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Glutathione Molecule
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Science Index


Effects of in utero administration of alcohol on glutathione levels in
brain and liver.
Reyes E; Ott S; Robinson B
Department of Pharmacology' School of Medicine' University of New
Mexico' Albuquerque 87131.
alcohol Clin Exp Res, 17(4):877-81 1993 Aug
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

Alteration of erythrocyte glutathione' cysteine and glutathione
synthetase in alcoholic and non-alcoholic cirrhosis.
Loguercio C; Del Vecchio Blanco C; Coltorti M; Nardi G
Istituto di Medicina Generale e Metodologia Clinica' I Facolt`a di
Medicina e Chirurgia' Universit`a di Napoli' Italy.
Scand J Clin Lab Invest, 52(3):207-13 1992 May
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

Regional variations in total and nonprotein sulfhydryl compounds in the
human gastric mucosa and effects of ethanol.
Loguercio C; Romano M; Di Sapio M; Nardi G; Taranto D; Grella A; Del
Vecchio Blanco C
Dept. of Digestive Physiopathology' First Medical School' University of
Naples' Italy.
Scand J Gastroenterol, 26(10):1042-8 1991 Oct
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.

Response of cardiac antioxidant system to alcohol and exercise training
in the rat.
Husain K; Somani SM
Department of Pharmacology' Southern Illinois University' School of
Medicine' Springfield 62794' USA.
alcohol, 14(3):301-7 1997 May-Jun
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.

Lipid peroxidation and antioxidant systems in rat brain: effect of
chronic alcohol consumption.
Omodeo-Sale F; Gramigna D; Campaniello R
Istituto di Fisiologia Generale e Chimica Biologica' Facolta di
Farmacia' Milano' Italy.
Neurochem Res, 22(5):577-82 1997 May
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

Interaction of exercise and ethanol on antioxidant enzymes in brain
regions of the rat.
Somani SM; Husain K; Diaz-Phillips L; Lanzotti DJ; Kareti KR; Trammell
Department of Pharmacology' Southern Illinois University' School of
Medicine' Springfield 62794-1222' USA.
alcohol, 13(6):603-10 1996 Nov-Dec
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.

Liver antioxidant defenses in mice fed ethanol and the AIN-76A diet.
Chen LH; Xi S; Cohen DA
Department of Nutrition and Food Science' University of Kentucky'
Lexington 40506-0054' USA.
alcohol, 12(5):453-7 1995 Sep-Oct
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.

Acute ethanol exposure alters hepatic glutathione metabolism in
riboflavin deficiency.
Dutta P; Seirafi J; Halpin D; Pinto J; Rivlin R
Department of Medicine' Memorial-Sloan Kettering Cancer Center' Cornell
University Medical College' New York' NY 10021' USA.
alcohol, 12(1):43-7 1995 Jan-Feb
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.

ethanol-induced changes in the content of thiol compounds and of lipid
peroxidation in livers and brains from mice: protection by thiazolidine
Wlodek L; Rommelspacher H
Institute of Medical Biochemistry' Jagiellonian University' Collegium
Medicum/Krakow' Poland.
alcohol alcohol, 29(6):649-57 1994 Nov
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

Role of oxidative stress and antioxidant therapy in alcoholic and
nonalcoholic liver diseases.
Lieber CS
Mount Sinai School of Medicine (CUNY)' alcohol Research and Treatment
Center' Bronx' USA.
Adv Pharmacol, 38():601-28 1997
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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