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Title
Lung protection by a thiol-containing antioxidant: N-acetylcysteine.
Author
Moldéus P; Cotgreave IA; Berggren M
Source
Respiration, 50 Suppl 1():31-42 1986
Abstract
N-acetylcysteine (NAC) is a thiol-containing compound which
nonenzymatically interacts and detoxifies reactive electrophiles
and
free radicals. NAC was shown to effectively protect human bronchial
fibroblasts against the toxic effects of tobacco smoke condensates
and
the isolated perfused lung against the glutathione (GSH)-depleting
effect of tobacco smoke. NAC was also shown to reduce the reactive
oxygen intermediate hydrogen peroxide (H2O2) and protect against
the
toxic effects of H2O2. In vivo studies, however, demonstrated
that NAC
when administered orally has very low bioavailability due to
rapid
metabolism to GSH among other metabolites. Thus, even though
NAC is
very effective in protecting cells of different origins from
the
toxicity of reactive components in tobacco smoke and reactive
oxygen
species, a direct scavenging effect by NAC in vivo, particularly
when
administered orally, does not seem likely. The bioavailability
of NAC
itself is very low when given this route. A more relevant mechanism
in
vivo for any protective effect NAC may exert against toxic species
may
be due to NAC acting as a precursor of GSH and facilitating its
biosynthesis. GSH will then serve as the protective agent and
detoxify
reactive species both enzymatically and nonenzymatically.
Title
Improved function with amino acids in the isolated perfused kidney.
Author
Epstein FH; Brosnan JT; Tange JD; Ross BD
Source
Am J Physiol, 243(3):F284-92 1982 Sep
Abstract
When isolated rat kidneys are perfused with glucose as the only
substrate' there is a progressive diminution in glomerular filtration
rate and fractional reabsorption of sodium. This is most marked
after 1
h. Renal glutathione content rapidly falls and is less than 30%
of
control levels after 1 h. Renal concentrating ability is markedly
impaired and structural lesions are consistently observed in
cells
lining the thick ascending limb of Henle`s loop. Addition of
20
physiologic amino acids including cysteine to the perfusate prevents
the fall in renal glutathione' prevents the anatomical damage
to
ascending limb cells' permits GFR and fractional sodium reabsorption
to
remain high and close to their initial levels for as long as
4 h' and
improves renal concentrating capacity. If amino acid supplementation
is
limited to three precursors of glutathione--cysteine' glycine'
and
glutamic acid--renal glutathione content is preserved and concentrating
ability is improved' but GFR and fractional sodium reabsorption
are not
maintained as well as with comprehensive amino acid supplements.
The
results suggest that amino acid deficiency and glutathione depletion
may contribute to disturbances in renal structure and function.
Title
N-acetylcysteine increases the glutathione content and protects
rat
alveolar type II cells against paraquat-induced cytotoxicity.
Author
Hoffer E; Baum Y; Tabak A; Taitelman U
Address
Israel Poison Information Center' Rambam Medical Center and Faculty
of
Medicine' Technion' Haifa' Israel.
Source
Toxicol Lett, 84(1):7-12 1996 Jan
Abstract
A protective effect of N-acetylcysteine in oxidative lung damage
was
reported by a number of workers; however' the mechanism underlying
this
effect was not thoroughly elucidated. The present research investigates
the protection by N-acetylcysteine against paraquat-induced
cytotoxicity to alveolar type II cells' which are known to be
specific
targets of paraquat toxicity in vivo. We found that addition
of 1 mM
N-acetylcysteine to alveolar type II cells incubated with 1 mM
paraquat
reduced the cytotoxic index from 17.4 +/- 1.3% to 9.3 +/- 1.5%.
This
effect could not be explained by the interference of N-acetylcysteine
with the active uptake of paraquat by type II cells. Incubation
of
these cells with N-acetylcysteine enhances their glutathione
content'
thus reducing the paraquat- induced depletion of glutathione
in these
cells. These results suggest that N-acetylcysteine exerts its
protective effect by acting as a precursor for glutathione in
alveolar
type II cells.
Title
Lack of effect of N-acetylcysteine on the release of oxygen radicals
from neutrophils and alveolar macrophages.
Author
Drost E; Lannan S; Bridgeman MM; Brown D; Selby C; Donaldson
K; MacNee
W
Address
Dept of Medicine (RIE)' Rayne Laboratory' City Hospital' Edinburgh'
UK.
Source
Eur Respir J, 4(6):723-9 1991 Jun
Abstract
N-acetylcysteine (NAC) is rapidly de-acetylated in vivo to cysteine
(CYSH)' a precursor of glutathione (GSH) which is an antioxidant
in
cells and body fluids. We investigated the effect of oral
administration of N-acetyl cysteine for 5 days on the spontaneous
and
stimulated generation of hydrogen peroxide (H2O2) and superoxide
anion
(O2-) from human and rat phagocytic leucocytes. Alveolar macrophages
(AM) were obtained by bronchoalveolar lavage (BAL) in control
rats and
rats given NAC in their drinking water. Neutrophils (PMNL) were
harvested from whole blood in normal nonsmoking volunteers before
and
after NAC was given by mouth. The stimulated release of H2O2
and O2
from both rat AM and human PMN was not changed by administration
of
NAC. However' a small but significant increase was observed in
both the
spontaneous generation of O2- from rat AM and the spontaneous
generation of H2O2 from human PMNL. Administration of NAC significantly
increased cysteine levels in human plasma and rat BAL' but the
levels
in human PMNL and rat AM after NAC did not differ from control
levels.
GSH levels were not altered significantly by NAC.
Title
Mechanisms of natural detoxication and antioxidant protection
Author
Tiunov LA
Source
Vestn Ross Akad Med Nauk, (3):9-13 1995
Abstract
This paper considers the mechanisms of energy-dependent and
synchronized detoxication and antioxidative defense (AOD) when
synchronized detoxication and antioxidative defense (AOD) when
the body
is exposed to chemicals. It emphasizes the role of glutathione
as a
binder of this system involving in the regulation of this activity.
It
also discusses the mechanisms that define the reliability and
efficiency of detoxication and AOD. The paper discusses whether
the
body`s resistance to technogenic toxicants can be enhanced by
using
metabolic precursors of glutathione and other natural and (or)
synthetic agents activating natural detoxication and AOD.
Title
Effect of antioxidative vitamins on immune function with clinical
applications.
Author
Grimble RF
Address
Institute of Human Nutrition, University of Southampton, U.K.
Source
Int J Vitam Nutr Res, 67(5):312-20 1997
Abstract
Infection and trauma cause inflammatory stress in patients. Tissue
damage, enhanced inflammatory mediator production and suppressed
lymphocyte function may occur as a consequence. The antioxidative
vitamins, ascorbic acid and the tocopherols, are important not
only for
limiting tissue damage but also in preventing increased cytokine
production which is a consequence of excessive activation of
NF kappa
B. glutathione is a major endogenous antioxidant and is important
for
lymphocyte replication. Two vitamins, vitamin B6 and riboflavin
participate in the maintainance of glutathione status. The former
vitamin acts as a cofactor in the synthesis of cysteine (the
rate
limiting precursor for glutathione biosynthesis) and the latter
vitamin
is a cofactor for glutathione reductase. Deficiencies in tocopherol,
vitamin B6 and riboflavin reduce cell numbers in lymphoid tissues
of
experimental animals and produce functional abnormalities in
the cell
mediated immune response. Ascorbic acid and tocopherols exert
anti-inflammatory effects in studies in man and animals. In humans,
dietary supplementation with ascorbic acid, tocopherols and vitamin
B6
enhances a number of aspects of lymphocyte function. The effect
is most
apparent in the elderly.
Title
Plasma cysteine concentrations in infants with respiratory distress.
Author
White CW; Stabler SP; Allen RH; Moreland S; Rosenberg AA
Address
Department of Pediatrics' Children`s Hospital' National Jewish
Center
for Immunology and Respiratory Medicine' Denver' CO 80206.
Source
J Pediatr, 125(5 Pt 1):769-77 1994 Nov
Abstract
Because factors that predispose infants to persistent pulmonary
hypertension of the newborn (PPHN) may cause oxidant stress'
which in
turn may increase demands for cysteine and glutathione' we investigated
the availability of cysteine and its precursors in PPHN and related
disorders. Plasma concentrations of four sulfur-containing and
two
non-sulfur-containing amino acids were measured by gas
chromatography-mass spectrometry in blood from infants with PPHN'
both
those managed conventionally (PPHN group) and those treated with
extracorporeal membrane oxygenation' as well as from infants
with
hyaline membrane disease. Concentrations also were measured in
umbilical venous cord blood samples from a healthy control population'
in venous plasma from infants receiving only intravenously administered
glucose-containing solutions because they had noncardiopulmonary
illnesses ("fasted" group)' and from otherwise healthy'
orally fed
infants ("fed" group). The plasma total cyst(e)ine
concentration was
markedly lower in the three groups (PPHN' PPHN and extracorpeal
membrane oxygenation' and hyaline membrane disease) receiving
an
elevated inspired oxygen concentration (0.6 to 1.0) than in fasted
or
fed control infants. In contrast' levels of plasma methionine'
the
other maJor sulfur amino acid' were low in the three groups receiving
an elevated inspired oxygen concentration' as well as in fasted
infants. glycine and serine' two non-sulfur-containing amino
acids' had
a pattern similar to that of plasma methionine. Thus infants
with PPHN
and hyaline membrane disease have low plasma total cyst(e)ine
levels'
an effect that does not appear to result primarily from nutritional
deprivation. We speculate that the role of cysteine in bioactivation
of
nitric oxide and as a precursor of glutathione may be relevant
to the
pathogenesis and evolution of PPHN and respiratory distress syndrome.
Further studies are needed to determine whether increased demands
for
cysteine exist in these disorders.
Title
A role of vitamin E in protection against cell injury. Maintenance
of
intracellular glutathione precursors and biosynthesis.
Author
Pascoe GA; Fariss MW; Olafsdottir K; Reed DJ
Source
Eur J Biochem, 166(1):241-7 1987 Jul 1
Abstract
The depletion of cell calcium from isolated rat hepatocytes results
in
stimulated lipid peroxidation, loss of intracellular and mitochondrial
GSH (reduced glutathione), and enhancement of both efflux and
oxidation
of GSH. These events are followed by cell injury and enhance
the
susceptibility of the cells to toxic chemicals. It is shown herein
that
an initial event in the generation of such injury is the depletion
of
cellular alpha-tocopherol. alpha-Tocopheryl succinate addition
(25
microM) to the calcium-depleted cells markedly elevated the
alpha-tocopherol content of the cells, inhibited the associated
lipid
peroxidation, and maintained intracellular GSH levels without
affecting
its efflux or redox status. This resulted in an enhanced formation
of
total glutathione after a 5-h incubation, which correlated with
the
alpha-tocopherol content of the cells, and was greater than that
expected by a direct sparing action of vitamin E. Inhibition
of
hepatocyte glutathione biosynthesis by buthionine sulfoximine
(0.5 mM)
eliminated the enhancement of GSH formation by vitamin E. Analysis
of
endogenous and 35S-labelled precursors of glutathione biosynthesis
by
high-performance liquid chromatography demonstrated that the
depletion
of cellular alpha-tocopherol resulted in the efflux of glutathione
precursors. It is concluded that cell injury associated with
alpha-tocopherol depletion is partly the result of the efflux
of
glutathione precursors, and hence diminished biosynthesis and
intracellular levels of GSH. These losses and resultant cell
injury are
preventable by maintenance of cellular alpha-tocopherol levels.
Title
The biosynthesis of glutathione in human erythrocytes (author's
transl)
Author
Heinle H; Sawatzki G; Wendel A
Source
Hoppe Seylers Z Physiol Chem, 357(11):1451-8 1976 Nov
Abstract
The concentrations of glutathione precursors in human erythrocytes
were
investigated. 300muM glutamate, 375 muM glycine, and 10muM cysteine
were found by automated amino acid analysis. The concentration
of
2-aminobutyrate, the precursor of ophthalmic acid, was 15muM.
The
influence of the activities of endogenous or added glutamyl-cysteine
synthetase and glutathione synthetase on the rate of glutathione
biosynthesis was measured in membrane-free hemolysates under
physiological conditions. The results show that the rate of the
overall
biosynthesis mainly depends on the formation of the dipeptide
glutamyl-cysteine. The effect of glutathione precursor concentrations
on the synthesis of the tripeptide was investigated at constant
(endogenous) activities of the synthesizing enzymes. The rate
was not
enhanced by addition of glutamate and/or glycine unless cysteine
or
glutamyl-cysteine was also added. It is concluded that the
concentration of cysteine limits the actual rate of the
glutamyl-cysteine-synthetase reaction in vivo. No cysteine or
bis(glutamyl)cystine was detected in human hemolysate; however,
these
disulfides were converted to glutathione. This indicates that
erythrocytes have an appropriate system for their reduction,
since the
disulfides themselves are not substrates for the
glutathione-synthesizing enzymes. Studies with intact human red
cells
indicate that the uptake of cysteine is the rate-determining
step in
the biosynthesis of glutathione.
Title
A simple technique to determine glutathione (GSH) levels and
synthesis
in ocular tissues as GSH-bimane adduct: application to normal
and
galactosemic guinea-pigs.
Author
Kannan R; Tang D; Mackic JB; Zlokovic BV; Fernandez-Checa JC
Address
Division of Gastrointestinal and Liver Diseases' Children`s Hospital
of
Los Angeles' University of Southern California School of Medicine.
Source
Exp Eye Res, 56(1):45-50 1993 Jan
Abstract
A fluorimetric technique previously described for other tissues
has
been applied to determine levels of glutathione and its synthetic
rates
in ocular tissues of Hartley guinea-pigs. Monochlorobimane forms
a
stable' fluorescent adduct with glutathione in a reaction catalyzed
by
glutathione-S-transferase. The fluorescent signal recorded over
time is
directly proportional to the synthetic rate of glutathione. Lens'
cornea and retina were homogenized and cytosolic fractions dialyzed
overnight to deplete endogeneous glutathione. glutathione synthetic
rates were determined from a mixture of glutathione precursors
and
co-factors' viz. cysteine+dithiothreitol' glutamate+glycine'
ATP and
Mg++ in the presence of monochlorobimane. The mixture was supplemented
with glutathione-S-transferase to catalyze the formation of the
fluorescent adduct. glutathione synthetic rates were determined
in the
absence and presence of buthionine sulfoximine' an inhibitor
of
gamma-glutamyl cysteine synthetase. The difference in fluorescence
change over time in the presence and absence of buthionine sulfoximine
was used to estimate glutathione synthesis. Basal levels of glutathione
in pre-dialyzed cytosolic fractions of the lens' cornea' and
retina
were 21.8 +/- 2.2' 36.5 +/- 4.1 and 38.6 +/- 2.8 nmol mg-1 protein'
respectively. The maximal glutathione synthetic rates in these
tissues
were 0.52 +/- 0.04' 2.25 +/- 0.67 and 3.35 +/- 0.65 nmol min-1
mg-1
protein' respectively. When gamma-glutamyl cysteine is used as
a
precursor instead of cysteine' the glutathione synthetase activities
from lenses and retinas were 0.19 +/- 0.08 and 1.54 +/- 0.76
nmol-1 min
mg-1 protein.(Abstract TRUNCATED AT 250 WORDS)
Title
The effects of age and glutathione depletion on hepatic glutathione
turnover in vivo determined by acetaminophen probe analysis.
Author
Lauterburg BH; Vaishnav Y; Stillwell WG; Mitchell JR
Source
J Pharmacol Exp Ther, 213(1):54-8 1980 Apr
Abstract
We have validated a method to assess hepatic glutathione turnover
in
individual animals in vivo. This method would be applicable to
man by
collection of bile samples via nasoduodenal intubation. The rate
of
glutathione turnover was calculated from the time course of the
specific activity of the glutathione-acetaminophen adduct in
bile after
the administration of a radiolabeled glutathione precursor and
a small
dose of acetaminophen. Identical results were obtained with
radiolabeled glutathione or with radiolabeled cysteine' glutamic
acid
or glycine as the precursors. The small dose of acetaminophen
administered to trap glutathione as an excretable adduct did
not
stimulate glutathione turnover' which reflects glutathione synthesis
under steady-state conditions. No evidence for two pools of glutathione
with different half-lives was found; previous reports of two
glutathione pools may have failed to account for hepatic protein
turnover with subsequent release of radiolabeled amino acids
for
glutathione synthesis. In male rats' the rate of glutathione
turnover
decreased from 0.52 per hr at 6 weeks of age to 0.12 per hr at
24 weeks
of age. After acute depletion of glutathione by diethylmaleate'
the
rate of glutathione turnover promptly doubled in all age groups.
Similar increases in the rate of glutathione synthesis and in
the
ability to stimulate glutathione production in response to acute
depletion in children might explain their decreased susceptibility
to
acetaminophen hepatotoxicity.
Title
Effects of glutathione precursors on human immunodeficiency virus
replication.
Author
Simon G; Moog C; Obert G
Address
Laboratoire common Universit]e Louis Pasteur/Synth]elabo' Strasbourg'
France.
Source
Chem Biol Interact, 91(2-3):217-24 1994 Jun
Abstract
Asymptomatic human immunodeficiency virus (HIV)-seropositive
individuals have reduced glutathione (GSH) levels. This has led
to the
suggestion that elevated intracellular thiols levels may inhibit
HIV
replication and progression of the disease. We confirmed that
N-acetyl-L-cysteine (NAC)' a cysteine prodrug which maintains
intracellular GSH levels during oxidative stress' inhibits in
the
chronically infected U1 cells' the stimulation of HIV replication
induced by phorbol 12-myristate 13-acetate (PMA)' interleukin-6
(IL-6)
or granulocyte-macrophage colony stimulating factor (GM-CSF).
However'
we found no significant inhibition of PMA-mediated long terminal
repeat
(LTR)-directed beta-galactosidase expression in transiently transfected
Jurkat T-cells. We have compared NAC effects with the effects
of other
GSH precursors on HIV expression. Treatment of the U1 cell line
by
L-2-oxo-4-thiazolidine carboxylic acid (OTC)' which is converted
to
cysteine by 5-oxoprolinase' or by homocysteine (HC)' a natural
cysteine
precursor' reduced the PMA-induced HIV expression' but surprisingly'
markedly stimulated the expression mediated by IL-6 and GM-CSF.
Several
experiments to investigate the effect of OTC on LTR transactivation
were carried out' but beta-galactosidase activity was never modified
in
a significant fashion in PMA-induced Jurkat T-cells after OTC
treatment. Furthermore' HC stimulated the PMA-mediated HIV-LTR
transactivation in Jurkat T-cells. GSH assays showed that treatment
of
U937 and Jurkat T-cells with NAC and OTC moderately increased
the GSH
level' while HC led to a significantly higher increase of the
thiol
level. In conclusion' it appeared that an increase of the GSH
intracellular level did not lead solely to an inhibition of HIV
replication but could also lead to an activation of viral expression.
This seemed the case when HIV replication was stimulated by compounds
which act mainly at a post-transcriptional level.
Title
Acetylcysteine: a drug that is much more than a mucokinetic.
Author
Ziment I
Address
Department of Medicine, Olive View Medical Center, Sylmar, CA
91342-1495.
Source
Biomed Pharmacother, 42(8):513-9 1988
Abstract
Acetylcysteine is the most widely used mucolytic drug, and it
has
greater documentation of effectiveness than any other mucokinetic
agent. Originally it was used as an aerosol, but currently it
is mostly
prescribed by the oral route. In addition to the lytic activities
of
acetylcysteine, the aerosolized drug has bronchorrheic effects,
while
oral therapy results in expectorant and mucoregulator actions.
Newer
uses of the drug depend on its effectiveness as a free-radical
scavenger, since it is a precursor of glutathione. It is well
established as the drug of choice for treating acetaminophen
poisoning,
and it offers an important role in protecting the lungs from
a variety
of insults that result in oxidant damage.
Title
Direct evidence of intercellular sharing of glutathione via metabolic
cooperation.
Author
Kavanagh TJ; Martin GM; Livesey JC; Rabinovitch PS
Address
Department of Pathology, University of Washington, Seattle 98195.
Source
J Cell Physiol, 137(2):353-9 1988 Nov
Abstract
Intracellular glutathione (GSH) content and cell density are
known to
be two important determinants of cell sensitivity to free radicals
and
radiation. We have investigated intercellular sharing of GSH
via
metabolic cooperation (MC) by measuring the GSH content of Chinese
hamster V79 cells under conditions that varied MC among cells.
GSH was
measured by flow cytometry with monochlorobimane, which becomes
fluorescent after conjugation to GSH by GSH-S-transferase.
High-performance liquid chromatography was used to confirm the
accuracy
of GSH measurements by flow cytometry. Several lines of evidence
indicate sharing of GSH or its precursor gamma-glutamylcysteine
via MC.
These include a cell density-dependent heterogeneity in GSH content,
reconstitution of GSH in GSH-depleted cells by coculture with
nondepleted cells (except when the depleted cells were MC deficient),
and decreased equilibration of GSH among GSH-depleted cells and
nondepleted cells when an inhibitor of MC (phorbol myristate
acetate)
was present. The equilibration of GSH among GSH-depleted cells
and
nondepleted cells in coculture was not inhibitable by acivicin,
suggesting that this form of intercellular sharing of GSH does
not rely
on gamma-glutamyltransferase-mediated extracellular transport
of GSH. |
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