Nitrofurantoin-Induced Hepatic and Pulmonary Biochemical Changes in Mice Fed Different Vitamin E Doses

Abstract: The hepatic and pulmonary effects of nitrofurantoin (40 mg/kg, intraperitoneally) were determined at 4 and 24 hr following its administration in mice fed for 10 weeks with a vitamin E sufficient, deficient or enriched diet. Liver glutathione (GSH) was reduced by nitrofurantoin at 4 hr but was unchanged 20 hr later. Nitrofurantoin did not affect liver glutathione peroxidase, glutathione reductase or superoxide dismutase activities. Liver catalase activities were decreased by nitrofurantoin at 4 hr. Lung GSH levels were increased whilst glutathione peroxidase activity was decreased at 4 and 24 hr. Lung glutathione reductase activity was reduced in certain groups. Nitrofurantoin did not affect lung superoxide dismutase, but catalase was decreased at 24 hr. Liver malondialdehyde levels were increased by nitrofurantoin in the vitamin E deficient group whilst lung malondialdehyde levels remained unchanged. Both liver and lung malondialdehyde levels were unaffected by vitamin E supplementation when compared to the vitamin E-sufficient group. These results suggest that nitrofurantoin (40 mg/kg) was deleterious to the liver and lung. Nitrofurantoin-induced lipid peroxidation was seen in vitamin E deficiency but an increase in dietary vitamin E content did not provide additional protection compared to the recommended daily allowance. The antioxidant acitivities of α-tocopherol and γ-enriched tocotrienol were similar.     

Vitamin E prevents buthionine sulfoximine-induced biochemical disorders in the rat

Antioxidant therapy can improve the protection and metabolic activity of cells and tissues. In this study, the effect of vitamin E administration on buthionine sulfoximine (BSO)-induced glutathione (GSH) depletion in the rat lung and liver was investigated. Hepatic GSH was depleted by intraperitoneal administration of BSO (4 mmol kg(-1)), twice a day, for 30 days to rats. We also investigated whether the lung and liver mitochondrial GSH contents were influenced by BSO administration and whether an extracellular supply of vitamin E could prevent the changes caused by BSO-mediated GSH depletion. Glutathione levels in lung and liver tissues were depleted by 47% and 60%, respectively. Depletion of hepatic and pulmonary GSH in turn causes decline in the levels of mitochondrial GSH, leading to impaired antioxidant defence function of mitochondria. Both the cytosolic and mitochondrial glutathione disulfides (GSSG) were altered during BSO treatment, and led to drastic increase in GSSG/GSH redox status. One of the experimental groups was given vitamin E (65 mg (kg diet)(-1)) mixed with rat feed. The rats fed with vitamin E were found to have partially restored GSH levels in liver and lung, diminished levels of TBARS and minimized tissue damage. The current findings suggest that the impaired glutathione and glutathione-dependent enzyme status may be correlated with the elevated lipid peroxidation and mitochondrial membrane damage and that vitamin E therapy to the BSO-administered rats prevents the above changes. However, vitamin E did not have any effect on the activity of gamma-glutamyl cysteine synthetase (gamma-GCS).     

Influence of rat brain superoxide dismutase inhibition by diethyldithiocarbamate upon the rate of development of central nervous system oxygen toxicity

Exposure to oxygen at pressures greater than 2.8 ATA (OHP) results in central nervous system toxicity seen as grand mal seizures. The time to onset of seizures (ts) is related to the pO2 above the 2.8 ATA threshold. The components of the endogenous antioxidant defense mechanism, superoxide dismutase (SOD), glutathione measured here as nonprotein sulfhydryl content (NPSH), glucose-6-phosphate dehydrogenase (G-6-PD), glutathione reductase (GR), and glutathione peroxidase (GPx) occur in brain. Their role in OHP-induced CNS toxicity is not clear. This study examined the effect of inhibition of SOD by diethyldithiocarbamate (DDC) on ts at 4 ATA O2. Antioxidant components (SOD, NPSH, G-6-PD, GR, and GPx) were measured in male Sprague-Dawley rats pretreated with 250, 500, and 1000 mg/kg DDC ip, 2 hr prior to termination in room air. SOD activity was inhibited 11, 31, and 49%, respectively, when compared with control values. Among the other antioxidant components, only GPx showed a significant loss of activity of 24% at 1000 mg/kg DDC. Rats were also pretreated 2 hr prior to exposure to hyperbaric oxygen with either 250, 500, or 1000 mg/kg DDC. Ts for the treated animals was significantly shortened by 12, 55, and 75%, respectively, compared to the saline-treated, oxygen-exposed control animals. These studies demonstrated that the rate of onset of CNS oxygen toxicity was increased by inhibition of SOD by DDC. These data suggested that SOD plays a role as part of an endogenous antioxidant defense mechanism in the brain.     

Melatonin protects against mercury(II)-induced oxidative tissue damage in rats

Mercury exerts a variety of toxic effects in the body. Lipid peroxidation, DNA damage and depletion of reduced glutathione by Hg(II) suggest an oxidative stress-like mechanism for Hg(II) toxicity. Melatonin, the main secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. N-Acetylcysteine, a precursor of reduced glutathione and an antioxidant, is used in the therapy of acute heavy metal poisoning. In this study the protective effects of melatonin in comparison to that of N-acetylcysteine against Hg-induced oxidative damage in the kidney, liver, lung and brain tissues were investigated. Wistar albino rats of either sex (200-250 g) were divided into six groups, each consisting of 8 animals. Rats were intraperitoneally injected with 1) 0.9% NaCl, control (C) group; 2) a single dose of 5 mg/kg mercuric chloride (HgCl2), Hg group; 3) melatonin in a dose of 10 mg/kg, 1 hr after HgCl2 injection, Hg-melatonin group; 4) melatonin in a dose of 10 mg/kg one day before and 1 hr after HgCl2 injection, melatonin-Hg-melatonin group; 5) N-acetylcysteine in a dose of 150 mg/kg, 1 hr after HgCl2 injection, Hg-N-acetylcysteine group, and 6) N-acetylcysteine in a dose of 150 mg/kg one day before and 1 hr after HgCl2 injection, N-acetylcysteine-Hg-N-acetylcysteine group. Animals were killed by decapitation 24 hr after the injection of HgCl2. Tissue samples were taken for determination of malondialdehyde, an end-product of lipid peroxidation; glutathione (GSH), a key antioxidant, and myeloperoxidase activity, an index of neutrophil infiltration. The results revealed that HgCl2 induced oxidative tissue damage, as evidenced by increases in malondialdehyde levels. Myeloperoxidase activity was also increased, and GSH levels were decreased in the liver, kidney and the lungs. All of these effects were reversed by melatonin or N-acetylcysteine treatment. Since melatonin or N-acetylcysteine administration reversed these responses, it seems likely that melatonin or N-acetylcysteine can protect all these tissues against HgCl2-induced oxidative damage.     

Brain lipid peroxidation and antioxidant status after acute methacrylonitrile intoxication

The status of brain antioxidant enzymes and glutathione in methacrylonitrile (MeAN)-intoxicated Wistar rats was correlated with the levels of lipid peroxidation products. Optimum changes were observed 30 min and 60 min after oral administration of MeAN at dosages of 50 mg/kg body weight per day (0.25 LD50) and 100 mg/kg body weight per day (0.5 LD50). An increase in lipid peroxidation products, decrease in the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione S-transferase (GST), and decrease in reduced glutathione (GSH) were observed. These studies suggest that the membrane lipid peroxidation observed in MeAN intoxication is related, in part, to a compromised antioxidant defense system.     

The role of vitamin C as antioxidant in protection of oxidative stress induced by imidacloprid

Pesticides may induce oxidative stress leading to generate free radicals and alternate antioxidant or oxygen free radical scavenging enzyme system. This study was conducted to investigate the acute toxicity of imidacloprid toward male mice and the oxidative stress of the sublethal dose (1/10 LD₅₀) on the lipid peroxidation level (LPO), reduced glutathione content (GSH) and activities of the antioxidant enzymes; catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glucose-6-phosphate dehydrogenase (G6PD), and glutathione-s-transferase (GST). Also, the protective effect of vitamin C (200 mg/kg bw) 30 min before or after administration of imidacloprid were investigated. The results demonstrated that the median lethal dose (LD₅₀) of imidacloprid after 24 h was 149.76 mg/kg bw. The oral administration of 14.976 mg/kg imidacloprid significantly caused elevation in LPO level and the activities of antioxidant enzymes including CAT, SOD, GPx and GST. However, G6PD activity remained unchanged, while the level of GSH content was decreased. In addition, the results showed that vitamin C might ameliorate imidacloprid-induced oxidative damage by decreasing LPO and altering antioxidant defense system in liver. The protective effect of the pre-treatment with vitamin C against imidacloprid-induced oxidative stress in liver mice is better than the post-treatment.     

Chemoprotection of ethylene glycol monoethyl ether-induced reproductive toxicity in male rats by kolaviron, isolated biflavonoid from Garcinia kola seed

The present study investigated the protective effect of kolaviron, a biflavonoid from the seed of Garcinia kola, on ethylene glycol monoethyl ether (EGEE)-induced reproductive toxicity in male rats. The protective effect of kolaviron was validated using vitamin E, a standard antioxidant. EGEE was administered at a dose of 200 mg/kg. Other groups of rats were simultaneously treated with kolaviron (100 and 200 mg/kg) and vitamin E (50 mg/kg) for 14 days. EGEE treatment resulted in significant decrease in glutathione (GSH) level, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities but markedly increased the glutathione-S-transferase (GST) and lactate dehydrogenase (LDH) activities in the testes. In the spermatozoa, administration of EGEE caused significant decrease in the activities of CAT, GPx, GST and LDH as well as in the level of GSH but significantly increased SOD activity with concomitant increase in hydrogen peroxide and malondialdehyde levels in both testes and spermatozoa. EGEE-exposed rats showed marked testicular degeneration with concomitant decrease in spermatozoa quantity and quality. Overall, EGEE causes reproductive dysfunction in rats by altering antioxidant systems in the testes and spermatozoa. Kolaviron or vitamin E exhibited protective effects against EGEE-induced male reproductive toxicity by enhancement of antioxidant status and improvement in spermatozoa quantity and quality.     

Brain Lipid Peroxidation and Antioxidant Status After Acute Methacrylonitrile Intoxication

The status of brain antioxidant enzymes and glutathione in methacrylonitrile (MeAN)-intoxicated Wistar rats was correlated with the levels of lipid peroxidation products. Optimum changes were observed 30 min and 60 min after oral administration of MeAN at dosages of 50 mg/kg body weight per day (0.25 LD₅₀) and 100 mg/kg body weight per day (0.5 LD₅₀). An increase in lipid peroxidation products, decrease in the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione S-transferase (GST), and decrease in reduced glutathione (GSH) were observed. These studies suggest that the membrane lipid peroxidation observed in MeAN intoxication is related, in part, to a compromised antioxidant defense system.     

The role of vitamin C, vitamin E, and selenium on cadmium-induced renal toxicity of rats

The aim of this study was to determine whether vitamin C, vitamin E, and selenium have protective effects against cadmium-induced renal toxicity of rats. Vitamin C (250 mg/kg/day), vitamin E (250 mg/kg/day), and sodium selenate (0.25 mg/kg/day) were given to rats orally for 8 days. Cadmium (2 mg/kg/day CdCl2) was given to rats intraperitoneally. Vitamin C, vitamin E, and selenium (in the same dose and time) were given 1 h prior to the administration of cadmium every day. The tissue and blood samples were taken from the rats for histological evaluation and biochemical analyses on the Day 9. Lipid peroxidation (LPO) and glutathione (GSH) determination were made in kidney tissue. In addition, urea and creatinine levels were determined in serum. The damage to the kidney tissue was moderate in the rats given cadmium. In this group, the distinctive changes in the proximal tubules were observed. Degenerative changes in kidney tissue were also observed in rats given vitamin C, vitamin E, selenium, and cadmium. LPO levels significantly increased and GSH levels decreased in kidney tissues following cadmium administration. Serum urea and creatinine levels were also increased in rats given cadmium. The administration of vitamin C, vitamin E, and selenium caused a significant decrease in LPO levels and an increase in GSH levels in the kidney of rats given cadmium. Serum urea and creatinine levels were decreased in rats given both the antioxidant and cadmium. It is concluded that vitamin C, vitamin E, and selenium showed some protective effect on the rat kidney.     

The Role of Vitamin C,Vitamin E,and Selenium on Cadmium-Induced Renal Toxicity of Rats

The aim of this study was to determine whether vitamin C, vitamin E, and selenium have protective effects against cadmium-induced renal toxicity of rats. Vitamin C (250 mg/kg/day), vitamin E (250 mg/kg/day), and sodium selenate (0.25 mg/kg/day) were given to rats orally for 8 days. Cadmium (2 mg/kg/day CdCl₂) was given to rats intraperitoneally. Vitamin C, vitamin E, and selenium (in the same dose and time) were given 1 h prior to the administration of cadmium every day. The tissue and blood samples were taken from the rats for histological evaluation and biochemical analyses on the Day 9. Lipid peroxidation (LPO) and glutathione (GSH) determination were made in kidney tissue. In addition, urea and creatinine levels were determined in serum. The damage to the kidney tissue was moderate in the rats given cadmium. In this group, the distinctive changes in the proximal tubules were observed. Degenerative changes in kidney tissue were also observed in rats given vitamin C, vitamin E, selenium, and cadmium. LPO levels significantly increased and GSH levels decreased in kidney tissues following cadmium administration. Serum urea and creatinine levels were also increased in rats given cadmium. The administration of vitamin C, vitamin E, and selenium caused a significant decrease in LPO levels and an increase in GSH levels in the kidney of rats given cadmium. Serum urea and creatinine levels were decreased in rats given both the antioxidant and cadmium. It is concluded that vitamin C, vitamin E, and selenium showed some protective effect on the rat kidney.     

Protection of rats against the effects of alpha-naphthylthiourea (ANTU) by elevation of non-protein sulphydryl levels

We have investigated the influence of the elevation of pulmonary glutathione (GSH) levels on the toxicity of the rodenticide alpha-naphthylthiourea (ANTU) to rat lung. Administration of phorone (diisopropylidene acetone; 200 mg/kg i.p.) caused an initial depletion of both pulmonary and hepatic GSH followed after 48 hr by a marked elevation in both tissues, due most probably to a compensatory rebound synthesis. In control rats, ANTU produced a dose-dependent lethality, hydrothorax and loss of ability of lung tissue to accumulate adenosine and spermidine (markers of endothelial and epithelial cell function, respectively). These effects were prevented or markedly ameliorated when ANTU was given 48 hr after pretreatment with phorone. The mechanism of the protection by phorone pretreatment against ANTU-induced pulmonary toxicity is unclear. It may be due, in part, to elevated GSH levels in pulmonary endothelial cells and, in addition, to increased detoxification of ANTU in the liver, resulting in a decreased availability to the lung.     

Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats

Cadmium (Cd) is a neurotoxic metal, which induces oxidative stress and membrane disturbances in nerve system. The garlic compound diallyl tetrasulfide (DTS) has the cytoprotective and antioxidant activity against Cd induced toxicity. The present study was carried out to investigate the efficacy of DTS in protecting the Cd induced changes in the activity of acetylcholinesterase (AChE), membrane bound enzymes, lipid peroxidation (LPO) and antioxidant status in the brain of rats. In rats exposed to Cd (3mg/kg/day subcutaneously) for 3 weeks, a significant (P<0.05) increase in the levels of LPO and protein carbonyls along with significant (P<0.05) decrease in the levels of reduced glutathione (GSH) and total sulphydryl groups (TSH) and the activities of AChE, superoxide dismutase, catalase, glutathione peroxidase, gluthione-S-transeferase, membrane bound enzymes (ATPases: Na(+)K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase) were observed in brain tissue. Oral administration of DTS (40mg/kg/day) with Cd significantly (P<0.05) diminished the levels of LPO and protein carbonyls and significantly (P<0.05) increased the activities of ATPases, antioxidant enzymes, GSH and TSH in brain. These results indicate that DTS attenuate the LPO and alteration of antioxidant and membrane bound enzymes in Cd exposed rats, which suggest that DTS protects the brain function from toxic effects of Cd.     

Impact of polychlorinated biphenyl Aroclor 1254 on testicular antioxidant system in adult rats

To clarify the reproductive toxicity of polychlorinated biphenyl compounds through determination of testicular lipid peroxidation, reactive oxygen species and enzymatic and non-enzymatic antioxidants in rats exposed to Aroclor 1254. Adult male rats were administered Aroclor 1254 at a dose of 2 mg/kg per day ip for 30 days. The rats were sacrificed 24 hours after last dosing and the serum and other tissues collected and processed for relevant determinations. The body weight and the weights of the testis, epididymis, ventral prostate and seminal vesicle and the serum testosterone and estradiol were significantly decreased in Aroclor 1254 treated rats. The testicular lipid peroxidation, hydrogen peroxide and hydroxyl radical were significantly elevated whereas, testicular antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-S-transferase (GST) and glutathione reductase (GR) were significantly decreased. The non-enzymatic antioxidants, vitamin C and vitamin E, were also decreased. These results suggest that Aroclor 1254 induces an increase in the lipid peroxidation, hydrogen peroxide and hydroxyl radical and diminish in the antioxidant defense system in rats, indicating that the free radical-dependent mechanism may play an important role in the testicular toxicity of polychlorinated biphenyls.     

Modulatory effects of curcumin on lipid peroxidation and antioxidant status during nicotine-induced toxicity

Nicotine, a pharmacologically active substance in tobacco, has been identified as a major risk factor for lung diseases. In the present study, we evaluated the protective effects of curcumin on tissue lipid peroxidation and antioxidants in nicotine-treated Wistar rats. Lung toxicity was induced by subcutaneous injection of nicotine at a dose of 2.5 mg/kg (5 days a week, for 22 weeks). Curcumin (80 mg/kg) was given simultaneously by intragastric intubation for 22 weeks. The enhanced level of tissue lipid peroxides in nicotine-treated rats was accompanied by a significant decrease in the levels of ascorbic acid, vitamin E, reduced glutathione, glutathione peroxidase, superoxide dismutase and catalase. Administration of curcumin significantly lowered the level of lipid peroxidation and enhanced the antioxidant status. The results of the present study suggest that curcumin exerts its protective effect against nicotine-induced lung toxicity by modulating the extent of lipid peroxidation and augmenting antioxidant defense system.     

Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: antioxidant defense system.

This study investigated the alterations that occur in auditory brainstem-evoked responses (ABRs) concurrent with changes in cochlear concentrations of glutathione (GSH), lipid peroxidation, and antioxidant enzyme activity in cisplatin-induced ototoxicity and in dose-dependent otoprotection by an antioxidant lipoate. Male Wistar rats were divided into different groups and were treated as follows, with: (1) vehicle (saline) control; (2) cisplatin (16 mg/kg, i.p.); (3) lipoate (100 mg/kg, i.p.) plus saline; (4) cisplatin plus lipoate (25 mg/kg); (5) cisplatin plus lipoate (50 mg/kg), and (6) cisplatin plus lipoate (100 mg/kg). Post-treatment ABRs were evaluated after three days, the rats were sacrificed, and cochleae were harvested and analyzed. The cisplatin-injected rats showed ABR threshold elevations above the pre-treatment thresholds. Rats treated with lipoate plus cisplatin did not show significant elevation of hearing thresholds. Cisplatin administration resulted in a depletion of cochlear GSH concentration (69% of control), whereas, cisplatin-plus-lipoate treatment increased GSH concentration close to control value. Cisplatin-treated rats showed a decrease in cochlear superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities (57, 78, 59, and 58% of control, respectively), and an increase in malondialdehyde (MDA) concentration (196% of control). Cochlear SOD, CAT, GSH-Px, and GR activities and MDA concentrations were restored in the rats injected with cisplatin plus graded doses of lipoate than those with cisplatin alone. It is concluded that cisplatin-induced ototoxicity is related to impairment of the cochlear antioxidant defense system, and the dose-dependent otoprotection conferred by an antioxidant lipoate against cisplatin ototoxicity is associated with sparing of the cochlear antioxidant defense system.     

Nitrofurantoin-induced pulmonary toxicity. In vivo evidence for oxidative stress-mediated mechanisms.

The present study was carried out to examine whether nitrofurantoin-induced pulmonary toxicity in normal rats was mediated via oxidant stress mechanisms. The relative importance of the cellular antioxidant enzymes in nitrofurantoin toxicity was also assessed. For this, the pulmonary toxicity induced by nitrofurantoin in rats was evaluated at various time intervals after a single subcutaneous injection. Data from this study showed that nitrofurantoin (200 mg/kg, s.c.) resulted in transient but measurable lung damage as evidenced by the increases in wet lung weight/body weight ratio and decreases in lung angiotensin converting enzyme activity. A transient decrease in GSH concentrations with a concurrent increase in GSSG concentrations as well as an increase in lipid peroxidation levels (measured by the formation of diene conjugates and thiobarbituric acid reactants) were also evident in lungs of nitrofurantoin-treated rats. In addition, nitrofurantoin did not alter the pulmonary superoxide dismutase and glutathione peroxidase activities, but it did produce transient decreases in catalase and glutathione reductase activities. These data indicate that impairment of the ability of the lung to detoxify reactive oxygen species may play an important role in the development of nitrofurantoin-induced pulmonary toxicity. The results of the present study suggest that nitrofurantoin can damage the lungs of rats, probably through oxidative stress-mediated mechanisms. Also, our data have provided in vivo evidence for substantiating lipid peroxidation as a possible cause of lung damage.     

Protective effect of thymoquinone,the main component of Nigella Sativa,against diazinon cardio-toxicity in rats

Several studies have shown that oxidative stress and cell damage can occur at very early stages of diazinon (DZN) exposure. The present study was designed to determine the beneficial effect of thymoquinone (Thy), the main component of Nigella sativa (black seed or black cumin), against DZN cardio-toxicity in rats. In the present experimental study, 48 male Wistar rats were randomly divided into six groups: control (corn oil gavages), DZN gavages (20?mg/kg/day), Thy gavages (10?mg/kg/day) and Thy?+?DVN gavages (2.5, 5 and 10?mg/kg/day). Treatments were continued for 28 days, then the animals were anesthetized by ether and superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), lactate dehydrogenize (LDH) and glutathione peroxide (GPX) activity was evaluated. In addition, glutathione (GSH) and malondialdehyde (MDA) the heart tissue and creatinephosphokinase-MB (CPK-MB) and troponin (TPI) levels and cholinesterase activity in the blood were evaluated. DZN-induced oxidative damage and elevated the levels of the cardiac markers CK-MB, TPI, MDA and LDH and decreased SOD, CAT and cholinesterase activity and GSH level compared with the control group. Treatment with Thy reduced DZN cardio-toxicity and cholinesterase activity. The success of Thy supplementation against DZN toxicity can be attributed to the antioxidant effects of its constituents. Administration of Thy as a natural antioxidant decreased DZN cardio-toxicity and improved cholinesterase activity in rats through the mechanism of free radical scavenging.     

Role of oxidative stress in thuringiensin-induced pulmonary toxicity

To understand the effect of thuringiensin on the lungs tissues, male Sprague-Dawley rats were administrated with thuringiensin by intratracheal instillation at doses 0.8, 1.6 and 3.2 mg/kg of body weight, respectively. The rats were sacrificed 4 h after treatment, and lungs were isolated and examined. Subsequently, an effective dose of 1.6 mg/kg was selected for the time course study (4, 8, 12, and 24 h). Intratracheal instillation of thuringiensin resulted in lung damage, as evidenced by increase in lung weight and decrease in alkaline phosphatase (10-54%), an enzyme localized primarily in pulmonary alveolar type II epithelial cells. Furthermore, the administration of thuringiensin caused increases in lipid peroxidation (21-105%), the indices of lung injury. In addition, the superoxide dismutase (SOD) and glutathione (GSH) activities of lung tissue extracts were measured to evaluate the effect of thuringiensin on antioxidant defense system. The SOD activity and GSH content in lung showed significant decreases in a dose-related manner with 11-21% and 15-37%, respectively. Those were further supported by the release of proinflammatory cytokines, as indicated by increases in IL-1beta (229-1017%) and TNF-alpha (234%) levels. Therefore, the results demonstrated that changes in the pulmonary oxidative-antioxidative status might play an important role in the thuringiensin-induced lung injury.     

Dose- and time-dependent effects of sulfur mustard on antioxidant system in liver and brain of rat

This study investigates the dose- and time-dependent effects of sulfur mustard (SM) on antioxidant system and lipid peroxidation in liver and brain of rats. For this purpose, male Wistar rats were randomly divided into eight groups and treated as follows: group 1 as control and groups 2-8 as experimental groups that received SM (1-80 mg/kg) through intraperitoneal injection. Rats were killed after 2, 7 and 14 days of exposure. SM dose-dependently decreased body weight. Superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) activities in liver were significantly increased at SM doses lower than 10 mg/kg after 2 and 7 days of exposure. However, the recovery of these parameters was observed after 14 days. At these concentrations, no significant change in glutathione (GSH) and malondialdehyde (MDA) levels were observed. At doses higher than 10 mg/kg, SM significantly decreased SOD, CAT, glutathione peroxidase (GPX), and GST activities in liver and brain and decreased glutathione reductase (GR) activity in liver, which was associated with a depletion of GSH and increased MDA level. Present data indicate that the effect of SM is dose- and time-dependent and at higher doses (>10 mg/kg) induces an oxidative stress response by depleting the antioxidant defense systems and increasing lipid peroxidation in liver and brain of rats.     

Promotion of trans-platinum in vivo effects on renal heme and hemoprotein metabolism by D,L-buthionine-S,R-sulfoximine. Possible role of glutathione

We have examined the toxicity of trans-platinum (trans-diamminedichloroplatinum II) to heme and hemoprotein metabolism in the kidney of glutathione (GSH)-depleted rats and compared it with that produced by cis-platinum. Unlike cis-platinum treatment (7.0 mg/kg, i.v.) which caused after 7 days significant increases in cytochromes P450 and b5, and a marked decrease in porphyrin content of the kidney, trans-platinum alone (7 mg/kg, i.v.) did not elicit notable changes in these variables when measured 1 or 7 days after treatment. Also, cis-platinum treatment significantly altered the heme degradation pathway by increasing the activity of heme oxygenase and decreasing that of biliverdin reductase; trans-platinum treatment did not elicit a response in these activities. However, when rats were given the inhibitor of GSH synthesis, D,L-buthionine-S,R-sulfoximine (BSO), the subsequent administration (2 hr later) of trans-platinum produced, in 1 day, the spectrum of responses that were mediated by cis-platinum after 7 days. In the kidneys of rats treated with BSO plus trans-platinum the concentration of platinum measured only about 50% of that detected in the kidneys of rats treated with trans-platinum alone. In the liver, trans-platinum by itself or in combination with BSO was ineffective in altering the measured variables of heme metabolism. The possibility that similarity between cis-platinum and trans-platinum plus BSO may extend to systems other than heme metabolism, e.g. GSH synthesis and degradation, was examined. cis-Platinum caused significant inhibition of both renal gamma-glutamyl synthetase and gamma-glutamyl transpeptidase after 7 days, but not after 1 day. Twenty-four hours after treatment, BSO + trans-platinum caused inhibition of gamma-glutamylcysteine synthetase activity, whereas this activity in animals treated with BSO alone had returned to control values. At this time point, neither oxidized glutathione (GSSG)-reductase nor gamma-glutamyl transpeptidase activity was affected by trans-platinum + BSO treatment. The findings suggest that GSH constitutes an important defense mechanism against trans-platinum alteration of heme metabolism and may play a role in cellular accumulation of the drug in an inactive complex. It is proposed that BSO treatment, despite resulting in a diminished intracellular concentration of trans-platinum, allows reaction of the metal complex with target molecules by virtue of its ability to deplete GSH.