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Title
Effects of in utero administration of alcohol on glutathione
levels in
brain and liver.
Author
Reyes E; Ott S; Robinson B
Address
Department of Pharmacology' School of Medicine' University of
New
Mexico' Albuquerque 87131.
Source
alcohol Clin Exp Res, 17(4):877-81 1993 Aug
Abstract
Previous studies in our laboratory have shown that the ontogenic
development of gamma-glutamyltranspeptidase (gamma-GTP) activity
is
delayed by the in utero administration of alcohol. gamma-GTP
is
responsible for the degradation and recycling of glutathione
(GSH) via
the gamma-glutamyl cycle. In this study' we examined the effects
of the
in utero administration of alcohol on GSH levels in gestational
age
21-day-old (g21) rats. Pregnant rats were placed on a liquid
diet
containing either 35% ethanol-derived calories (35% EDC) or a
pair-fed
(PF) diet or a lab chow (LC) diet starting on day 1 of gestation
and
maintained on their respective diets until gestational day 21.
On
gestational day 21' the pups were delivered by Cesarean section
and
brains and livers removed and prepared for analysis of GSH' gamma-GTP'
or gamma-glutamyl-cysteine synthetase (gamma-GCSyn). GSH levels
in
brain and liver were found to be significantly lower in the offspring
of the 35% EDC-treated mothers than from the PF and LC controls.
gamma-GTP activity was higher in brain and liver of the 35% EDC
group
than the PF group. gamma-GCSyn' the enzyme involved in the
rate-limiting step of GSH synthesis' was not affected in liver'
but was
found to be decreased in brain of the 35% EDC and PF groups when
compared with the LC group. GSH is involved in many cellular
reactions
that appear to protect the cell from damage.(ABSTRACT TRUNCATED
AT 250
WORDS)
Title
Alteration of erythrocyte glutathione' cysteine and glutathione
synthetase in alcoholic and non-alcoholic cirrhosis.
Author
Loguercio C; Del Vecchio Blanco C; Coltorti M; Nardi G
Address
Istituto di Medicina Generale e Metodologia Clinica' I Facolt`a
di
Medicina e Chirurgia' Universit`a di Napoli' Italy.
Source
Scand J Clin Lab Invest, 52(3):207-13 1992 May
Abstract
glutathione (GSH) and cysteine were determined in the plasma
and the
erythrocytes of alcoholic and non-alcoholic cirrhotics as fluorescent
monobromobimane derivatives by high-performance liquid chromatography
(HPLC). Cirrhotic patients displayed a significant decrease of
plasma
GSH' as well as of plasma cysteine' that was related to the degree
of
liver disease but not to the nutritional conditions. On the contrary'
erythrocyte cysteine was found to increase significantly in all
cirrhotics' particularly in alcoholics' regardless of the severity
of
disease. In an attempt to find a possible explanation of these
alterations' the GSH synthesizing enzymes' gamma-glutamylcysteine
synthetase (GC-s) and GSH synthetase (GSH-s) activities were
determined
in the erythrocytes. GSH-s activity was significantly lower in
cirrhotic patients' whereas GC-s activity did not differ in the
three
groups.
Title
Regional variations in total and nonprotein sulfhydryl compounds
in the
human gastric mucosa and effects of ethanol.
Author
Loguercio C; Romano M; Di Sapio M; Nardi G; Taranto D; Grella
A; Del
Vecchio Blanco C
Address
Dept. of Digestive Physiopathology' First Medical School' University
of
Naples' Italy.
Source
Scand J Gastroenterol, 26(10):1042-8 1991 Oct
Abstract
This study evaluated the regional distribution of sulfhydryl
compounds
in the human gastric mucosa and the effect of ethanol on gastric
sulfhydryl tissue levels. Total sulfhydryl' glutathione' and
cysteine
and their oxidized forms were measured in biopsy specimens taken
from
the gastric body and antrum of 22 healthy volunteers. Total sulfhydryl
and glutathione contents of the body of the stomach were significantly
higher than those of the antrum. In contrast' cysteine concentration
was higher in the gastric antrum than in the body. No difference
was
found in the levels of oxidized sulfhydryls between the gastric
body
and antrum. The effect of acute administration of ethanol on
gastric
sulfhydryl content was studied in nine subJects. ethanol caused
gross
mucosal damage and lowered the concentration of sulfhydryl compounds
in
both the body and the antrum. In 10 chronic alcoholics total
sulfhydryl
and glutathione' but not cysteine' were markedly decreased in
the
gastric body but not in the antrum as compared with nonalcoholic
controls. In conclusion' 1) the human gastric body contains
significantly higher tissue levels of total sulfhydryls and glutathione
and lower concentrations of cysteine than the antrum; 2) ethanol
in a
damaging concentration significantly decreases gastric tissue
levels of
sulfhydryl compounds; and 3) chronic ethanol intake lowers total
sulfhydryl and glutathione tissue levels in the gastric body.
Title
Response of cardiac antioxidant system to alcohol and exercise
training
in the rat.
Author
Husain K; Somani SM
Address
Department of Pharmacology' Southern Illinois University' School
of
Medicine' Springfield 62794' USA.
Source
alcohol, 14(3):301-7 1997 May-Jun
Abstract
Recent evidence has shown that alcohol as well as exercise induces
oxidative stress. However' the combination of both on the cardiac
antioxidant system is not known. This study investigates the
interactive effects of exercise training and chronic ethanol
consumption on the antioxidant system of the rat heart. Male
Fisher-344
rats were treated as follows: 1) sedentary control (SC); 2) exercise
training (ET) for 6.5 weeks; 3) ethanol (2 g/kg' PO) for 6.5
weeks' and
4) ET plus ethanol for 6.5 weeks. Rats were sacrificed and hearts
were
isolated. glutathione (GSH)' oxidized glutathione (GSSG)' superoxide
dismutase (SOD)' catalase (CAT)' glutathione peroxidase (GSH-Px)'
glutathione reductase (GR)' and lipid peroxidation (MDA) were
determined in heart tissues. SOD and GSH-Px activities were
significantly increased 118% and 148% of SC' respectively' due
to ET.
GSH level increased 118% of SC in ET rats. GSH-Px activity increased
118% of SC whereas SOD activity and CuZn-SOD protein level and
GR
activity decreased 87%' 71%' and 90% of SC due to chronic ethanol
administration. GSH level decreased 87% of SC and lipid peroxidation
increased 149% of SC due to ethanol consumption. GSH-Px activity
and
GSH levels increased 143% and 130% of SC due to combination of
ET and
ethanol. This study suggests that ET and chronic ethanol ingestion
augments the antioxidant enzyme activity and GSH levels in the
heart.
This combination reduced the extent of ethanol-induced lipid
peroxidation. The data suggest that ET may reduce the extent
of the
damage caused by ethanol consumption on the myocardium.
Title
Lipid peroxidation and antioxidant systems in rat brain: effect
of
chronic alcohol consumption.
Author
Omodeo-Sale F; Gramigna D; Campaniello R
Address
Istituto di Fisiologia Generale e Chimica Biologica' Facolta
di
Farmacia' Milano' Italy.
Source
Neurochem Res, 22(5):577-82 1997 May
Abstract
The effect of chronic ethanol exposure' in a liquid diet' on
lipid
peroxidation and some antioxidant systems of rat brain was
investigated. Chronic ethanol administration induced a greater
susceptibility to iron/ascorbate-induced lipid peroxidation'
estimated
as thiobarbituric reactive substances (TBARS) production' in
the
microsomal fraction' but a lower lipid peroxidation in the total
homogenate. glutathione (GSH) levels as well as GSH peroxidase
and GSH
reductase were unaffected' while the activity of Cu-Zn superoxide
dismutase was decreased and that of catalase increased. Lipid
peroxidation experiments performed in the presence of some hydroxyl
radical scavengers suggested that a greater OH. generation may
be
responsible of the greater TBARS production in the microsomal
fraction
of ethanol treated rats; differently' in total homogenate of
control
and ethanol rats a relationship was found between the redox state
of
iron and TBARS production' suggesting that the lower lipid peroxidation
in treated rats may depend on a different modulation of the iron
redox
state.
Title
Interaction of exercise and ethanol on antioxidant enzymes in
brain
regions of the rat.
Author
Somani SM; Husain K; Diaz-Phillips L; Lanzotti DJ; Kareti KR;
Trammell
GL
Address
Department of Pharmacology' Southern Illinois University' School
of
Medicine' Springfield 62794-1222' USA.
Source
alcohol, 13(6):603-10 1996 Nov-Dec
Abstract
This study investigates the effect of ethanol ingestion on antioxidant
enzymes (AOE) and lipid peroxidation (malondialdehyde' (MDA)
in
different brain regions of the rat after acute exercise. Acute
exercise
(100% VO2max) significantly increased glutathione peroxidase
(GSH-Px)
activity and decreased glutathione reductase (GR) activity in
the
cerebral cortex. Acute exercise significantly increased MDA level
in
the corpus striatum. ethanol (20%) (1.6 g/kg' PO) significantly
increased MDA level in the cerebral cortex. ethanol also significantly
increased superoxide dismutase (SOD) activity in the cortex and
catalase (CAT)' GSH-Px' and GR activities in the corpus striatum.
ethanol significantly augmented CAT activity in the medulla and
GSH-Px
activity in the hypothalamus. However' CAT activity significantly
decreased in the hypothalamus after ethanol ingestion. The combination
significantly increased GSH-Px activity in the hypothalamus'
SOD
activity in the cortex' GR activity in the striatum' and MDA
level in
the medulla. In conclusion' the cerebral cortex' striatum medulla'
and
hypothalamus reacted differentially in response to ethanol as
well as
to acute exercise-induced oxidative stress whereas the combination
moderated the changes in AOE activity in specific brain regions.
Title
Liver antioxidant defenses in mice fed ethanol and the AIN-76A
diet.
Author
Chen LH; Xi S; Cohen DA
Address
Department of Nutrition and Food Science' University of Kentucky'
Lexington 40506-0054' USA.
Source
alcohol, 12(5):453-7 1995 Sep-Oct
Abstract
The effects of chronic alcohol (EtOH) ingestion on antioxidant
defenses
in mice fed AIN-76A liquid diets were investigated. C57Bl/6 female
mice
were divided into three groups and fed the AIN-76A liquid EtOH
diet
containing EtOH to provide 31% of total caloric intake (TCI)'
the same
basic diet containing EtOH to provide 35% of TCI' or an isocaloric
AIN-76A liquid control diet. After 3 weeks' the mice were killed
and
livers were excised for biochemical analysis. Liver reduced glutathione
(GSH) levels' and activities of both Mn-superoxide dismutase
(SOD) and
Cu/Zn-SOD were significantly decreased by both levels of EtOH.
Activities of catalase and glutathione transferase (GT) were
significantly increased' whereas glutathione peroxidase (GP)
activity
was not affected by either level of EtOH. Our previous study
using the
Lieber-DeCarli liquid EtOH diet caused a decline of total SOD
and GP
activities. The results suggest that chronic EtOH administration
decreases liver antioxidant defenses; however' the mice fed the
AIN-76A
EtOH liquid diet can maintain a higher antioxidant defense capability
than those fed Lieber-DeCarli EtOH liquid diet.
Title
Acute ethanol exposure alters hepatic glutathione metabolism
in
riboflavin deficiency.
Author
Dutta P; Seirafi J; Halpin D; Pinto J; Rivlin R
Address
Department of Medicine' Memorial-Sloan Kettering Cancer Center'
Cornell
University Medical College' New York' NY 10021' USA.
Source
alcohol, 12(1):43-7 1995 Jan-Feb
Abstract
Since acute ethanol consumption and riboflavin deficiency each
induces
oxidative stress within tissues' we examined whether their combined
effects compromise the maJor antioxidative system in liver' namely'
reduced glutathione (GSH) metabolism. Four hours before sacrifice'
half
the riboflavin-deficient (RD) and riboflavin-sufficient (RS)
rats were
treated with ethanol (3 g/kg). Livers were excised and analyzed
for GSH
and enzymes that control its metabolism. In RD rats' GSH increased
while glucose-6-phosphate dehydrogenase (G6PD) activity decreased.
ethanol had no effect on these measurements in RS rats. In RD
rats'
ethanol administration decreased GSH along with the activities
of GSH
peroxidase' glutathione reductase' and G6PD. These data suggest
that
riboflavin deficiency alone does not compromise hepatic GSH metabolism.
By contrast' ethanol consumption together with riboflavin deficiency
depletes hepatic GSH' blunts enzyme activities controlling GSH
metabolism and may enhance alcohol-induced liver inJury.
Title
ethanol-induced changes in the content of thiol compounds and
of lipid
peroxidation in livers and brains from mice: protection by thiazolidine
derivatives.
Author
Wlodek L; Rommelspacher H
Address
Institute of Medical Biochemistry' Jagiellonian University' Collegium
Medicum/Krakow' Poland.
Source
alcohol alcohol, 29(6):649-57 1994 Nov
Abstract
Treatment of mice with ethanol for 5 days resulted in a drop
of total
glutathione in the liver' possibly due to an ethanol-stimulated
increased conversion into L-cysteine. The levels of L-cysteine
and the
rate of lipid peroxidation were above control levels. Similar
but less
pronounced changes were observed with brain tissue. The continuation
of
the treatment with ethanol led to an adaptation in both tissues
as
assessed at days 10 and 15. These findings suggest induction
of enzymes
involved in the defence mechanisms against lipid peroxidation.
However'
at day 23 of treatment the levels of total glutathione and L-cysteine
were reduced in the liver whereas lipid peroxidation was increased.
Thus' a state of impaired defence mechanisms occurred during
prolonged
treatment. Interestingly' the concentration of total glutathione
was
increased in the brain suggesting protective mechanisms in this
organ
and possibly a supply from other organs. No increase of lipid
peroxidation levels in the brain was observed. The substitution
of the
deficit of thiol compounds is a maJor problem because neither
L-cysteine nor glutathione can be utilized for different reasons.
Therefore' we treated mice with thiazolidine derivatives which
can be
regarded as `frozen` L-cysteine. Two days of treatment with
2-methyl-thiazolidine-2'4-dicarboxylic acid were sufficient to
observe
an increase of total glutathione and free L-cysteine levels and
a
decrease of lipid peroxidation in the liver. These findings demonstrate
a new treatment for the tissue-damaging effects of chronic ethanol
ingestion.(ABSTRACT TRUNCATED AT 250 WORDS)
Title
Role of oxidative stress and antioxidant therapy in alcoholic
and
nonalcoholic liver diseases.
Author
Lieber CS
Address
Mount Sinai School of Medicine (CUNY)' alcohol Research and Treatment
Center' Bronx' USA.
Source
Adv Pharmacol, 38():601-28 1997
Abstract
The main pathway for the hepatic oxidation of ethanol to acetaldehyde
proceeds via ADH and is associated with the reduction of NAD
to NADH;
the latter produces a striking redox change with various associated
metabolic disorders. NADH also inhibits xanthine dehydrogenase
activity' resulting in a shift of purine oxidation to xanthine
oxidase'
thereby promoting the generation of oxygen-free radical species.
NADH
also supports microsomal oxidations' including that of ethanol'
in part
via transhydrogenation to NADPH. In addition to the classic alcohol
dehydrogenase pathway' ethanol can also be reduced by an accessory
but
inducible microsomal ethanoloxidizing system. This induction
is
associated with proliferation of the endoplasmic reticulum' both
in
experimental animals and in humans' and is accompanied by increased
oxidation of NADPH with resulting H2O2 generation. There is also
a
concomitant 4- to 10-fold induction of cytochrome P4502E1 (2E1)
both in
rats and in humans' with hepatic perivenular preponderance. This
2E1
induction contributes to the well-known lipid peroxidation associated
with alcoholic liver inJury' as demonstrated by increased rates
of
superoxide radical production and lipid peroxidation correlating
with
the amount of 2E1 in liver microsomal preparations and the inhibition
of lipid peroxidation in liver microsomes by antibodies against
2E1 in
control and ethanol-fed rats. Indeed' 2E1 is rather "leaky"
and its
operation results in a significant release of free radicals.
In
addition' induction of this microsomal system results in enhanced
acetaldehyde production' which in turn impairs defense systems
against
oxidative stress. For instance' it decreases GSH by various mechanisms'
including binding to cysteine or by provoking its leakage out
of the
mitochondria and of the cell. Hepatic GSH depletion after chronic
alcohol consumption was shown both in experimental animals and
in
humans. alcohol-induced increased GSH turnover was demonstrated
indirectly by a rise in alpha-amino-n-butyric acid in rats and
baboons
and in volunteers given alcohol. The ultimate precursor of cysteine
(one of the three amino acids of GSH) is methionine. Methionine'
however' must be first activated to S-adenosylmethionine by an
enzyme
which is depressed by alcoholic liver disease. This block can
be
bypassed by SAMe administration which restores hepatic SAMe levels
and
attenuates parameters of ethanol-induced liver inJury significantly
such as the increase in circulating transaminases' mitochondrial
lesions' and leakage of mitochondrial enzymes (e.g.' glutamic
dehydrogenase) into the bloodstream. SAMe also contributes to
the
methylation of phosphatidylethanolamine to phosphatidylcholine.
The
methyltransferase involved is strikingly depressed by alcohol
consumption' but this can be corrected' and hepatic phosphatidylcholine
levels restored' by the administration of a mixture of polyunsaturated
phospholipids (polyenylphosphatidylcholine). In addition' PPC
provided
total protection against alcohol-induced septal fibrosis and
cirrhosis
in the baboon and it abolished an associated twofold rise in
hepatic
F2-isoprostanes' a product of lipid peroxidation. A similar effect
was
observed in rats given CCl4. Thus' PPC prevented CCl4- and
alcohol-induced lipid peroxidation in rats and baboons' respectively'
while it attenuated the associated liver inJury. Similar studies
are
ongoing in humans. |
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