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Glutathione Metabolism and Its Implications for Health


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Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.
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Recent Advances in Nutritional Sciences
Glutathione Metabolism and Its
Implications for Health
Guoyao Wu,
Yun-Zhong Fang,* Sheng Yang,
Joanne R. Lupton, and Nancy D. Turner
Faculty of Nutrition, Texas A&M University, College Station, TX,
77843; *Department of Biochemistry and Molecular Biology,
Beijing Institute of Radiation Medicine, Beijing, China 100850; and
Department of Animal Nutrition, China Agricultural University,
Beijing, China 100094
ABSTRACT Glutathione (
-glutamyl-cysteinyl-glycine; GSH)
is the most abundant low-molecular-weight thiol, and GSH/
glutathione disulfide is the major redox couple in animal
cells. The synthesis of GSH from glutamate, cysteine, and
glycine is catalyzed sequentially by two cytosolic enzymes,
-glutamylcysteine synthetase and GSH synthetase. Com-
pelling evidence shows that GSH synthesis is regulated
primarily by
-glutamylcysteine synthetase activity, cys-
teine availability, and GSH feedback inhibition. Animal and
human studies demonstrate that adequate protein nutrition
is crucial for the maintenance of GSH homeostasis. In ad-
dition, enteral or parenteral cystine, methionine, N-acetyl-
cysteine, and
L-2-oxothiazolidine-4-carboxylate are effec-
tive precursors of cysteine for tissue GSH synthesis.
Glutathione plays important roles in antioxidant defense,
nutrient metabolism, and regulation of cellular events (in-
cluding gene expression, DNA and protein synthesis, cell
proliferation and apoptosis, signal transduction, cytokine
production and immune response, and protein glutathiony-
lation). Glutathione deficiency contributes to oxidative
stress, which plays a key role in aging and the pathogene-
sis of many diseases (including kwashiorkor, seizure, Alz-
heimer’s disease, Parkinson’s disease, liver disease, cystic
fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack,
stroke, and diabetes). New knowledge of the nutritional
regulation of GSH metabolism is critical for the develop-
ment of effective strategies to improve health and to treat
these diseases. J. Nutr. 134: 489 492, 2004.
amino acids
oxidative stress
The work with glutathione (
has greatly advanced biochemical and nutritional sci-
ences over the past 125 y (1,2). Specifically, these studies have
led to the free radical theory of human diseases and to the
advancement of nutritional therapies to improve GSH status
under various pathological conditions (2,3). Remarkably, the
past decade witnessed the discovery of novel roles for GSH in
signal transduction, gene expression, apoptosis, protein gluta-
thionylation, and nitric oxide (NO) metabolism (2,4). Most
recently, studies of in vivo GSH turnover in humans were
initiated to provide much-needed information about quanti-
tative aspects of GSH synthesis and catabolism in the whole
body and specific cell types (e.g., erythrocytes) (3,5–7). This
article reviews the recent developments in GSH metabolism
and its implications for health and disease.
Abundance of GSH in Cells and Plasma. Glutathione is
the predominant low-molecular-weight thiol (0.5–10 mmol/L)
in animal cells. Most of the cellular GSH (85–90%) is present
in the cytosol, with the remainder in many organelles (includ-
ing the mitochondria, nuclear matrix, and peroxisomes) (8).
With the exception of bile acid, which may contain up to 10
mmol/L GSH, extracellular concentrations of GSH are rela-
tively low (e.g., 2–20
mol/L in plasma) (4,9). Because of the
cysteine residue, GSH is readily oxidized nonenzymatically to
glutathione disulfide (GSSG) by electrophilic substances (e.g.,
free radicals and reactive oxygen/nitrogen species). The GSSG
efflux from cells contributes to a net loss of intracellular GSH.
Cellular GSH concentrations are reduced markedly in re-
sponse to protein malnutrition, oxidative stress, and many
pathological conditions (8,9). The GSH 2GSSG concen-
tration is usually denoted as total glutathione in cells, a sig-
nificant amount of which (up to 15%) may be bound to
protein (1). The [GSH]:[GSSG] ratio, which is often used as
an indicator of the cellular redox state, is 10 under normal
physiological conditions (9). GSH/GSSG is the major redox
couple that determines the antioxidative capacity of cells, but
its value can be affected by other redox couples, including
and thioredoxin
GSH Synthesis. The synthesis of GSH from glutamate,
cysteine, and glycine is catalyzed sequentially by two cytosolic
-glutamylcysteine synthetase (GCS) and GSH syn-
thetase (Fig. 1). This pathway occurs in virtually all cell types,
with the liver being the major producer and exporter of GSH.
In the GCS reaction, the
-carboxyl group of glutamate reacts
with the amino group of cysteine to form a peptidic
which protects GSH from hydrolysis by intracellular pepti-
dases. Although
-glutamyl-cysteine can be a substrate for
-glutamylcyclotransferase, GSH synthesis is favored in ani-
mal cells because of the much higher affinity and activity of
GSH synthetase (9).
Mammalian GCS is a heterodimer consisting of a catalyt-
ically active heavy subunit (73 kDa) and a light (regulatory)
subunit (31 kDa) (8). The heavy subunit contains all substrate
binding sites, whereas the light subunit modulates the affinity
of the heavy subunit for substrates and inhibitors. The K
values of mammalian GCS for glutamate and cysteine are 1.7
and 0.15 mmol/L, respectively, which are similar to the intra-
cellular concentrations of glutamate (2– 4 mmol/L) and cys-
teine (0.15–0.25 mmol/L) in rat liver (9). Mammalian GSH
Supported by grants from the American Heart Association (0255878Y), the
National Institutes of Health (R01CA61750), the National Space Biomedical Re-
search Institute (00202), and the National Institute of Environmental Health Sci-
ences (P30-ES09106).
To whom correspondence should be addressed. E-mail:
Abbreviations used: GCS,
-glutamylcysteine synthetase; GSH, glutathione;
GSSG, glutathione disulfide.
0022-3166/04 $8.00 © 2004 American Society for Nutritional Sciences.
Manuscript received 5 December 2003. Initial review completed 16 December 2003. Revision accepted 18 December 2003.
by on January 9, 2008 jn.nutrition.orgDownloaded from
synthetase is a homodimer (52 kDa/subunit) and is an alloste-
ric enzyme with cooperative binding for
-glutamyl substrate
(10). The K
values of mammalian GSH synthetase for ATP
and glycine are 0.04 and 0.9 mmol/L, respectively, which are
lower than intracellular concentrations of ATP (24 mmol/L)
and glycine (1.52 mmol/L) in rat liver. Both subunits of rat
GCS and GSH synthetase have been cloned and sequenced
(9), which facilitates the study of molecular regulation of GSH
-Glutamylcysteine synthetase is the rate-control-
ling enzyme in de novo synthesis of GSH (8).
Knowledge regarding in vivo GSH synthesis is limited, due
in part to the complex compartmentalization of substrates and
their metabolism at both the organ and subcellular levels. For
example, the source of glutamate for GCS differs between the
small intestine and kidney (e.g., diet vs. arterial blood). In
addition, liver GSH synthesis occurs predominantly in
perivenous hepatocytes and, to a lesser extent, in periportal
cells (11). Thus, changes in plasma GSH levels may not
necessarily reect changes in GSH synthesis in specic cell
types. However, recent studies involving stable isotopes (57)
have expanded our understanding of GSH metabolism. In
healthy adult humans, the endogenous disappearance rate
(utilization rate) of GSH is 25
mol/(kg h) (6), which
accounts for 65% of whole body cysteine ux [38.3
h)]. This nding supports the view that GSH acts as a major
transport form of cysteine in the body. On the basis of dietary
cysteine intake [9
mol/(kg h)] in healthy adult humans (6),
it is estimated that most of the cysteine used for endogenous
GSH synthesis is derived from intracellular protein degrada-
tion and/or endogenous synthesis. Interestingly, among extra-
hepatic cells, the erythrocyte has a relatively high turnover
rate for GSH. For example, the whole-blood fractional syn-
thesis rate of GSH in healthy adult subjects is 65%/d (6),
which means that all the GSH is completely replaced in 1.5 d;
this value is equivalent to 3
mol/(kg h). Thus, whole blood
(mainly erythrocytes) may contribute up to 10% of whole-
body GSH synthesis in humans (5,6).
Regulation of GSH Synthesis by GCS. Oxidant stress,
nitrosative stress, inammatory cytokines, cancer, cancer che-
motherapy, ionizing radiation, heat shock, inhibition of GCS
activity, GSH depletion, GSH conjugation, prostaglandin A
heavy metals, antioxidants, and insulin increase GCS tran-
scription or activity in a variety of cells (2,8). In contrast,
dietary protein deciency, dexamethasone, erythropoietin, tu-
mor growth factor
, hyperglycemia, and GCS phosphoryla-
tion decrease GCS transcription or activity. Nuclear factor
mediates the upregulation of GCS expression in response to
oxidant stress, inammatory cytokines, and buthionine sulfox-
imineinduced GSH depletion (2,8). S-nitrosation of GCS
protein by NO donors (e.g., S-nitroso-
L-cysteine and S-ni-
L-cysteinylglycine) reduces enzyme activity (8), suggest-
ing a link between NO (a metabolite of
L-arginine) and GSH
metabolism. Indeed, an increase in NO production by induc-
ible NO synthase causes GCS inhibition and GSH depletion
in cytokine-activated macrophages and neurons (12). In this
regard, glucosamine, taurine, n-3 PUFAs, phytoestrogens,
polyphenols, carotenoids, and zinc, which inhibit the expres-
sion of inducible NO synthase and NO production (13), may
prevent or attenuate GSH depletion in cells. Conversely,
high-fat diet, saturated long-chain fatty acids, low-density
lipoproteins, linoleic acid, and iron, which enhance the ex-
pression of inducible NO synthase and NO production (13),
may exacerbate the loss of GSH from cells.
Regulation of GSH Synthesis by Amino Acids. Cysteine
is an essential amino acid in premature and newborn infants
and in subjects stressed by disease (14). As noted above, the
intracellular pool of cysteine is relatively small, compared with
the much larger and often metabolically active pool of GSH in
cells (15). Recent studies provide convincing data to support
the view that cysteine is generally the limiting amino acid for
GSH synthesis in humans, as in rats, pigs, and chickens
(6,14,15). Thus, factors (e.g., insulin and growth factors) that
stimulate cysteine (cystine) uptake by cells generally increase
intracellular GSH concentrations (8). In addition, increasing
the supply of cysteine or its precursors (e.g., cystine, N-acetyl-
cysteine, and
L-2-oxothiazolidine-4-carboxylate) via oral or
intravenous administration enhances GSH synthesis and pre-
vents GSH deciency in humans and animals under various
nutritional and pathological conditions (including protein
malnutrition, adult respiratory distress syndrome, HIV, and
AIDS) (2). Because cysteine generated from methionine ca-
tabolism via the transsulfuration pathway (primarily in hepa-
tocytes) serves as a substrate for GCS, dietary methionine can
replace cysteine to support GSH synthesis in vivo.
Cysteine is readily oxidized to cystine in oxygenated extra-
cellular solutions. Thus, the plasma concentration of cysteine
is low (1025
mol/L), compared with that of cystine (50
mol/L). Cysteine and cystine are transported by distinct
membrane carriers, and cells typically transport one more
FIGURE 1 Glutathione synthesis and utilization in animals. En-
zymes that catalyze the indicated reactions are: 1)
-glutamyl transpep-
tidase, 2)
-glutamyl cyclotransferase, 3) 5-oxoprolinase, 4)
cysteine synthetase, 5) glutathione synthetase, 6) dipeptidase, 7)
glutathione peroxidase, 8) glutathione reductase, 9) superoxide dis-
mutase, 10) BCAA transaminase (cytosolic and mitochondrial), 11)
glutaminase, 12) glutamate dehydrogenase, 13) glutamine:fructose-6-
phosphate transaminase (cytosolic), 14) nitric oxide synthase, 15) glu-
tathione S-transferase, 16) NAD(P)H oxidase and mitochondrial respi-
ratory complexes, 17) glycolysis, 18) glutathione-dependent thioldisulde
or thioltransferase or nonenzymatic reaction, 19) transsulfuration path-
way, 20) deacylase, and 21) serine hydroxymethyltransferase. Abbre-
viations: AA, amino acids; BCKA, branched-chain
-ketoacids; GlcN-
6-P, glucosamine-6-phosphate; GS-NO, glutathionenitric oxide
adduct; KG,
-ketoglutarate; LOO
, lipid peroxyl radical; LOOH, lipid
hydroperoxide; NAC, N-acetylcysteine; OTC,
carboxylate; R
, radicals; R, nonradicals; R-5-P, ribulose-5-phosphate;
X, electrophilic xenobiotics.
WU ET AL.490
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efciently than the other (8). It is interesting that some cell
types (e.g., hepatocytes) have little or no capacity for direct
transport of extracellular cystine. However, GSH that efuxes
from the liver can reduce cystine to cysteine on the outer cell
membrane, and the resulting cysteine is taken up by hepato-
cytes. Other cell types (e.g., endothelial cells) can take up
cystine and reduce it intracellularly to cysteine (Fig. 1); cel-
lular reducing conditions normally favor the presence of cys-
teine in animal cells.
Extracellular and intracellularly generated glutamate can be
used for GSH synthesis (16). Because dietary glutamate is
almost completely utilized by the small intestine (16), plasma
glutamate is derived primarily from its de novo synthesis and
protein degradation. Phosphate-dependent glutaminase, gluta-
mate dehydrogenase, pyrroline-5-carboxylate dehydrogenase,
BCAA transaminase, and glutamine:fructose-6-phosphate
transaminase may catalyze glutamate formation (Fig. 1), but
the relative importance of these enzymes likely varies among
cells and tissues. Interestingly, rat erythrocytes do not take up
or release glutamate (17), and glutamine and/or BCAAs may
be the precursors of glutamate in these cells (Fig. 1). Indeed,
glutamine is an effective precursor of the glutamate for GSH
synthesis in many cell types, including enterocytes, neural
cells, liver cells, and lymphocytes (18). Thus, glutamine sup-
plementation to total parenteral nutrition maintains tissue
GSH levels and improves survival after reperfusion injury,
ischemia, acetaminophen toxicity, chemotherapy, inamma-
tory stress, and bone marrow transplantation (19).
Glutamate plays a regulatory role in GSH synthesis through
two mechanisms: 1) the uptake of cystine, and 2) the preven-
tion of GSH inhibition of GCS. Glutamate and cystine share
the system X
amino acid transporter (8). When extracellular
glutamate concentrations are high, as in patients with ad-
vanced cancer, HIV infection, and spinal cord or brain injury
as well as in cell culture medium containing high levels of
glutamate, cystine uptake is competitively inhibited by gluta-
mate, resulting in reduced GSH synthesis (20). GSH is a
nonallosteric feedback inhibitor of GCS, but the binding of
GSH to the enzyme competes with glutamate (9). When
intracellular glutamate concentrations are unusually high, as
in canine erythrocytes, GSH synthesis is enhanced and its
concentration is particularly high (9).
Glycine availability may be reduced in response to protein
malnutrition, sepsis, and inammatory stimuli (21,22). When
hepatic glycine oxidation is enhanced in response to high
levels of glucagon or diabetes (23), this amino acid may
become a limiting factor for GSH synthesis. In vivo studies
show that glycine availability limits erythrocyte GSH synthe-
sis in burned patients (7) and in children recovering from
severe malnutrition (21). It is important to note that dietary
glycine supplementation enhances the hepatic GSH concen-
tration in protein-decient rats challenged with TNF-
The evidence indicates that the dietary amino acid balance
has an important effect on protein nutrition and therefore on
GSH homeostasis (8). In particular, the adequate provision of
sulfur-containing amino acids as well as glutamate (glutamine
or BCAAs) and glycine (or serine) is critical for the maximi-
zation of GSH synthesis. Thus, in the erythrocytes of children
with edematous protein-energy malnutrition and piglets with
protein deciency, GSH synthesis is impaired, leading to GSH
deciency (3). An increase in urinary excretion of 5-oxopro-
line, an intermediate of the
-glutamyl cycle (Fig. 1), is a
useful indicator of reduced availability of cysteine and/or gly-
cine for GSH synthesis in vivo (7,21)
Interorgan GSH Transport. Glutathione can be trans-
ported out of cells via a carrier-dependent facilitated mecha-
nism (2). Plasma GSH originates primarily from the liver, but
some of the dietary and intestinally derived GSH can enter the
portal venous plasma (8). Glutathione molecules leave the
liver either intact or as
owing to
transpeptidase activity on the outer plasma membrane (Fig. 1).
The extreme concentration gradient across the plasma mem-
brane makes the transport of extracellular GSH or GSSG into
cells thermodynamically unfavorable. However,
is readily taken up by extrahepatic cells for GSH synthesis.
The kidney, lung, and intestine are major consumers of the
liver-derived GSH (8). The interorgan metabolism of GSH
functions to transport cysteine in a nontoxic form between
tissues, and also helps to maintain intracellular GSH concen-
trations and redox state (8).
Roles of GSH. Glutathione participates in many cellular
reactions. First, GSH effectively scavenges free radicals and
other reactive oxygen species (e.g., hydroxyl radical, lipid
peroxyl radical, peroxynitrite, and H
) directly, and indi-
rectly through enzymatic reactions (24). In such reactions,
GSH is oxidized to form GSSG, which is then reduced to
GSH by the NADPH-dependent glutathione reductase (Fig.
1). In addition, glutathione peroxidase (a selenium-containing
enzyme) catalyzes the GSH-dependent reduction of H
other peroxides (25).
Second, GSH reacts with various electrophiles, physiolog-
ical metabolites (e.g., estrogen, melanins, prostaglandins, and
leukotrienes), and xenobiotics (e.g., bromobenzene and acet-
aminophen) to form mercapturates (24). These reactions are
initiated by glutathione-S-transferase (a family of Phase II
detoxication enzymes).
Third, GSH conjugates with NO to form an S-nitroso-
glutathione adduct, which is cleaved by the thioredoxin sys-
tem to release GSH and NO (24). Recent evidence suggests
that the targeting of endogenous NO is mediated by intracel-
lular GSH (26). In addition, both NO and GSH are necessary
for the hepatic action of insulin-sensitizing agents (27), indi-
cating their critical role in regulating lipid, glucose, and amino
acid utilization.
Fourth, GSH serves as a substrate for formaldehyde dehy-
drogenase, which converts formaldehyde and GSH to
S-formyl-glutathione (2). The removal of formaldehyde (a
carcinogen) is of physiological importance, because it is pro-
duced from the metabolism of methionine, choline, methanol
(alcohol dehydrogenase), sarcosine (sarcosine oxidase), and
xenobiotics (via the cytochrome P450 dependent monooxy-
genase system of the endoplasmic reticulum).
Fifth, GSH is required for the conversion of prostaglan-
din H
(a metabolite of arachidonic acid) into prostaglandins
and E
by endoperoxide isomerase (8).
Sixth, GSH is involved in the glyoxalase system, which
converts methylglyoxal to
D-lactate, a pathway active in mi-
croorganisms. Finally, glutathionylation of proteins (e.g., thio-
redoxin, ubiquitin-conjugating enzyme, and cytochrome c ox-
idase) plays an important role in cell physiology (2).
Thus, GSH serves vital functions in animals (Table 1).
Adequate GSH concentrations are necessary for the prolifer-
ation of cells, including lymphocytes and intestinal epithelial
cells (28). Glutathione also plays an important role in sper-
matogenesis and sperm maturation (1). In addition, GSH is
essential for the activation of T-lymphocytes and polymorpho-
nuclear leukocytes as well as for cytokine production, and
therefore for mounting successful immune responses when the
host is immunologically challenged (2). Further, both in vitro
and in vivo evidence show that GSH inhibits infection by the
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inuenza virus (29). It is important to note that shifting the
GSH/GSSG redox toward the oxidizing state activates several
signaling pathways (including protein kinase B, protein phos-
phatases 1 and 2A, calcineurin, nuclear factor
B, c-Jun N-
terminal kinase, apoptosis signal-regulated kinase 1, and mi-
togen-activated protein kinase), thereby reducing cell
proliferation and increasing apoptosis (30). Thus, oxidative
stress (a deleterious imbalance between the production and
removal of reactive oxygen/nitrogen species) plays a key role
in the pathogenesis of many diseases, including cancer, inam-
mation, kwashiorkor (predominantly protein deciency), sei-
zure, Alzheimers disease, Parkinsons disease, sickle cell ane-
mia, liver disease, cystic brosis, HIV, AIDS, infection, heart
attack, stroke, and diabetes (2,31).
Concluding Remarks and Perspectives. GSH displays
remarkable metabolic and regulatory versatility. GSH/GSSG
is the most important redox couple and plays crucial roles in
antioxidant defense, nutrient metabolism, and the regulation
of pathways essential for whole body homeostasis. Glutathione
deciency contributes to oxidative stress, and, therefore, may
play a key role in aging and the pathogenesis of many diseases.
This presents an emerging challenge to nutritional research.
Protein (or amino acid) deciency remains a signicant nutri-
tional problem in the world, owing to inadequate nutritional
supply, nausea and vomiting, premature birth, HIV, AIDS,
cancer, cancer chemotherapy, alcoholism, burns, and chronic
digestive diseases. Thus, new knowledge regarding the efcient
utilization of dietary protein or the precursors for GSH syn-
thesis and its nutritional status is critical for the development
of effective therapeutic strategies to prevent and treat a wide
array of human diseases, including cardiovascular complica-
tions, cancer, and severe acute respiratory syndrome.
We thank Tony Haynes for assistance in manuscript preparation.
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Roles of glutathione in animals
Antioxidant defense
Scavenging free radicals and other reactive species
Removing hydrogen and lipid peroxides
Preventing oxidation of biomolecules
Synthesis of leukotrienes and prostaglandins
Conversion of formaldehyde to formate
Production of D-lactate from methylglyoxal
Formation of mercapturates from electrophiles
Formation of glutathione-NO adduct
Storage and transport of cysteine
Intracellular redox status
Signal transduction and gene expression
DNA and protein synthesis, and proteolysis
Cell proliferation and apoptosis
Cytokine production and immune response
Protein glutathionylation
Mitochondrial function and integrity
WU ET AL.492
by on January 9, 2008 jn.nutrition.orgDownloaded from
... Gamma-glutamyltransferase (GGT) is shown to cleave GSH into glutamic acid and cysteinylglycine, resulting in GSH depletion. Studies showed that deficiency of GSH contributes oxidative stress which plays an key role in the progression of various pathological conditions like liver disease, cystic fibrosis, sickle cell anemia, alzheimer's disease, parkinson's disease, cancer, and diabetes [39]. In the present study, purified curcumin restores the glutathione level and decreases the GGT activity in AAPH treated platelets. ...
Platelets are known for their indispensable role in haemostasis and thrombosis. During oxidative stress, alteration in platelet function contributes towards multiple health complications. To date, various synthesized compounds have shown antiplatelet activity however, their uses are still ambiguous as these compounds display multiple side effects. Commercially used curcumin is a mixture of curcumin, demethoxy curcumin and bisdemethoxy curcumin. Majority of the studies demonstrate the effect of crude curcumin lacking specific understanding on the effect of pure curcumin. Therefore, in this study, curcumin was purified from crude curcumin mixture and examined against oxidative stress-induced platelet apoptosis and activation. Purified curcumin restored the AAPH-induced platelet apoptotic markers like reactive oxygen species, intracellular calcium level, mitochondrial membrane potential, cardiolipin peroxidation, cytochrome c release from mitochondria to the cytosol, and phosphatidyl serine externalization. Further, it inhibited agonists-induced platelet activation and aggregation, demonstrating its antiplatelet activity. Western blot analysis confirms the protective effect of purified curcumin against oxidative stress-induced platelet apoptosis and activation via down regulation of MAPKs protein activation including ASK1, JNK, p-38. This suggests that purified curcumin could be a potential therapeutic bioactive molecule to treat oxidative stress-induced platelet activation, apoptosis, and associated complications.
... Most of the cellular GSH is present in the cytosol (85-90%) and the remainder exists in many organelles. The extracellular concentrations of GSH are relatively low (for example: 2-20 µmol/L in plasma) [2]. GSH combats free radicals that can damage the cells and also has a significant role in many processes in the human body, such as immune system response regulation, cell propagation control, cysteine transport and storage, and tissue building [3,4]. ...
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Glutathione (GSH) is an antioxidant thiol that has a vital role in the pathogenesis of various human diseases such as cardiovascular disease and cancer. Hence, it is necessary to study effective methods of GSH evaluation. In our work, an effective GSH sensor based on a nitrogen and phosphorus co-doped carbon dot (NPCD)-MnO2 nanocoral composite was fabricated. In addition to utilizing the strong fluorescence of the NPCDs, we utilized the reductant ability of the NPCDs themselves to form MnO2 and then the NPCD-MnO2 nanocoral composite from MnO4−. The characteristics of the nanocoral composite were analyzed using various electron microscopy techniques and spectroscopic techniques. The overlap between the absorption spectrum of MnO2 and the fluorescence emission spectrum of the NPCDs led to effective fluorescence resonance energy transfer (FRET) in the nanocoral composite, causing a decrease in the fluorescent intensity of the NPCDs. A linear recovery of the fluorescent intensity of the NPCDs was observed with the GSH level raising from 20 to 250 µM. Moreover, our GSH sensor showed high specificity and sensing potential in real samples with acceptable results.
... Glutathione S-transferases (GSTs) are a family of detoxification enzymes that catalyse the nucleophilic coupling reactions of reduced glutathione with electrophilic compounds [63]. The catalytic activity of GSTs is associated with the detoxification of chemical compounds with electrophilic properties and reactive products of oxidative stress. ...
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The plant-based nutraceuticals are receiving increasing interest in recent time. The high attraction to the phytochemicals is associated with their anti-inflammatory and antioxidant activities, which can lead to reduced risk of the development of cardiovascular and other non-communicable diseases. One of the most disseminated groups of plant bioactives are phenolic compounds. It was recently hypothesized that phenolic compounds can have the ability to improve the functioning of the gut barrier. The available studies showed that one of the polyphenols, resveratrol, has great potential to improve the integrity of the gut barrier. Very promising results have been obtained with in vitro and animal models. Still, more clinical trials must be performed to evaluate the effect of resveratrol on the gut barrier, especially in individuals with increased intestinal permeability. Moreover, the interplay between phenolic compounds, intestinal microbiota and gut barrier should be carefully evaluated in the future. Therefore, this review offers an overview of the current knowledge about the interaction between polyphenols with a special emphasis on resveratrol and the gut barrier, summarizes the available methods to evaluate the intestinal permeability, discusses the current research gaps and proposes the directions for future studies in this research area.
... The main principle of redox-responsive drug delivery systems is employing the distinct differences in redox potentials between tumors and normal tissues. The reducing environment of cancerous tissue is based on the reduction and oxidation state of NADPH/NADP + and glutathione (GSH, GSH/GSSG) [123,124]. The most popular redox couple is GSH/glutathione disulfide (GSSG) [125]. ...
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Doxorubicin (DOX) is one of the most commonly used drugs in liver cancer. Unfortunately, the traditional chemotherapy with DOX presents many limitations, such as a systematic release of DOX, affecting both tumor tissue and healthy tissue, leading to the apparition of many side effects, multidrug resistance (MDR), and poor water solubility. Furthermore, drug delivery systems’ responsiveness has been intensively studied according to the influence of different internal and external stimuli on the efficiency of therapeutic drugs. In this review, we discuss both internal stimuli-responsive drug-delivery systems, such as redox, pH and temperature variation, and external stimuli-responsive drug-delivery systems, such as the application of magnetic, photo-thermal, and electrical stimuli, for the controlled release of Doxorubicin in liver cancer therapy, along with the future perspectives of these smart delivery systems in liver cancer therapy.
... As is known there is excessive oxidation during RM induced renal injury (Moore et al., 1998;Giannoglou et al., 2007). Glutathione (GSH) metabolism is one of the most important antioxidant systems against oxidative stress, which plays an important role in regulating oxidative stress in many diseases, such as diabetes, stroke, and neurodegenerative disease etc. (Wu et al., 2004). The downregulation or deficiency of GSH has been associated with excessive oxidative stress in renal ischemic repercussion disease (Shang et al., 2016). ...
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Objective: To investigate the role and mechanisms of action of nafamostat mesylate (NM) in rhabdomyolysis-induced acute kidney injury (RIAKI). Methods: RIAKI rats were assigned into control group (CN), RIAKI group (RM), and NM intervention group (NM). Inflammatory cytokines and proenkephalin a 119–159 (PENKID) were assessed. Cell apoptosis and glutathione peroxidase-4 (GPX4) were detected using TUNEL assay and immunohistochemical staining. Mitochondrial membrane potential (MMP) was detected by JC-1 dye. The expression of genes and metabolites after NM intervention was profiled using transcriptomic and metabolomic analysis. The differentially expressed genes (DEGs) were validated using qPCR. The KEGG and conjoint analysis of transcriptome and metabolome were used to analyze the enriched pathways and differential metabolites. The transcription factors were identified based on the animal TFDB 3.0 database. Results: Serum creatinine, blood urea nitrogen, and PENKID were remarkably higher in the RM group and lower in the NM group compared to the CN group. Pro-inflammatory cytokines increased in the RM group and notably decreased following NM treatment compared to the CN group. Tubular pathological damages were markedly attenuated and renal cell apoptosis was reduced significantly in the NM group compared to the RM group. The expression of GPX4 was lower in the RM group compared to the CN group, and it increased significantly after NM treatment. A total of 294 DEGs were identified in the RM group compared with the NM group, of which 192 signaling pathways were enriched, and glutathione metabolism, IL-17 signaling, and ferroptosis-related pathways were the top-ranking pathways. The transcriptional levels of Anpep, Gclc , Ggt1 , Mgst2 , Cxcl13 , Rgn , and Akr1c1 were significantly different between the NM and RM group. Gclc was the key gene contributing to NM-mediated renal protection in RIAKI. Five hundred and five DEGs were annotated. Compared with the RM group, most of the upregulated DEGs in the NM group belonged to Glutathione metabolism, whereas most of the downregulated DEGs were related to the transcription factor Cytokine-cytokine receptor interaction. Conclusion: NM protects the kidneys against RIAKI, which is mainly associated with NM mediated regulation of glutathione metabolism, inflammatory response, ferroptosis-related pathways, and the related key DEGs. Targeting these DEGs might emerge as a potential molecular therapy for RIAKI.
... Glutathione is synthesized by the cysteine amino acids, glutamic acid, and glycine in the liver. Glutathione is also one of the introduced antioxidants that can fight oxidative stress conditions through complex mechanisms and also diminish the production of proinflammatory cytokines [169]. Glutathione, along with selenium, forms the enzyme glutathione peroxidase, which, as mentioned before, plays an important antioxidant role in the body. ...
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Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) that causes COVID-19 disease could progress to Acute Respiratory Distress Syndrome (ARDS). The immune cells' migration in response to the virus leads to cell death by releasing oxidizing free radicals. These oxidizing free radicals mediate NF-κB (Nuclear Factor 'kappa-light-chain-enhancer' of activated B-cells) activation and induce transcription of cytokine-producing genes that eventually causes cytokine storm and septic shock. The over-expression of oxidative stress and enhancing Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) production activate transcription factors like NF-κB. So repeating this cycle intensifies the host's inflammatory responses. In this way, antioxidants as compounds that inhibit oxidation by terminating chain reactions are suggested to alleviate COVID-19 symptoms. In the present review study, the pathogenesis of the virus, the virus immunopathology, and the balance between immune responses and oxidative stress are discussed. Also, in this review, due to the importance of oxidative stress in the pathogenesis of the disease, some of the most important antioxidant agents whose therapeutic effects have been shown in improving many viral infections, ARDS, and acute lung injury, are recommended to improve the patient's condition infected with SARS-CoV-2. Besides, the recent COVID-19 clinical studies in this field are summarized in this review article. In the present review study, the pathogenesis of the virus, the virus immunopathology, and the balance between immune responses and oxidative stress are discussed. Also, in this review, due to the importance of oxidative stress in the pathogenesis of the disease, some of the most important antioxidant agents whose therapeutic effects have been shown in improving many viral infections, ARDS, and acute lung injury, are recommended to improve the patient's condition infected with SARS-CoV-2. Besides, the recent COVID-19 clinical studies in this field are summarized in this review article. According to these studies, melatonin through promoting sleep quality, decreasing vascular permeability, reducing anxiety, and regulating blood pressure; vitamin C through decreasing the mortality rates and the requirement for mechanical ventilation; glutathione through decreasing respiratory distress in the pneumonia of COVID-19 patients; and high selenium levels could improve the COVID-19 patients' clinical outcomes.
Proses penuaan pada lansia mengakibatkan turunnya berbagai fungsifisiologis, termasuk munculnya berbagai penyakit saraf. Berbagai studimenunjukkan hubungan antara status gizi yang dinilai dari Indeks MassaTubuh (IMT) terhadap penurunan fungsi kognitif. Penelitian ini dilakukanuntuk mengetahui hubungan antara status gizi dan penurunan dari fungsikognitif pada lansia. Penelitian menggunakan studi observasional dengandesain potong lintang yang mengikutsertakan 82 lansia di Panti Sosial TresnaWerda Budi Mulia 2. Data karakteristik meliputi jenis kelamin, tingkatpendidikan dan status pernikahan diperoleh dengan cara wawancaramenggunakan kuesioner. Fungsi kognitif dinilai menggunakan Mini-MentalState Examination. Status gizi dinilai dengan mengukur berat badan dantinggi badan dan menghitung IMT, serta pengukuran lingkar pinggangresponden. Analisis data menggunakan SPSS 23.0 dengan tingkat kemaknaan0,05. Analisis chi-square menunjukkan adanya hubungan yang secara statistikbermakna antara jenis kelamin (p=0,001), tingkat pendidikan (p=0,000), danlingkar pinggang (p=0,016). Sedangkan tidak terdapat hubungan yangbermakna antara IMT (p=0,217) dan status pernikahan (p=0,282) denganfungsi kognitif. Jenis kelamin, tingkat pendidikan, dan lingkar pinggangberhubungan dengan fungsi kognitif, sedangkan IMT dan status pernikahantidak berhubungan dengan fungsi kognitif.
The lipid kinase VPS34 orchestrates autophagy, endocytosis, and metabolism and is implicated in cancer and metabolic disease. The proximal tubule in the kidney is a key metabolic organ that controls reabsorption of nutrients such as fatty acids, amino acids, sugars, and proteins. Here, by combining metabolomics, proteomics, and phosphoproteomics analyses with functional and superresolution imaging assays of mice with an inducible deficiency in proximal tubular cells, we revealed that VPS34 controlled the metabolome of the proximal tubule. In addition to inhibiting pinocytosis and autophagy, VPS34 depletion induced membrane exocytosis and reduced the abundance of the retromer complex necessary for proper membrane recycling and lipid retention, leading to a loss of fuel and biomass. Integration of omics data into a kidney cell metabolomic model demonstrated that VPS34 deficiency increased β-oxidation, reduced gluconeogenesis, and enhanced the use of glutamine for energy consumption. Furthermore, the omics datasets revealed that VPS34 depletion triggered an antiviral response that included a decrease in the abundance of apically localized virus receptors such as ACE2. VPS34 inhibition abrogated SARS-CoV-2 infection in human kidney organoids and cultured proximal tubule cells in a glutamine-dependent manner. Thus, our results demonstrate that VPS34 adjusts endocytosis, nutrient transport, autophagy, and antiviral responses in proximal tubule cells in the kidney.
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In the present study, we evaluated the acute response of mice exposed to IQOS aerosol, a brand-name heated tobacco product (HTP), in the lung tissue. First, the thiobarbituric acid-reactive substances (TBA-RS) value was measured as an index to assess oxidative stress, and a significant increase was observed after exposure, followed by a significant increase in the total lung GSH concentration. The stress responses induced by IQOS aerosols was then analyzed by focusing on the changes in Nrf2 and ATF4, which are transcription factors that induce the expression of genes involved in GSH biosynthesis or metabolism. Although Nrf2 activation was not observed, significant accumulation of ATF4 in the nuclear fraction was noted three hours after exposure to IQOS aerosols. Upon an examination of changes in factors in the GSH biosynthetic system, a significant increase in cystine concentration in the lung tissue was measured, and an increase in xCT expression level was observed in the cell membrane fraction three–six hours after IQOS exposure. Furthermore, characteristic changes in HO-1, a stress-response protein regulated by ATF4, was discovered six hours after IQOS exposure. Moreover, analysis of the upstream ATF4 regulatory system revealed that phosphorylation of eIF2α was enhanced in the lung cytoplasmic fraction three hours after exposure to IQOS aerosols. These findings suggest that ER stress might be induced as an early response to IQOS aerosol exposure, accompanied by the activation of the eIF2α-ATF4 axis. These intracellular changes have also been reported after exposure to combustible cigarette smoke. Thus, the acute response found in the lungs of mice in the present study demonstrate that the inhalation of aerosols from IQOS elicits a biological response similar to that of combustible cigarette smoke. In conclusion, our results provide evidence that the biological effects of HTPs, such as IQOS, cannot be ignored in the lungs.
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Mucosal proliferation, together with differentiation and apoptosis, are a continuous homeostatic process in the intestinal epithelium. The glutathione/glutathione disulfide redox status plays a key role in intestinal growth control wherein a reduced redox potential maintains a proliferative state. An oxidative shift in this potential elicits growth arrest and cell transition to a differentiated or apoptotic phenotype.
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We hypothesized that a limitation in the endogenous formation of glycine might constrain catch-up growth during recovery from severe childhood malnutrition. The urinary excretion of 5-L-oxoproline is increased when the glycine available for glutathione synthesis is limited. Urinary excretion of 5-L-oxoproline was measured throughout recovery in 12 children (aged 16 +/- 6 mo) with severe malnutrition. Urinary 5-L-oxoproline was similar at admission and after recovery, but was increased significantly during rapid catch-up growth. There was a significant relationship between the rate of weight gain and 5-L-oxoproline excretion in urine. In nine children (aged 15 +/- 5 mo), the effect of oral supplementation with glycine, [1.7 mmol/(kg x d) for 48 h] during rapid catch-up growth on 5-L-oxoprolinuria and blood glutathione concentration was determined. In seven of the nine children weight gain was less than 17 g/(kg x d) and following oral glycine supplements 5-L-oxoproline excretion was reduced up to 64% and blood glutathione concentration increased up to 100%. In the two children who were gaining weight at a rate > 17 g/(kg x d), glycine supplementation was associated with a further increase in 5-L-oxoproline excretion and a decrease in blood glutathione. If 5-L-oxoproline is an index of the relative availability of glycine, then the data indicate that glycine may be limiting during rapid catch-up growth. This would have important implications for repletion of muscle and gain in height.
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The glycine cleavage enzyme system (GCS) is found in mitochondria. In liver it is activated by glucagon and other hormones but it is not known how the hormonal signal is transmitted to the mitochondria. We found that the cell-permeant protein phosphatase inhibitor okadaic acid stimulated flux through GCS and could induce a significant increase in the sensitivity of GCS and of glycogenolysis to glucagon. Half-maximal stimulation of GCS by glucagon occurred at 3.2+/-0.6 nM, whereas it was fully activated at 0.3 nM in the presence of 1 microM okadaic acid. The protein kinase A agonist adenosine-3',5'-cyclic monophosphorothioate, Sp isomer (10 microM) stimulated the GCS flux by approx. 100%. This stimulation was inhibited by the protein kinase A antagonist 8-bromoadenosine-3', 5'-cyclic monophosphorothioate, Rp isomer (Rp-8-Br-cAMPS). Although Rp-8-Br-cAMPS significantly inhibited glucagon-stimulated glycogenolysis it had no effect on the glucagon-stimulated GCS flux. These results indicate that a cytoplasmic phosphorylated protein is involved in transmitting glucagon's effect to the mitochondria. However, protein kinase A does not have a necessary role in transmitting glucagon's signal. We also examined the role of protein kinase C because angiotensin II also stimulated flux through GCS. However, the phorbol ester PMA had no effect on either GCS or on glycogenolysis.
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Although several studies have documented intra- and extracellular glutathione (GSH) deficiency in asymptomatic human immunodeficiency virus (HIV) infection, the mechanisms responsible for the altered GSH homeostasis remain unknown. To determine whether decreased synthesis contributes to this alteration of GSH homeostasis, a primed-constant infusion of [2H2]glycine was used to measure the fractional and absolute rates of synthesis of GSH in five healthy and five symptom-free HIV-infected subjects before and after supplementation for 1 wk with N-acetylcysteine. The erythrocyte GSH concentration of the HIV-infected group was lower (P < 0.01) than that of the control group (1.4 +/- 0.16 vs. 2.4 +/- 0.08 mmol/l). The smaller erythrocyte GSH pool of the HIV-infected group was associated with a significantly slower (P < 0.01) absolute synthesis rate of GSH (1.15 +/- 0.14 vs. 1.71 +/- 0.15 mmol. l-1. day-1) compared with controls. Cysteine supplementation elicited significant increases in both the absolute rate of synthesis and the concentration of erythrocyte GSH. These results suggest that the GSH deficiency of HIV infection is due in part to a reduced synthesis rate secondary to a shortage in cysteine availability.
Background. Our previous results have showed that oral glutamine (GLN) supplementation decreased carcinogenesis in 7,12-dimethylbenz[a]antracene (DMBA) breast cancer model. We also have found that GLN raises blood glutathione (GSH) levels in an implantable breast cancer model. The process of tumor growth was accompanied by depressed GSH production and increased levels of insulin-like growth factor-I (IGF-I) and transforming growth factor β1 (TGF-β1). GSH is counter-regulatory to IGF-I. We therefore hypothesized that in DMBA model of breast cancer, the increased GSH levels seen with oral GLN would be associated with lowered levels of IGF-I &TGF-β1.Methods. Time-dated pubertal Sprague-Dawley rats were gavaged at time 0 with 1 g/kg/day glutamine (GLN) (n = 18), isonitrogenous Freamine (FA) (n = 18), or water (H2O) (n = 18). Rats were further randomized on day 7 to 100 mg/kg DMBA or oil. After 14 days, the animals were sacrificed and blood GSH, IGF-1, TGF-β1, breast tissue, and gut mucosa GSH levels were measured.Results. Oral GLN increased significantly blood, breast tissue, and gut mucosa levels of GSH in both DMBA and control groups in comparison with the control groups not treated with GLN. At the same time, the levels of blood IGF-I and TGF-β1 decreased significantly in both DMBA-treated and control groups. DMBA did not significantly affect any of these levels.Conclusions. Oral GLN increased GSH levels and lowered IGF-I and TGF-β1 in a range that is considered clinically significant. However, the effect of GLN in maintaining normal gut GSH production in the presence of DMBA was much more significant. Inconsistent with our hypothesis, reduction in IGF and TGF-β1 levels did not correlate with DMBA’s effect on gut GSH production.
The oxidative degradation of polyunsaturated fatty acids is the primary factor in limiting the shelf-life of most manufactured foods. Free radical mechanisms are implicated in the pathogenesis of human diseases and in the process of ageing. This has led to the suggestion that antioxidants, and plant diet-derived antioxidants in particular, might have health benefits as prophylactic agents. Delineating the in vivo contribution of plant extracts and/or plant-derived antioxidants (the pure active principles in plant extracts with antioxidant indications) to the modulation of the pathological consequences of oxidative stress in the human body is complicated by the fact that antioxidant actions may be achieved through more than one mechanism. The interest in the health promoting qualities of plant foods may be ascribed to the observation that various compounds present in these foods possess antioxidant properties in vitro. From a food stability perspective, one would be interested in the integrity of the food and the effects of storage on the molecular components of the food. For humans, the emphasis is on the importance of nutritional antioxidants in health and disease management. [Translated abstract - see PDF]
Responses to cytokines entail synthesis of substances rich in cysteine and glycine, such as glutathione (GSH), metallothionein and some plasma proteins. To examine the importance of an adequate supply of cysteine and glycine, we fed rats a low protein diet supplemented with L-cysteine and glycine, separately or in combination, or L-alanine, or a high protein diet for 1 wk before injection with tumor necrosis factor alpha (TNF) or saline. The high protein diet-fed group had greater liver weight and zinc and GSH concentrations after TNF than the group fed the low protein diet supplemented with alanine. Glycine and cysteine supplementation resulted in greater liver weight after TNF treatment than did alanine supplementation. Cysteine supplementation had a similar influence on GSH concentration. Ceruloplasmin, alpha-2-macroglobulin and alpha-1-acid glycoprotein were higher in TNF-treated rats than in saline controls in each dietary group. However, feeding supplementary glycine and cysteine and the high protein diet often resulted in different values than seen in animals fed the low protein diet supplemented with alanine. Paradoxically, lower ceruloplasmin concentrations were observed in animals fed the former diets than in those fed the latter. alpha-2-Macroglobulin concentration was lower in all animals fed low protein diets than in those fed the high protein diet. alpha-1-Acid glycoprotein was lowest in groups fed cysteine-supplemented diets and highest in the glycine-supplemented group.(ABSTRACT TRUNCATED AT 250 WORDS)
Chick and rat experiments were conducted to determine the efficacy of L-2-oxothiazolidine-4-carboxylate (OTC) as a cysteine (Cys) precursor for growth and hepatic glutathione (GSH) biosynthesis. Isosulfurous graded increments of OTC and Cys were added to Cys-free purified amino acid diets that were adequate in methionine. Curvilinear responses to both Cys and OTC for chicks and rats were obtained. Hepatic GSH accumulated in chicks only at dietary Cys levels above 0.10%. In rats, hepatic GSH increased linearly as dietary Cys content increased from deficient to adequate and from adequate to excessive. Utilization of OTC by chicks was as efficacious as isosulfurous levels of Cys for growth and hepatic GSH biosynthesis. In rats, OTC was slightly inferior to Cys for growth and hepatic GSH biosynthesis. Exponential regression slope-ratio growth efficacy values for OTC were 78.5% for chicks and 70.2% for rats; multiple linear regression slope-ratio GSH biosynthesis efficacy values were 80.3% for chicks and 83.7% for rats. It is concluded that orally administered OTC is active as a Cys precursor.
To measure the source and rate of mucosal glutathione (GSH) synthesis, fed piglets (28 days old; 7.7 kg) received a 6-h infusion of intragastric [U-13C]glutamate (n = 11) either with (n = 5) or without (n = 6) an intragastric infusion of [1-13C]glycine (0-6 h) and [1,2-13C2(U-13C)]glycine (3-6 h). Eighty-four percent of the labeled mucosal GSH-glutamate and 86% of the luminal GSH-glutamate was 13C5. The tracer-to-tracee ratio of GSH-[U-13C]glutamate was 75% of that of mucosal glutamate. Sixty percent of the labeled mucosal glutamate was 13C1, 13C2, or 13C3, but the tracer-to-tracee ratios of these isotopomers in GSH-glutamate were not significantly different from zero. After 3 h of infusion, the tracer-to-tracee ratio of GSH-[U-13C]glycine was 46%, and after 6 h of infusion GSH-[13C1]glycine was 82% of that of mucosal glycine. This suggested that the half-life of mucosal GSH was 2.7 +/- 0.1 h. We concluded that, in fed piglets, mucosal GSH-glutamate derived largely from the direct metabolism of enteral glutamate rather than from glutamate that was metabolized within the mucosa.
Glutathione (L-gamma-glutamyl-L-cysteinylglycine, GSH) is synthesized from its constituent amino acids by the sequential action of gamma-glutamylcysteine synthetase (gamma-GCS) and GSH synthetase. The intracellular GSH concentration, typically 1-8 mM, reflects a dynamic balance between the rate of GSH synthesis and the combined rate of GSH consumption within the cell and loss through efflux. The gamma-GCS reaction is rate limiting for GSH synthesis, and regulation of gamma-GCS expression and activity is critical for GSH homeostasis. Transcription of the gamma-GCS subunit genes is controlled by a variety of factors through mechanisms that are not yet fully elucidated. Glutathione synthesis is also modulated by the availability of gamma-GCS substrates, primarily L-cysteine, by feedback inhibition of gamma-GCS by GSH, and by covalent inhibition of gamma-GCS by phosphorylation or nitrosation. Because GSH plays a critical role in cellular defenses against electrophiles, oxidative stress and nitrosating species, pharmacologic manipulation of GSH synthesis has received much attention. Administration of L-cysteine precursors and other strategies allow GSH levels to be maintained under conditions that would otherwise result in GSH depletion and cytotoxicity. Conversely, inhibitors of gamma-GCS have been used to deplete GSH as a strategy for increasing the sensitivity of tumors and parasites to certain therapeutic interventions.