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Protective antioxidant mechanisms in rat and guinea pig tissues
challenged by acute exposure to cigarette smoke.
Bilimoria MH; Ecobichon DJ
Pathology Institute McGill University' Montreal' Quebec' Canada.
Toxicology, 72(2):131-44 1992
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.

Lung protection by a thiol-containing antioxidant: N-acetylcysteine.
Moldéus P; Cotgreave IA; Berggren M
Respiration, 50 Suppl 1():31-42 1986
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.

Effect of cigarette smoke inhalation on antioxidant enzymes and lipid
peroxidation in the rat.
Gupta MP; Khanduja KL; Sharma RR
Biophysics Department, Postgraduate Institute of Medical Education and
Research, Chandigarh, India.
Toxicol Lett, 41(2):107-14 1988 May
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.

Combined effects of ethanol and cigarette smoke on hepatic and
pulmonary xenobiotic metabolizing enzymes in rats.
Eke BC; Vural N; I,scan M
Department of Toxicology' Faculty of Pharmacy' Ankara University'
Chem Biol Interact, 102(3):155-67 1996 Dec 20
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

N-acetylcysteine protection against the toxicity of cigarette smoke and
cigarette smoke condensates in various tissues and cells in vitro.
Moldéus P; Berggren M; Grafström R
Eur J Respir Dis Suppl, 139():123-9 1985
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.

Mechanisms of cigarette smoke induced increased airspace permeability.
Li XY; Rahman I; Donaldson K; MacNee W
Department of Medicine' Royal Infirmary' Edinburgh' UK.
Thorax, 51(5):465-71 1996 May
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.

Carcinogenicity studies of masheri: pyrolysed tobacco product' in
vitamin-A-deficient Sprague Dawley rats.
Ammigan N; Nair UJ; Lalitha VS; Bhide SV
Carcinigenesis Division' Cancer Research Institute' Tata Memorial
Centre' Parel' Bombay' India.
J Cancer Res Clin Oncol, 117(1):50-4 1991
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

Modulation of the mutagenic activity of cigarette smoke' cigarette
smoke condensate and benzo[a pyrene in vitro and in vivo.
Balansky R; Mircheva Z; Blagoeva P
National Centre of Oncology' Sofia' Bulgaria.
Mutagenesis, 9(2):107-12 1994 Mar
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

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
Ammigan N; Nair UJ; Amonkar AJ; Bhide SV
Carcinogenesis Division' Tata Memorial Centre' Parel' Bombay' India.
Cancer Lett, 52(2):153-9 1990 Jul 16
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-

Chemical carcinogenesis' mutagenesis' and teratogenesis.
O`Brien PJ; Hales BF; Josephy PD; Castonguay A; Yamazoe Y; Guengerich
Faculty of Pharmacy' University of Toronto' ON' Canada.
Can J Physiol Pharmacol, 74(5):565-71 1996 May
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

Age dependent differential effects of cigarette smoke on hepatic and
pulmonary xenobiotic metabolizing enzymes in rats.
Eke BC; Vural N; I,scan M
Department of Toxicology, Faculty of Pharmacy, Ankara University, Tando
gan-Ankara, Turkey.
Arch Toxicol, 71(11):696-702 1997
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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