glutathione.[4]"
"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]"
"The superoxide radical is converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD), and once this occurs the enzyme glutathione peroxidase (GPx) [involves selenium] is able to reduce it to H2O via utilization of two glutathione tripeptides (and formation of GSSG afterwards).[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 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]"
"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]"
"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]"
"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. [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] "
- Acetylcysteine - Wikipedia
"Acetylcysteine was initially patented in 1960 and licensed for use in 1968.[9] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[10] It is available as a generic medication and is inexpensive.[11]"
"Although both IV and oral acetylcysteine are equally effective for this indication, oral administration is poorly tolerated because high oral doses are required due to low oral bioavailability,[14] because of its very unpleasant taste and odour, and because of adverse effects, particularly nausea and vomiting."
"Although N-acetylcysteine prevented liver damage when taken before alcohol, when taken four hours after alcohol it made liver damage worse in a dose-dependent fashion.[49]"
"Although both IV and oral acetylcysteine are equally effective for this indication, oral administration is poorly tolerated because high oral doses are required due to low oral bioavailability,[14] because of its very unpleasant taste and odour, and because of adverse effects, particularly nausea and vomiting."
Pharmacokinetics of N-acetylcysteine in man (not the reference above)
"The oral availability of N-acetylcysteine varied between 6 and 10%, with the slow-release tablet having the lowest and the fast dissolving tablet the highest availability."
"The oral availability of N-acetylcysteine varied between 6 and 10%, with the slow-release tablet having the lowest and the fast dissolving tablet the highest availability."
"Although N-acetylcysteine prevented liver damage when taken before alcohol, when taken four hours after alcohol it made liver damage worse in a dose-dependent fashion.[49]"
- Glutathione synthesis (Chris)
"Cysteine is unstable extracellularly where it readily autoxidizes to cystine, which is taken up by some cells and is rapidly reduced to cysteine intracellularly [47]."
"GS[ynth(et)ase] has received relatively little attention in the field of GSH biosynthesis. GS is composed of two identical subunits and is not subject to feedback inhibition by GSH [48]. GS deficiency in humans can result in dramatic metabolic consequences because the accumulated γ-glutamylcysteine is converted to 5-oxoproline, which can cause severe metabolic acidosis, hemolytic anemia and central nervous system damage [137,138]."
Source: the internet.
"There is accumulating data that reduced GSH levels occur in many human diseases and they contribute to worsening of the condition [4]. While oxidative injury plays a dominant role in GSH depletion in many of these disorders, some are causally related to reduced expression of GSH synthetic enzymes [13]."
"Endotoxemia lowers GSH levels in the liver [156,157], peritoneal macrophages and lymphocytes [158]. Septic patients have lower blood GSH:GSSG ratios [159]. Exogenous GSH treatment suppressed LPS-induced systemic inflammatory response and reduced mortality [160]. GSH level is an important variable that determines susceptibility to LPS-induced injury in multiple tissues [157,160,161]. This may be related to GSH’s ability to influence toll like receptor 4 (TLR4) signaling. Specifically, LPS-induced mortality and TNFα secretion were higher when GSH level was reduced [162]. The fall in GSH is multifactorial. In liver, increased GSH efflux and increased oxidative stress both contribute [153,156]."
- The Consequences Of Cheese As A Main Source Of Protein
The difference between meats and cheeses for every 35 g or so of protein is about 200 mg of cystine (first quoted paragraph from the last link).
- Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study.
"Cysteine is the [major?] limiting factor for GSH synthesis and its represents 33.6% of the GSH molecule [24]. Providing 200 mg of cysteine (commercial dosage) would be sufficient for the body to theoretically synthetize de novo up to 600 mg of GSH."
- https://chrismasterjohnphd.com/2017/01/13/manage-glutathione-status/
"[Healthy humans] make about 185 mg of glutathione per day."
NAC is 75% cysteine and the standard dose of supplements is 600 mg, providing 850 kg. But then there's the bioavaialisbity issues which might be different from foods.
- An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly
- A Review on Various Uses of N-Acetyl Cysteine
