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Title
Oxidant-protease interaction in the lung. Prospects for antioxidant
therapy.
Author
Buhl R; Meyer A; Vogelmeier C
Address
Medizinische Klinik II, Zentrum der Inneren Medizin, Johann-Wolfgang-Goethe-UniversitÍat,
Frankfurt, Germany.
Source
Chest, 110(6 Suppl):267S-272S 1996 Dec
Abstract
In inflammatory lung disorders, oxidants and proteases complement
each other in their potential to destroy lung parenchyma. It
is therefore rational to combine therapeutic strategies aimed
at augmenting the antiproteolytic defenses of the lung in diseases
such as emphysema with antioxidant strategies. In the healthy
lung, the oxidant burden is balanced by the local antioxidant
defenses. However, both an increased oxidant burden and/or decreased
antioxidant defenses may reverse the physiologic oxidant-antioxidant
balance in favor of oxidants, leading to lung injury. This concept
points to an obvious therapeutic strategy: augmentation of the
antioxidant screen of the lung to prevent oxidant-mediated tissue
damage. Studies using reduced glutathione (GSH), the major pulmonary
antioxidant, as a model therapeutic agent demonstrated that GSH
can be administered directly to the respiratory epithelial surface
by aerosol and is fully functional as an antioxidant both in
vitro and in vivo. In pulmonary diseases such as idiopathic pulmonary
fibrosis or following HIV infection, GSH aerosol therapy not
only normalized deficient pretherapy GSH levels in the lung,
but was capable of favorably influencing cellular events such
as oxidant release by pulmonary inflammatory cells. The same
was true for oral antioxidant therapy with N-acetylcysteine,
a glutathione precursor. These results suggest that it is possible
to use antioxidants to reverse the imbalance between oxidants
and antioxidants at the site of oxidant injury to prevent the
progressive tissue damage in lung disorders characterized by
high oxidant states. Antioxidants, alone and in combination with
antiproteases, merit further long-term studies for clinical therapy.
Title
Acetaminophen toxicity to cultured rat embryos.
Author
Weeks BS; Gamache P; Klein NW; Hinson JA; Bruno M; Khairallah
E
Address
Center for Environmental Health, Department of Animal Science,
University of Connecticut, Storrs.
Source
Teratog Carcinog Mutagen, 10(5):361-71 1990
Abstract
We tested the effects of acetaminophen on cultured rat embryo
development. When added directly to culture media at 300 microM,
a concentration approximately twice the human therapeutic blood
level, acetaminophen caused abnormalities in the cultured embryos.
Sera from both rats and monkeys following gavage with acetaminophen
were also toxic to cultured embryos. The sera toxicities were
related to acetaminophen concentrations, and the toxicity could
be removed by serum dialysis. With regard to the metabolism of
acetaminophen, glutathione levels in the yolk sac decreased in
a concentration related fashion with addition of the drug. Also,
buthionine sulfoximine, an inhibitor of glutathione synthesis,
appeared to enhance acetaminophen embryo toxicity, and N-acetylcysteine,
a glutathione precursor, appeared to protect embryos from acetaminophen
toxicity. These results suggested that acetaminophen embryo toxicity
resulted from direct exposure of embryos to acetaminophen and
not a maternal metabolite.
Title
Elevation of cysteine and replenishment of glutathione in rat
lung slices by cysteine isopropylester and other cysteine precursors.
Author
Butterworth M; Upshall DG; Hobbs M; Cohen GM
Address
Medical Research Council Toxicology Unit, Carshalton, Surrey,
U.K.
Source
Biochem Pharmacol, 45(9):1769-74 1993 May 5
Abstract
In this study, we have used a rat lung slice model to compare
the ability to several potential cysteine delivery systems (L-cysteine
isopropylester, L-cysteine cyclohexylester, N-acetylcysteine,
L,2-oxo-4-thiazolidine carboxylic acid and cysteine) to elevate
cysteine and glutathione (GSH) levels in control lung slices
and slices depleted of their GSH by diethyl maleate. The esters
of cysteine produced the greatest rise in lung slice cysteine.
All the cysteine delivery systems were capable of replenishing
GSH in lung slices previously depleted of GSH by diethyl maleate.
Title
Drug antioxidant effects. A basis for drug selection?
Author
Halliwell B
Address
Pulmonary Medicine, UC Davis Medical Center, Sacramento.
Source
Drugs, 42(4):569-605 1991 Oct
Abstract
A free radical is any species capable of independent existence
that contains one or more unpaired electrons. Free radical reactions
have been implicated in the pathology of more than 50 human diseases.
Radicals and other reactive oxygen species are formed constantly
in the human body, both by deliberate synthesis (e.g. by activated
phagocytes) and by chemical side-reactions. They are removed
by enzymic and nonenzymic antioxidant defence systems. Oxidative
stress, occurring when antioxidant defences are inadequate, can
damage lipids, proteins, carbohydrates and DNA. A few clinical
conditions are caused by oxidative stress, but more often the
stress results from the disease. Sometimes it then makes a significant
contribution to the disease pathology, and sometimes it does
not. Several antioxidants are available for therapeutic use.
They include molecules naturally present in the body [superoxide
dismutase (SOD), alpha-tocopherol, glutathione and its precursors,
ascorbic acid, adenosine, lactoferrin and carotenoids] as well
as synthetic antioxidants [such as thiols, ebselen (PZ51), xanthine
oxidase inhibitors, inhibitors of phagocyte function, iron ion
chelators and probucol]. The therapeutic efficacy of SOD, alpha-tocopherol
and ascorbic acid in the treatment of human disease is generally
unimpressive to date although dietary deficiencies of the last
two molecules should certainly be avoided. Xanthine oxidase inhibitors
may be of limited relevance as antioxidants for human use. Exciting
preliminary results with probucol (antiatherosclerosis), ebselen
(anti-inflammatory), and iron ion chelators (in thalassaemia,
leukaemia, malaria, stroke, traumatic brain injury and haemorrhagic
shock) need to be confirmed by controlled clinical trials. Clinical
testing of N-acetylcysteine in HIV-1-positive subjects may also
be merited. A few drugs already in clinical use may have some
antioxidant properties, but this ability is not widespread and
drug-derived radicals may occasionally cause significant damage.
Title
Reduction of lower motor neuron degeneration in wobbler mice
by N-acetyl-L-cysteine.
Author
Henderson JT; Javaheri M; Kopko S; Roder JC
Address
Samuel Lunenfeld Research Institute, Program in Development and
Fetal Health, Mount Sinai Hospital, Toronto, Ontario, Canada.
Source
J Neurosci, 16(23):7574-82 1996 Dec 1
Abstract
The murine mutant wobbler is a model of lower motoneuron degeneration
with associated skeletal muscle atrophy. This mutation most closely
resembles Werdnig-Hofmann disease in humans and shares some of
the clinical features of amyotrophic lateral sclerosis (ALS).
It has been suggested that reactive oxygen species (ROS) may
play a role in the pathogenesis of disorders such as ALS. To
examine the relationship between ROS and neural degeneration,
we have studied the effects of agents such as N-acetyl-L-cysteine
(NAC), which reduce free radical damage. Litters of wobbler mice
were given a 1% solution of the glutathione precursor NAC in
their drinking water for a period of 9 weeks. Functional and
neuroanatomical examination of these animals revealed that wobbler
mice treated with NAC exhibited (1) a significant reduction in
motor neuron loss and elevated glutathione peroxidase levels
within the cervical spinal cord, (2) increased axon caliber in
the medial facial nerve, (3) increased muscle mass and muscle
fiber area in the triceps and flexor carpi ulnaris muscles, and
(4) increased functional efficiency of the forelimbs, as compared
with untreated wobbler littermates. These data suggest that reactive
oxygen species may be involved in the degeneration of motor neurons
in wobbler mice and demonstrate that oral administration of NAC
effectively reduces the degree of motor degeneration in wobbler
mice. This treatment thus may be applicable in the treatment
of other lower motor neuropathies.
Title
The protective effects of N-acetyl-L-cysteine against methyl
mercury embryotoxicity in mice.
Author
Ornaghi F; Ferrini S; Prati M; Giavini E
Address
Research and Development Division, Zambon Research S.p.a., Bresso,
Milan, Italy.
Source
Fundam Appl Toxicol, 20(4):437-45 1993 May
Abstract
N-Acetyl-L-cysteine (NAC) has been widely used in the protection
against the toxic effects produced by several chemicals because
of its radical scavenger properties and because NAC is a precursor
of glutathione, one of the most important intracellular defenses
against oxidants. The aim of this investigation was to verify
the potential protective activity of NAC against the well-known
embryotoxicity induced by methyl mercuric chloride (MMC) in mice.
Three experimental approaches were carried out. In the first
investigation, acute treatment of MMC (25 mg/kg po) was given
in CD female mice on Day 10 of pregnancy, and was followed immediately
and/or after 24, 48, and 72 hr by administrations of NAC (800
mg/kg i.v.). The embryolethal effects caused by MMC poisoning
were completely antagonized by just a single administration of
NAC, while the incidence of palatoschisis was reduced in relation
to the number of NAC administrations. In the second experiment
MMC was chronically gavaged (3 mg/kg/day po) during the period
of organogenesis on Days 5 to 14 of gestation. During the same
period of time some of these females were also exposed to 1%
NAC dissolved in drinking water. MMC poisoning reduced the body
weight of viable fetuses and induced many cases of palatoschisis.
The body weight of fetuses from MMC-poisoned mothers treated
with NAC was improved and the incidence of palatoschisis was
in the normal range. In the last experiment the treatment with
NAC (400 mg/kg i.v., during the period of organogenesis) drastically
reduced the severe embryolethality induced by MMC (6 mg/kg/day
po) administered during the same period of time.(Abstract
TRUNCATED AT 250 WORDS)
Title
glutathione content as an indicator for the presence of metabolic
pathways of amino acids in astroglial cultures.
Author
Dringen R; Hamprecht B
Address
Physiologisch-chemisches Institut der Universität, Tübingen,
Germany.
Source
J Neurochem, 67(4):1375-82 1996 Oct
Abstract
The intracellular content of glutathione in astroglia-rich primary
cultures derived from the brains of newborn rats was measured
to be 32.1 +/- 5.4 nmol/mg of protein. During a 24-h incubation
in a minimal medium lacking amino acids and glucose, the content
of glutathione in these cultures was reduced to 52% of the original
content. On refeeding of glucose, glutamic acid, glycine, and
cysteine, glutathione was resynthesized. A maximal content of
glutathione was found 4 h after refeeding, exceeding the amount
of glutathione of untreated cultures by 72%. Maximal glutathione
synthesis was observed only if glutamic acid, cysteine, and glycine
were present. If successively each one of these amino acids was
made limiting for the synthesis of glutathione, half-maximal
contents of glutathione were found at 0.2 mM glutamic acid, 20
microM cysteine, or 10 microM glycine. Replacement of glutamic
acid or glycine by other amino acids revealed the potential of
astroglial cells to convert glutamine, aspartate, asparagine,
proline, and ornithine into glutamic acid, and serine into glycine.
These results demonstrate that the concentration of intracellular
glutathione can serve as an indicator for the presence of metabolic
pathways of amino acids in cultured cells.
Title
Use of dipeptides for the synthesis of glutathione by astroglia-rich
primary cultures.
Author
Dringen R; Kranich O; Löschmann PA; Hamprecht B
Address
Physiologisch-chemisches Institut der Universität, Tübingen,
Germany.
Source
J Neurochem, 69(2):868-74 1997 Aug
Abstract
The intracellular content of glutathione in astroglia-rich primary
cultures derived from the brains of newborn rats was used as
an indicator for the ability of these cells to use dipeptides
for glutathione synthesis. For restoration of the glutathione
level, after a 24-h starvation period in the absence of glucose
and amino acids, glucose, glutamic acid, cysteine, and glycine
have to be present in the incubation buffer. The dipeptides CysGly
and gammaGluCys were able to substitute for cysteine plus glycine
and glutamic acid plus cysteine, respectively. Half-maximal contents
of glutathione were found at 20 microM CysGly and 3 mM gammaGluCys.
In addition, the oxidized forms of the dipeptides CysGly and
GlyCys could replace cysteine plus glycine for glutathione restoration,
and the glycine-containing dipeptides GlyGly, GlyLeu, GlyGlu,
GlyGln, and gammaGluGly could partially substitute for the glycine
necessary for the replenishment of glutathione. The glutathione
resynthesis in the presence of CysGly plus glutamic acid was
totally inhibited in the presence of buthionine sulfoximine,
an inhibitor of gamma-glutamylcysteine synthetase. In contrast,
glutathione restoration from gammaGluCys at a concentration of
10 mM in the presence of glycine was not influenced by the inhibitor.
The use of CysGly or gammaGluCys was not affected by the presence
of the dipeptidase inhibitors cilastatin or bestatin. In addition,
carnosine and several other dipeptides applied in a 50-fold excess
only slightly prevented the use of CysGly, hinting at the existence
in astroglial cells of a transport system specific for CysGly.
The results demonstrate that astroglial cells can use dipeptides
for intracellular glutathione synthesis and that the dipeptides
most likely are taken up as intact molecules into astroglial
cells before intracellular hydrolysis occurs.
Title
Changes in levels of glutathione and related compounds and activities
of glutathione-related enzymes during rat liver regeneration.
Author
Teshigawara M; Matsumoto S; Tsuboi S; Ohmori S
Address
Department of Biochemistry, Faculty of Pharmaceutical Sciences,
Okayama
University, Japan.
Source
Res Exp Med (Berl), 195(2):55-60 1995
Abstract
The levels of glutathione and glutathione disulfide increased
during the regeneration process of rat liver, reaching a maximum
(about twice the control value) on day 2 and reverting to the
normal level within 5 days. During this regeneration process,
changes in the hepatic level of cysteine, glycine and glutamic
acid, the substrates for glutathione synthesis, were determined.
The cysteine level in liver increased, reaching a maximum on
day 2 and returned to the normal level after 5 days. The levels
of glycine and glutamic acid did not change. The enzyme activities
of cystathionine-beta synthase and gamma-cystathionase for cysteine
synthesis, and of gamma-glutamylcysteine synthetase, which is
a limiting enzyme for glutathione synthesis, were clearly increased
in regenerating liver. The increase of glutathione level could
be clearly accounted for by the elevation of these enzyme activities.
Title
glutathione-induced sodium currents in neocortex.
Author
Shaw CA; Pasqualotto BA; Curry K
Address
Department of Ophthalmology, University of British Columbia,
Vancouver, Canada.
Source
Neuroreport, 7(6):1149-52 1996 Apr 26
Abstract
The present report demonstrates that glutathione (GSH), a tripeptide
composed of glutamic acid, glycine and cysteine (gamma-L-glutamyl-L-cysteinyl-glycine)
and best known as a free radical scavenger, elicits a large fast
depolarizing potential when applied to cortical slices. This
potential is maximally larger than that produced by either NMDA
or AMPA. Like AMPA, the GSH current appears to be carried by
sodium ions, but cannot be blocked by the glutamic acid receptor
antagonists AP5 or DNQX. In addition, removal of external calcium
or blockade of potassium currents by TEA does not diminish the
GSH-induced potential. Together, these results suggest that GSH
acts through its own receptor-mediated channels, independently
of the known EAA receptors, and that its receptors may be a key,
and previously unknown, component of cortical excitatory neurotransmission.
Title
Different preferences in the utilization of amino acids for glutathione
synthesis in cultured neurons and astroglial cells derived from
rat brain.
Author
Kranich O; Hamprecht B; Dringen R
Address
Physiologisch-chemisches Institut der Universität, Tübingen,
Germany.
Source
Neurosci Lett, 219(3):211-4 1996 Nov 29
Abstract
The intracellular contents of glutathione in neuron-rich and
astroglia-rich primary cultures derived from the brains of embryonal
and newborn rats were found to be 23.1 +/- 3.0 and 31.2 +/- 6.5
nmol/mg of protein, respectively. Deprivation of amino acids
for 4 h reduced the level of glutathione in neuron-rich cultures
by 24%. glutathione was resynthesized on refeeding of cysteine,
glutamine, and glycine. A maximal content of glutathione was
found 4 h after refeeding, exceeding that of untreated neuron-rich
cultures by 84%. Replacement of cysteine by cystine or glutamine
by glutamic acid during the 4 h refeeding period resulted in
a lower intracellular amount of glutathione. An increase in the
glutathione level of neuron-rich cultures by 76% was found if
the culture medium was supplemented with 250 microM cysteine.
However, no such increase occurred if cystine was used instead.
In contrast to neuron-rich cultures, astroglia-rich primary cultures
restored a maximal content of glutathione if glutamic acid and
cystine were refed after amino acid deprivation. These results
demonstrate that cysteine is the limiting compound in the culture
medium for glutathione synthesis in neuron-rich cultures and
that astroglial cells and neurons in culture have different preferences
for uptake and utilization of amino acids for glutathione synthesis.
Title
Skeletal muscle glutathione after surgical trauma.
Author
Luo JL; Hammarqvist F; Andersson K; Wernerman J
Address
Anaesthesiological Metabolism Unit, Clinical Research Centre,
Karolinska Institute, Stockholm, Sweden.
Source
Ann Surg, 223(4):420-7 1996 Apr
Abstract
OBJECTIVE: The authors investigate the effect of surgical trauma
on skeletal muscle concentrations of glutathione in patients
undergoing selective abdominal surgery. SUMMARY BACKGROUND DATA:
The posttraumatic state is accompanied by characteristic changes
in the pattern of free amino acids and a decline of protein synthesis
in human skeletal muscle. glutathione has multiple metabolic
functions that are involved in cellular homeostasis. It is unknown
how surgical trauma affects the glutathione metabolism of skeletal
muscle in surgical patients. METHODS: Eight patients undergoing
elective abdominal surgery were investigated. Percutaneous muscle
biopsies and blood samples were taken before operation and at
6, 24, and 48 hours after operation. The concentrations of glutathione
were determined in muscle tissue, plasma, and whole blood, as
well as the concentrations of the related amino acids in muscle
and plasma. RESULTS: In skeletal muscle, the levels of both reduced
and total glutathione decreased by 40% (p<0.01) at 24 hours
and remained low at 48 hours after operation compared with the
preoperative values. The glutathione concentration in plasma
was 20% lower after operation compared with the concentration
before operation (p<0.05). There were no changes at the whole
blood levels of glutathione. Tissue glutamic acid and glutamine
decreased significantly after operation (p<0.001), whereas
intracellular cysteine and glycine remained unchanged. CONCLUSIONS:
Skeletal muscle glutathione deficiency occurs after surgical
trauma. This may lead to an increase in the susceptibility to
intracellular oxidative injury.
Title
glutathione release and catabolism during energy substrate restriction
in astrocytes.
Author
Juurlink BH; Schültke E; Hertz L
Address
Saskatchewan Stroke Research Centre, College of Medicine, University
of Saskatchewan, Saskatoon, Canada.
Source
Brain Res, 710(1-2):229-33 1996 Feb 26
Abstract
This study examined the effect of simulated ischemia (deprivation
of both oxygen and substrate) on astrocyte reduced-glutathione
(GSH). We have demonstrated that under normoxic conditions there
is no GSH efflux from living astrocytes; this suggests that the
high levels of GSH in astrocytes in vivo are not available for
neighbouring neural cells. Under simulated ischemia there is
release of GSH from astrocytes only when astrocytes die. Furthermore,
when astrocytic energy stores are depleted GSH is catabolized,
such that after 12 h of simulated ischemia approximately 20%
of GSH is catabolized. This GSH catabolism can be increased at
an earlier time by causing increased ATP utilization through
activating the sodium pump either by introducing glutamic acid
into the culture medium or by raising medium potassium. Since
GSH is catabolized into glycine, glutamic acid and cysteine,
the latter two amino acids being neurotoxic, our findings indicate
that the high levels of GSH in astrocytes may be used by these
cells to survive ischemic insults, but the catabolism of GSH
may result in increased neuronal damage. |
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