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Title
In vivo metabolism of the cardiovascular toxin, allylamine.
Author
Boor PJ; Sanduja R; Nelson TJ; Ansari GA
Address
Department of Pathology, University of Texas Medical Branch,
Galveston
77550
Source
Biochem Pharmacol, 36(24):4347-53 1987 Dec 15
Abstract
Previous evidence from this laboratory demonstrated that allylamine,
a
known cardiovascular toxin, is metabolized in vitro to acrolein,
which
has been hypothesized to act as a distal toxin. In this study,
3-hydroxypropylmercapturic acid was isolated and identified by
MS, NMR,
and 2D-NMR spectroscopy as the sole urinary metabolite of allylamine
metabolism in vivo. Parallel experiments showed reduced glutathione
(GSH) depletion in several organs (most marked in aorta, blood,
and
lung), which is consistent with GSH conjugation of the proposed
acrolein intermediate. These findings indicate that allylamine
was
metabolized in vivo to a highly reactive aldehyde which was converted
to a mercapturic acid through a GSH conjugation pathway; the
exact
mechanisms of cellular damage remain unclear.
Title
Deleterious effects of buthionine sulfoximine on cardiac function
during continuous endotoxemia.
Author
Lee KJ; Andrejuk T; Dziuban SW Jr; Goldfarb RD
Address
Department of Physiology, Albany Medical College, New York 12208,
USA.
Source
Proc Soc Exp Biol Med, 209(2):178-84 1995 Jun
Abstract
Sepsis has been associated with reversible cardiac injury. To
determine
whether this injury is mediated by generation of reactive oxidants,
tissue glutathione (GSH)--the major intracellular antioxidant--was
depleted before endotoxemia. Basal values of cardiac contractile
function, perfusion, and cardiac output were measured 5-7 days
postsurgery. Salmonella enteritidis endotoxin was continuously
infused
at 3 micrograms/kg/hr iv via an osmotic pump (Alzet Corp). Endotoxemia
significantly reduced myocardial glutathione content (394 +/-
46) to
206 +/- 9 micrograms/g), indicating oxidant stress during endotoxemia.
Buthionine sulfoximine (BSO) pretreatment significantly reduced
cardiac
glutathione in sham pigs from 394 +/- 46 to 199 +/- 26 micrograms/g;
and in endotoxemic pigs, BSO pretreatment significantly reduced
cardiac
glutathione to 106 +/- 18 micrograms/g. Vehicle- and BSO-treated
endotoxemic groups demonstrated similar cardiovascular responses
to
endotoxin challenge. Heart rate increases (122 +/- 15 to 140
+/- 17
bpm) and cardiac outputs decreases (1.50 +/- 0.24 to 1.11 +/-
0.35
l/min) were similar, indicating similar cardiovascular insults
induced
by endotoxemia. Percent short axis shortening and end-systolic
pressure-diameter relation (ESPDR) were significantly reduced
in BSO
pretreated compared with vehicle-treated endotoxemic pigs. Results
support a conclusion that endotoxemia-induced cardiac injury
is
mediated, in part, by free radical injury. This conclusion is
based
upon the finding that endogenous myocardial glutathione was depleted
by
continuous endotoxin infusion and that prior depletion of myocardial
glutathione by buthionine sulfoximine exacerbated cardiac injury.
Title
Cellular antioxidant properties of human natural killer enhancing
factor B.
Author
Sarafian TA; Rajper N; Grigorian B; Kim A; Shau H
Address
Department of Pathology, UCLA 90095, USA.
Source
Free Radic Res, 26(3):281-9 1997 Mar
Abstract
The protein, NKEF (natural killer enhancing factor), has been
identified as a member of an antioxidant family of proteins capable
of
protecting against protein oxidation in cell-free assay systems.
The
mechanism of action for this family of proteins appears to involve
scavenging or suppressing formation of protein thiyl radicals.
In the
present study we investigated the antioxidant protective properties
of
the NKEF-B protein overexpressed in an endothelial cell line
(ECV304).
Nkef-B-transfected cells displayed significantly lower levels
of
reactive oxygen species (ROS) compared with control or
vector-transfected cells. Tert-Butylhydroperoxide-induced ROS
was 15%
lower in nkef-B-transfected cells and cytotoxicity was slightly,
though
not significantly, lower. NKEF-B had no effect on ROS induced
by
menadione or xanthine plus xanthine oxidase. NKEF-B overexpression
resulted in slightly (approximately 10%) lower levels of cellular
glutathione (GSH) and had no effect on rate or extent of GSH
depletion
following either diethylmaleate (DEM) or buthionine sulfoximine
(BSO)
treatment. Lipid peroxidation, assessed as thiobarbituric acid-reactive
substances, was 40% lower in nkef-B-transfected cells compared
with
vector-only-transfected cells. DEM-induced lipid peroxidation
was
suppressed by NKEF-B at DEM concentrations of 20 microM to 1
mM. At 10
mM DEM, lipid peroxidation was unaffected by NKEF-B. NKEF-B expression
also protected cells against menadione-induced inhibition of
[3H]-thymidine uptake. The NKEF-B protein appears most effective
in
suppressing basal low-level oxidative injury such as that produced
during normal metabolism. These results indicate that overexpression
of
the NKEF-B protein promotes resistance to oxidative stress in
this
endothelial cell line.
Title
Effect of oral administration of T-2 toxin on glutathione shuttle
enzymes, microsomal reductases and lipid peroxidation in rat
liver.
Author
Suneja SK; Wagle DS; Ram GC
Address
Department of Pharmacology, University of Connecticut Health
Center,
Farmington 06032.
Source
Toxicon, 27(9):995-1001 1989
Abstract
Effects of T-2 toxin on liver lipid peroxidation, glutathione
shuttle
enzymes and microsomal reductases have been studied in rats at
8, 16
and 24 hr after feeding a single dose of toxin (2.0 mg/kg) and
at 7, 14
and 21 days after feeding of toxin (0.75 mg/kg) daily. Feeding
of a
single dose of T-2 toxin caused significant increase in liver
lipid
peroxidation in rats at 8, 16 and 24 hr post treatment. The liver
lipid
peroxidation was also significantly increased at 14 and 21 days
after
feeding of 0.75 mg/kg of T-2 toxin daily to rats. The activities
of
liver GSH-shuttle enzymes, i.e. glutathione peroxidase, glutathione
reductase and glucose-6-phosphate dehydrogenase, were significantly
higher in rats after both feeding schedules of T-2 toxin.
NADPH-cytochrome c reductase activity was significantly lower
at 8, 16
and 24 hr in liver of rats fed a single dose of T-2 toxin, whereas
NADH-cytochrome b5 reductase was significantly higher until 16
hr and
then declined below normal at 24 hr post treatment. In rats fed
multiple doses of T-2 toxin, both liver microsomal reductases
were
significantly reduced. These results suggest that T-2 toxin/or
its
metabolites in the liver may be involved in the generation of
free
radicals which cause the observed increase in lipid peroxidation.
Title
Oxidative stress: a role in the pathogenesis of Parkinson's disease.
Author
Götz ME; Freyberger A; Riederer P
Address
Klinische Neurochemie, Universitäts-Nervenklinik Würzburg,
Federal
Republic of Germany.
Source
J Neural Transm Suppl, 29():241-9 1990
Abstract
The degeneration of nigro-striatal dopaminergic neurons is considered
to be a predominant pathogenetic factor of Parkinson's disease
(PD).
However, the etiology of this degeneration is not known. Hypotheses
assume accumulation of endogenous and/or exogenous toxins as
trigger of
the disease. An increase in the concentration of free radicals
has been
suggested to be toxic to cells, especially when combined with
certain
metals like free iron or copper. The role of melanin in the
degenerative process is not clear, but autoxidative reactions
such as
the oxidation of dopamine (DA) to melanin generating radicals
and toxic
metabolites seem to enhance the vulnerability of neurons in the
substantia nigra (SN). Disappearance of melanin in the SN, increase
of
total iron and ferric iron, extreme decrease of glutathione (GSH)
levels, reduced activity of enzymes involved in the detoxification
of
hydrogen peroxide, hydroxyl and superoxide radicals (peroxidases,
catalase, glutathione peroxidase), an increase of monoamine oxidase
B
(MAO B) activity and the substantial increase of malondialdehyde,
a
marker of lipid peroxidation, in the SN seem to indicate a role
of an
oxidative stress syndrome in the SN causing or aggravating PD.
Title
glutathione and its related enzymes in the small intestinal mucosa
of
rats: effects of starvation and diet.
Author
Ogasawara T; Ohnhaus EE; Hoensch HP
Address
Department of Internal Medicine, University of Essen, Federal
Republic
of Germany.
Source
Res Exp Med (Berl), 189(3):195-204 1989
Abstract
Starvation for 24 h causes a striking fall in glutathione content
from
3.19 +/- 0.27 to 1.88 +/- 0.14 (X +/- SEM) mumol/g tissue and
of GGT
activity from 31.75 +/- 4.17 to 19.49 +/- 3.13 (X +/- SEM) nmol/min/mg
protein in the homogenate from whole mucosa of the upper small
intestinal segments. This was associated with a significant increase
in
GSH-Px activity and the content of lipid peroxides (measured
by the
thiobarbituric assay). On semi-synthetic iron-supplemented diet
the
activities of GSH-T and GGT were significantly decreased as compared
with crude diet. On semisynthetic iron-depleted diet GSH-T and
GGT
activities were further depressed, but this was accompanied with
an
additional depression of GSH, glutathione reductase (GSSG-R),
and
glutathione peroxidase (GSH-Px) activities and lipid peroxide
concentrations. Food deprivation significantly lowers the mucosal
GSH-content and could lead to a destabilization of this system
presumably by increased oxidative stress. As compared to normal
"crude"
diet, semisynthetic diets and oral iron depletion have been shown
to
cause a depression of the intestinal GSH system. As a consequence
of
these effects, the resistance of the small intestinal mucosa
toward
exogeneous dietary toxins might be reduced.
Title
glutathione-induced enhancement of neutrophil locomotion.
Author
Elferink JG; de Koster BM
Address
Department of Medical Biochemistry, University of Leiden, The
Netherlands.
Source
Immunobiology, 184(1):25-36 1991 Dec
Abstract
Both reduced glutathione (GSH) and and its oxidized form, glutathione
disulfide (GSSG), enhance neutrophil locomotion. The enhancement
is
mainly due to a chemokinetic effect, and partly due to a chemotactic
effect. A number of other SH-group containing compounds were
not
effective in enhancing neutrophil migration. While random locomotion
is
not inhibited by the slowly-penetrating sulfhydryl agent
5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), the enhancement of
migration due to GSH is completely inhibited. Pretreatment of
neutrophils with pertussis toxin completely inhibited the GSH-induced
stimulation of locomotion, suggesting that stimulation of migration
by
glutathione was mediated by a pertussis toxin sensitive G-protein.
Chemotaxis towards GSH is inhibited by the same agents that inhibit
fMet-Leu-Phe induced chemotaxis, except that colchicine was a
more
effective inhibitor of GSH-induced chemotaxis than of fMet-Leu-Phe
directed chemotaxis. GSH enhances the intracellular concentration
of
cGMP, which might indicate that the effect on neutrophil locomotion
is
mediated by an effect on cGMP.
Title
glutathione depletion: its effects on other antioxidant systems
and
hepatocellular damage.
Author
Comporti M; Maellaro E; Del Bello B; Casini AF
Address
Istituto di Patologia Generale dell'Università di Siena,
Italy.
Source
Xenobiotica, 21(8):1067-76 1991 Aug
Abstract
1. The mechanisms of the liver damage produced by three glutathione
(GSH)-depleting agents, bromobenzene, allyl alcohol and diethyl
maleate, were investigated. 2. With each toxin liver necrosis
was
accompanied by lipid peroxidation that developed only after severe
depletion of GSH. 3. Changes in antioxidant systems by alpha-tocopherol
(vitamin E) and ascorbic acid were studied. A decrease in the
hepatic
level of vitamin E, and a change in the redox state of vitamin
C
(increase in oxidized over reduced form) were evident whenever
extensive lipid peroxidation developed. However, in the case
of
bromobenzene intoxication these alterations preceded lipid
peroxidation, and may be an index of oxidative stress leading
to
subsequent membrane damage. 4. Experiments carried out with vitamin
E-deficient or supplemented diets indicated that pathological
phenomena
occurring as a consequence of GSH depletion depend on hepatic
levels of
vitamin E. In vitamin E-deficient animals, lipid peroxidation
and liver
necrosis appeared earlier than in animals fed the control diet.
In
animals fed a vitamin E-supplemented diet, bromobenzene and allyl
alcohol had only limited toxicity, and diethyl maleate none,
in spite
of similar hepatic GSH depletion. Thus, vitamin E may largely
modulate
the expression of toxicity by GSH-depleting agents.
Title
Effects of dietary saturated or polyunsaturated fat on hepatic
glutathione S-transferase activity.
Author
Norred WP; Marzuki A
Source
Drug Nutr Interact, 3(1):11-20 1984
Abstract
Microsomal mixed function oxidases (MFO) responsible for phase
I
xenobiotic metabolism are partially dependent on dietary
polyunsaturated fat. The reduced activity of the MFO when fat-free
or
saturated fat diets are fed has been associated with alterations
of
microsomal phospholipid fatty acid content. glutathione S-transferases
(GSH-transferases) catalyze phase II conjugation reactions, and
are
important detoxification pathways for highly reactive phase I-produced
intermediates. We hypothesized that activity of membrane-bound,
but not
soluble, GSH-transferases would be affected by type of dietary
fat.
Rats were fed diets that contained either 20% coconut oil, 20%
corn
oil, or a mixture of 18% coconut oil plus 2% corn oil as the
sole
source of dietary fatty acids. At the end of the 3-week feeding
period
the activity of both microsomal and soluble fraction GSH-transferases
of rat liver was determined. The original hypothesis that dietary
fat
type would alter membrane-bound transferase activity was not
supported
by the results since GSH-transferase activity in the microsomal
fraction was not affected. However, feeding 20% coconut oil produced
a
25 to 40% decrease in soluble transferase activity compared to
corn oil
feeding. The Michaelis constant (Km) for soluble GSH-transferase
was
threefold higher when the diet was devoid of polyunsaturated
fat.
Ultrafiltration of the soluble fraction to remove compounds with
molecular weights below 50,000 did not eliminate the differences
in
transferase activity due to dietary fat. Separation of the soluble
transferases by fast protein liquid chromatography indicated
that
quantities of the various transferases were affected equally
by type of
dietary fat. The results indicate that type of dietary fat may
be
important in determining the ability to detoxify carcinogens
or other
toxins that are conjugated with glutathione. |
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