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Title
Protective antioxidant mechanisms in rat and guinea pig tissues
challenged by acute exposure to cigarette smoke.
Author
Bilimoria MH; Ecobichon DJ
Address
Pathology Institute McGill University' Montreal' Quebec' Canada.
Source
Toxicology, 72(2):131-44 1992
Abstract
Cellular damage from reactive intermediates formed during xenobiotic
biotransformation is prevented by the presence of adequate levels
of
antioxidant chemicals in the tissues. Equally important for cell
protection is the rate at which these chemicals are replaced
if tissue
stores are depleted. The present experiments' using adult male
Sprague-Dawley rats and Hartley guinea pigs' were conducted to
ascertain what effects mainstream (MS) and sidestream (SS) tobacco
smoke would have on the water-soluble' cytoplasmic antioxidants'
ascorbic acid (AA) and reduced glutathione (GSH). The animals
were
exposed by nose-only inhalation to varying doses (40' 120' 240
puffs)
of a 1:5 dilution of a 35-ml volume of freshly generated MS from
cigarettes made from different types of tobacco and delivered
by a
B.-A.T-Mason inhalation apparatus. The animals were euthanized
either
immediately following exposure or at 3 and 6 h. The blood' lungs'
liver' kidneys' heart and bladder were removed for the quantitation
of
AA and GSH following homogenization and deproteinization. Immediately
following exposure to MS' dose-dependent decreases in pulmonary
and
renal GSH were observed in rats whereas' in guinea pigs' reductions
in
pulmonary' hepatic and renal GSH were observed only at the highest
level of exposure. No reductions in tissue AA were observed in
either
species at any exposure level. In both species' blood levels
of GSH and
AA remained unchanged following exposure. Mainstream smoke (240
puffs)
from flue-cured or dark' air-cured tobaccos elicited a significant'
immediate reduction in pulmonary and renal GSH' but MS from low
tar'
filter cigarettes was without effect. Within 3 h of exposure'
GSH in
all tissues has returned to pre-exposure levels. Whole-body'
chamber
exposure to concentrated SS' generated from smouldering cigarettes'
caused a dose-dependent reduction in rat pulmonary' hepatic'
renal'
cardiac and bladder muscle GSH but only affected pulmonary GSH
in the
guinea pig. Lesser effects were observed in tissues of rats exposed
to
diluted SS. In the rat' a comparison of the results of diethylmaleate-
and smoke-induced depletion of tissue GSH suggested that' even
at
exceptionally high levels of exposure' there was a significant
store of
GSH in tissues that did not interact with tobacco smoke.
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
Effect of cigarette smoke inhalation on antioxidant enzymes and
lipid
peroxidation in the rat.
Author
Gupta MP; Khanduja KL; Sharma RR
Address
Biophysics Department, Postgraduate Institute of Medical Education
and
Research, Chandigarh, India.
Source
Toxicol Lett, 41(2):107-14 1988 May
Abstract
Inhalation of cigarette smoke significantly increased glutathione
(GSH)
content and increased lipid peroxidation without altering the
activities of superoxide dismutase (SOD), catalase, glutathione
peroxidase (GSH-Px) or glutathione reductase (GR) in the lung
(six male
Wistar rats). Following intratracheal administration of benzo[a]pyrene
(BP), an increase in pulmonary GSH-Px activity, GSH content and
lipid
peroxidation was observed after 12 h. GSH-Px activity and GSH
content
returned to control values by 7 and 30 days, respectively, whereas
lipid peroxidation in the lung remained significantly greater
than the
control value for up to 7 days of BP administration. Hepatic
activity
of SOD was increased significantly, whereas the activities of
GSH-Px,
catalase, GR, and GSH content were not changed by inhalation
of
cigarette smoke. On administration of BP, a significant increase
in the
activities of SOD and GSH-Px was observed at 12 h. After 7 and
30 days,
the activities of these antioxidant enzymes were comparable to
their
respective control group values. No change in the activity of
catalase
or in the level of lipid peroxidation was noted throughout the
entire
study period.
Title
Combined effects of ethanol and cigarette smoke on hepatic and
pulmonary xenobiotic metabolizing enzymes in rats.
Author
Eke BC; Vural N; I,scan M
Address
Department of Toxicology' Faculty of Pharmacy' Ankara University'
Turkey.
Source
Chem Biol Interact, 102(3):155-67 1996 Dec 20
Abstract
The combined effects of ethanol (EtOH) and cigarette smoke (CS)
on
hepatic and pulmonary monooxygenase (MO) activities (aniline
4-hydroxylase (AH)' aminopyrine N-demethylase (AMND)' 7-ethoxyresorufin
O-deethylase (EROD)' p-nitroanisole O-demethylase (p-NAOD))'
lipid
peroxidation (LP) and reduced glutathione (GSH) levels and glutathione
S-transferase (GST) activities toward several substrates
(l-chloro-2'4-dinitrobenzene (CDNB)' 1'2-dichloro-4-nitrobenzene
(DCNB)' ethacrynic acid (EAA)' 1'2-epoxy-3-(p-nitrophenoxy)-propane
(ENPP)) were determined and compared with those of EtOH or CS
alone in
rats. When the male adult rats (225-275 g) were treated with
10% EtOH
(v/v) in their drinking for 21 days AH' AMND and EROD activities
and LP
and GSH levels increased significantly whereas GST activity for
EAA
decreased significantly in liver as compared to controls. EtOH
did not
change the hepatic p-NAOD and GST activities toward CDNB' DCNB
and
ENPP. In lung' EtOH increased GST activities toward CDNB and
ENPP and
LP level but decreased GST activity toward DCNB' significantly.
No
alterations were noted in pulmonary MO activities and GST activity
toward EAA and GSH level by EtOH treatment. When the animals
were
exposed to CS five times a day' with 1 h intervals' for 3 days
in a
chamber where smoke and fresh air lead alternatively' AMND' EROD
and
p-NAOD activities' GST activity toward EAA and GSH level increased
but
LP level and GST activity for ENPP decreased significantly in
liver. CS
did not alter the hepatic AH and GST activities toward CDNB and
DCNB.
In lung' CS increased AH' EROD and p-NAOD activities and LP and
GSH
levels and decreased all the GST activities studied significantly.
CS
had no influence on pulmonary AMND activity. For the combined
treatment' the animals were treated with 10% EtOH (v/v) in their
drinking water for 21 days and during the last 3 days they were
exposed
to CS five times a day' with 1 h intervals' in a chamber where
smoke
and fresh air lead alternatively. In these animals' augmentation
of
elevations were noted in AH and p-NAOD activities and LP and
GSH levels
but not in EROD and AMND activities in liver. Combined treatment
significantly decreased GST activity toward CDNB' ameliorated
the
alteration caused by either EtOH or CS treatment alone on GST
activity
toward EAA and potentiated the depression of GST activity toward
ENPP
to a greater degree. No change was observed in GST activity toward
DCNB. In lung' combined treatment potentiated the elevations
of AMND
and p-NAOD activities and LP level and not those of AH and EROD
activities. GST activities toward CDNB' DCNB and ENPP were highly
elevated by the combined treatment. No changes were observed
in
pulmonary GSH level and GST activity for EAA by the combined
treatment.
These results reveal that the regulations of the hepatic and
pulmonary
MO and GST are differentially influenced by EtOH' CS and the
combined
treatment.
Title
N-acetylcysteine protection against the toxicity of cigarette
smoke and
cigarette smoke condensates in various tissues and cells in vitro.
Author
Moldéus P; Berggren M; Grafström R
Source
Eur J Respir Dis Suppl, 139():123-9 1985
Abstract
The protective effect of N-acetylcysteine on the toxicity of
tobacco
smoke condensates was investigated using different cellular in
vitro
systems. Cigarette smoke condensates, and the non-volatile and
semi-volatile fractions separated from the condensate were used.
All
three smoke condensate fractions were toxic to isolated rat hepatocytes
and lung cells and caused a loss of cell membrane integrity.
A rapid
depletion of cellular reduced glutathione (GSH) preceded the
toxicity.
The loss of GSH was due to conjugation of reactive compounds
in the
condensate fractions and not to oxidation since no increase in
oxidized
glutathione (GSSG) could be observed. N-acetylcysteine at a
concentration of 1 mM protected both from the GSH loss and cell
toxicity caused by the condensate fractions. The effect of the
tobacco
smoke condensate on the colony forming efficiency (CFE) of cultured
human bronchial cells was also investigated. Already at concentrations
of 50 micrograms/ml the survival decreased to 40% of control
and at 100
micrograms/ml almost no cells formed colonies. N-acetylcysteine
substantially increased survival when added at 10 mM concentration.
Title
Mechanisms of cigarette smoke induced increased airspace permeability.
Author
Li XY; Rahman I; Donaldson K; MacNee W
Address
Department of Medicine' Royal Infirmary' Edinburgh' UK.
Source
Thorax, 51(5):465-71 1996 May
Abstract
BACKGROUND: Increased epithelial permeability of the airspaces
occurs
commonly in the lungs of cigarette smokers. It is likely to be
important in augmenting the inflammatory response in the airspaces
and
hence may have a role in the pathogenesis of emphysema. It has
previously been shown that intratracheal instillation of cigarette
smoke condensate induces increased epithelial permeability in
vivo in
rats and in vitro in epithelial cell monolayers' associated with
a
disturbance in the lung antioxidant' glutathione (GSH). The aim
of this
study was to assess the role of neutrophils' GSH' and tumour
necrosis
factor (TNF) in the increased epithelial permeability following
intratracheal instillation of cigarette smoke condensate. METHODS:
Epithelial permeability of the airspaces was measured in rat
lungs as
the passage of intratracheally instilled 125-iodine labelled
bovine
serum albumin (BSA) into the blood. The permeability of a monolayer
of
human type II alveolar epithelial cells to 125I-BSA was also
measured.
RESULTS: Cigarette smoke condensate produced a 59.7% increase
in
epithelial permeability over control values peaking six hours
after
instillation and returning to control values by 24 hours. Depletion
of
neutrophils and' to a lesser extent' macrophages by an intraperitoneal
inJection of antineutrophil antibody did not influence the increased
epithelial permeability induced by cigarette smoke condensate.
Although
instillation of human recombinant TNF alpha produced an increase
in
epithelial permeability in the rat lung from 0.62 (0.61)% to
1.27
(0.08)%' only a trivial amount of TNF alpha was detected in
bronchoalveolar lavage (BAL) fluid in vivo or in culture medium
from
BAL leucocytes obtained from animals treated with cigarette smoke
condensate (94.9 (28.8) units/ml). Furthermore' antiTNF antibody
did
not abolish the increased epithelial permeability produced by
cigarette
smoke condensate. The role of GSH was assessed by measuring the
changes
in both the reduced (GSH) and oxidised form (GSSG) in lung tissue
and
in BAL fluid. One hour after instillation of cigarette smoke
condensate
there was a marked fall in the GSH content in the lung (from
809.8
(31.8) to 501.7 (40.5) nmol/g) in association with increased
GSSG
levels (from 89.8 (2.7) to 148.7 (48.8) nmol/g). This was followed
by a
return of GSH levels to control values' with a concomitant decrease
in
GSSG levels six hours after instillation. GSH levels in BAL fluid
fell
dramatically following cigarette smoke condensate (from 2.56
(0.30) to
0.31 (0.21) nmol/ml) and this fall was sustained up to six hours
after
instillation of cigarette smoke condensate. CONCLUSIONS: These
studies
suggest that neutrophils and TNF do not have a maJor role in
the
increased epithelial permeability induced by cigarette smoke
condensate. However' the data support a role for the depletion
of the
antioxidant glutathione in the increased epithelial permeability
caused
by cigarette smoke condensate.
Title
Carcinogenicity studies of masheri: pyrolysed tobacco product'
in
vitamin-A-deficient Sprague Dawley rats.
Author
Ammigan N; Nair UJ; Lalitha VS; Bhide SV
Address
Carcinigenesis Division' Cancer Research Institute' Tata Memorial
Centre' Parel' Bombay' India.
Source
J Cancer Res Clin Oncol, 117(1):50-4 1991
Abstract
The carcinogenicity of long-term feeding of masheri extract to
animals
in a vitamin-A-sufficient (SLO+) and deficient (SLO-) state was
studied
in Sprague Dawley rats by feeding daily dose of 3 mg extract
over a
period of 21 months. The phase I activating enzymes' the glutathione
(GSH)/glutathione S-transferase (GST) detoxification system'
and the
hepatic and circulating levels of vitamins A and C were also
monitored
at 12 and 21 months. It was observed that the phase I enzyme
activities
were significantly higher in SLO+ than in SLO- rats at both 12
months
and 21 months. Moreover' the SLO- masheri-treated animals also
showed a
decreased in the GSH/GST detoxification system while the reverse
was
observed in SLO+ group. Masheri extract treatment significantly
lowered
the hepatic and circulating levels of vitamin A while a concurrent
increase was observed in the vitamin C level. The extract was
found to
be tumorigenic in both the SLO+ and SLO- groups. Benign tumours
were
observed in the SLO+ group while a high incidence of malignant
tumours
of the lung were observed in the SLO- group upon treatment with
masheri
extract.
Title
Modulation of the mutagenic activity of cigarette smoke' cigarette
smoke condensate and benzo[a pyrene in vitro and in vivo.
Author
Balansky R; Mircheva Z; Blagoeva P
Address
National Centre of Oncology' Sofia' Bulgaria.
Source
Mutagenesis, 9(2):107-12 1994 Mar
Abstract
A series of naturally occurring compounds were tested for the
ability
to modulate the mutagenicity induced by cigarette smoke (CS)'
cigarette
smoke condensate (CSC) and benzo[a pyrene (BP) in the
Salmonella/microsome mutagenicity assay and the micronucleus
test in
mouse bone marrow. Sodium selenite' retinol acetate and
alpha-tocopherol significantly decreased the mutagenic activity
of CS
in Salmonella typhimurium TA98. Ascorbic acid' reduced glutathione
(GSH)' cysteine' caffeine' theophylline' cobalt chloride' folic
acid'
adenine' adenosine' guanosine' cytidine and cytosine were conversely
devoid of any significant effect. Sodium selenite slightly decreased
the mutagenic activity of CSC in the same bacterial strain' while
caffeine was ineffective and ascorbic acid potentiated its
mutagenicity. Ascorbic acid inhibited the mutagenic activity
of BP in
S. typhimurium TA98' but not in TA100. Retinol acetate diminished
the
number of BP-induced his+ revertants in TA98 but only at the
highest
concentrations used' whereas alpha-tocopherol' GSH' cysteine'
sodium
selenite and caffeine had no effect. Selenite and GSH' which
were
ineffective when applied individually' inhibited in a dose-dependent
manner the BP-induced mutagenesis in S. typhimurium TA98 when
simultaneously added to the top agar. All other combinations
tested'
including selenite plus either GSH' cysteine or caffeine towards
CS or
CSC' or selenite plus cysteine' or selenite plus retinol acetate
and
alpha-tocopherol towards BP' failed to produce interactive effects.
Sodium selenite and caffeine' given either alone or in combination
in
drinking water' did not influence the clastogenesis induced in
mouse
bone marrow by a single treatment with CS or BP. Ascorbic acid
was also
ineffective towards CS clastogenicity but significantly decreased
the
number of micronucleated polychromatic erythrocytes induced by
BP.(ABSTRACT TRUNCATED AT 250 WORDS)
Title
Effect of tobacco extract and N`-nitrosonornicotine on the carcinogen
metabolising enzymes under different dietary vitamin B status
[published erratum appears in Cancer Lett 1990 Aug;53(1):79
Author
Ammigan N; Nair UJ; Amonkar AJ; Bhide SV
Address
Carcinogenesis Division' Tata Memorial Centre' Parel' Bombay'
India.
Source
Cancer Lett, 52(2):153-9 1990 Jul 16
Abstract
Studies were carried out to evaluate the changes in the phase
I and II
enzymes of xenobiotic metabolism' on treatment with tobacco extract
(TE) and a tobacco specific carcinogen' N`-nitrosonornicotine
(NNN) in
Sprague-Dawley rats maintained on vitamin B complex sufficient
and
deficient semi-synthetic diets. Both TE and NNN significantly
increased
the hepatic and pulmonary phase I enzymes in the vitamin B sufficient
(SB+) and deficient (SB-) animals. However' the percent increase
in
enzyme activities was drastically higher in the SB- treated group
as
compared to those in the SB(+)-treated group. On the other hand'
TE and
NNN significantly depressed the liver and lung glutathione (GSH)
level
and glutathione S-transferase (GST) activity in the SB- animals'
while
the opposite effect was observed in the SB(+)-treated animals.
Furthermore' both the treatments depleted the hepatic pool of
vitamin
A' with a concurrent increase in that of vitamin C in SB+ and
SB-
groups.
Title
Chemical carcinogenesis' mutagenesis' and teratogenesis.
Author
O`Brien PJ; Hales BF; Josephy PD; Castonguay A; Yamazoe Y; Guengerich
FP
Address
Faculty of Pharmacy' University of Toronto' ON' Canada.
peter.obrien@utoronto.ca
Source
Can J Physiol Pharmacol, 74(5):565-71 1996 May
Abstract
An international symposium entitled Chemical Carcinogenesis'
Mutagenesis and Teratogenesis: a Tribute to James and Elizabeth
Miller
was held in Toronto' Ont.' July 19' 1994. This symposium theme
was
discussed in the presence of James Miller' 79 years young' who
with his
wife' Elizabeth Miller (1920-1987)' are considered to be the
pioneers
of this medical and environmental toxicology research field.
It is
generally believed that the susceptibility of an individual to
chemical
carcinogenesis or teratogenesis varies considerably depending
upon
their genetic makeup' diet' lifestyle' and their environmental
exposure. One goal of the research discussed at this symposium
was an
examination of the role of the enzymes involved in the metabolic
activation and detoxification of carcinogens and teratogens.
The
interindividual variabilities in the levels and activity of these
enzymes could contribute to the susceptibility of the individual
to
chemical carcinogens or teratogens. At the symposium evidence
was
presented indicating that theta-class glutathione (GSH) S-transferase
levels activate dihalomethanes and could therefore initiate the
carcinogenic response to butadiene and 1'2-dibromo-3-chloropropane.
The
dramatic genetic polymorphism of this class of GSH S-transferase
could
thereby contribute to the individual`s susceptibility to these
carcinogens. Similarly' the GSH S-transferase and GSH levels
in the
embryo and yolk sac that are determined during organogenesis
could also
be important factors in determining the susceptibility of the
embryo to
teratogens. The levels of cytochrome P450 1A2' aromatic amine
N-acetyltransferases' and sulfotransferases could also determine
the
susceptibility of the individual to carcinogenic arylamines.
Accordingly' an Ames tester strain was described that was genetically
engineered so as to express both aromatic amine N-acetyltransferase
and
human cytochrome P450 1A2. This should prove useful for predicting
which arylamines are likely to be carcinogenic to humans. Nonsteroidal
anti-inflammatory drugs may also prove useful in inhibiting the
cytochrome P450s that activate the nitrosamines found in tobacco
smoke
suspected to cause lung cancer. Finally' the sulfotransferase
isoforms
involved in the metabolic activation of carcinogenic arylamines
were
identified.
Title
Age dependent differential effects of cigarette smoke on hepatic
and
pulmonary xenobiotic metabolizing enzymes in rats.
Author
Eke BC; Vural N; I,scan M
Address
Department of Toxicology, Faculty of Pharmacy, Ankara University,
Tando
gan-Ankara, Turkey.
Source
Arch Toxicol, 71(11):696-702 1997
Abstract
The effects of cigarette smoke (CS) on hepatic and pulmonary
monooxygenase (MO) activities (aniline 4-hydroxylase, AH; aminopyrine
N-demethylase, AMND; 7-ethoxyresorufin O-deethylase, EROD;
p-nitroanisole O-demethylase, p-NAOD), lipid peroxidation (LP),
and
reduced glutathione (GSH) levels and glutathione S-transferase
(GST)
activities toward several substrates (1-chloro-2,4-dinitrobenzene,
CDNB; 1,2-dichloro-4-nitrobenzene, DCNB; ethacrynic acid, EAA;
1,2-epoxy-3-(p-nitrophenoxy)-propane, ENPP) were determined in
20-, 90-
and 360-day-old male rats. The animals were exposed to CS five
times a
day, with 1 h intervals, for 3 days in a chamber supplied alternatively
with smoke and fresh air, and were killed 16 h after the last
treatments. The hepatic AH activity increased significantly in
20-day-old rats and remained unaltered in older age groups. The
hepatic
AMND activity unaltered, significantly increased and decreased
in 20-,
90- and 360-day-old rats, respectively. The pulmonary AH activity
increased significantly in 20- and 90-day-old rats whereas no
alteration was noted in 360-day-old rats. CS was ineffective
on
pulmonary AMND activity at all ages. CS increased hepatic and
pulmonary
EROD and p-NAOD activities significantly in all age groups compared
to
controls. In liver, LP level was significantly increased, decreased,
and unaltered in 20-, 90- and 360-day-old rats, respectively.
CS
increased hepatic GSH level significantly in 90-day-old rats
but was
not effective in the other age groups. In lung, LP level was
increased
in 90- and 360-day-old rats and unaltered in 20-day-old rats.
CS
increased pulmonary GSH level significantly in 90-day-old rats
and did
not have any effect in the other age groups. The hepatic GST
activities
toward CDNB and DCNB decreased significantly in 360-day-old rats
and
were unaltered in the younger age groups. The hepatic GST activity
toward EAA was unaltered, significantly increased and decreased
in 20-,
90- and 360-day-old rats, respectively. The hepatic GST activity
toward
ENPP decreased significantly in 20- and 90-day-old rats but was
unaltered in the oldest group of rats. In 20-day-old rats, the
pulmonary GST activity toward ENPP increased significantly whereas
the
other GST activities did not alter. In 90-day-old rats, however,
CS
significantly decreased all the pulmonary GST activities studied.
Unaltered DCNB GST, significant increase in EAA GST and decrease
in
CDNB and ENPP GST activities of lung were noted in 360-day-old
rats.
These results reveal that the regulation in rats of hepatic and
pulmonary MO and GST activities are differentially influenced
by CS as
a function of age. |
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