Effects on levels of glutathione and some related enzymes in tissues after an acute arsenic exposure in rats and their relationship to dietary protein deficiency

Arsenic is a potent toxin, carcinogen and modulator of antioxidant defense system. In this study, male rats of Wistar strain, maintained on either 18% or 6% protein (casein) diet, received an acute i.p. exposure to sodium arsenite (As3+) at its LD50 dose (15.86 mg/kg body weight). One hour after the arsenic exposure, glutathione (GSH) concentration was significantly depleted and lipid peroxidation was increased. A relationship between any two of tissue arsenic concentrations, GSH levels and lipid peroxidation values was observed only for liver when the proportional changes of respective parameters in either of the dietary groups of animals were compared. This suggests that, in liver, arsenic metabolism appears dependant upon the GSH concentration. Acute arsenic exposure significantly increased the glutathione peroxidase (GPx) activity in liver of both dietary groups and in kidney of only the 18% protein-fed group of animals. The glutathione-S-transferase (GST) activity significantly decreased in liver of the 18% protein-fed animals while GST increased in kidney of both the 18% and the 6% protein-fed groups. No significant change in glutathione reductase (GR) or glucose-6-phosphate dehydrogenase (G6PDH) activity was observed. In the present investigation, liver as a whole seems to be more affected in terms of GSH level and GST activity. The mode of responses of GPx and GR activities as well as the unaltered G6PDH activity might result in arsenic-induced GSH depletion and increase in lipid peroxidation. The animals of the 6% protein-fed group, appeared to be affected less in terms of tissue arsenic concentration, GSH level and GST activity. lipid peroxidation,     

Oxidative damage and changes in the glutathione redox system in erythrocytes from rats treated with hexachlorocyclohexane.

The concentration of reduced glutathione in the erythrocytes of rats was significantly decreased 24-72 hr after the rats were treated with 300 mg commercial hexachlorocyclohexane/kg body weight (one-third of the LD50), given ip. The activities of glutathione reductase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase were also significantly decreased 24 hr after treatment but there was no change in glutathione peroxidase activity. The results suggest that hexachlorocyclohexane produces significant changes in the glutathione redox system of rat erythrocytes leading to oxidative membrane damage.     

Arsenic-induced cell death in liver and brain of experimental rats

Arsenic is a well established human carcinogen and is ubiquitous in the environment. The present study demonstrates the effect of acute arsenic administration at three different doses in liver and brain of Wistar rats. Sodium arsenite was administered orally at doses of 6.3 mg/kg, 10.5 mg/kg and 12.6 mg/kg of body weight on the basis of a lethal dose 50% (LD50) for 24 hr. After administration of arsenites, liver and brain were analyzed for various parameters of oxidative stress, histopathological changes and caspase-3 activity. Glutathione levels were decreased significantly in the liver at all doses. In liver the following biochemical changes were observed, a significant lipid peroxidation and cytochrome-P450 induction along with significant decrease in catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione peroxidase was increased significantly at all doses. In brain, no significant change was observed at 6.3 mg/kg. However, a significant increase in lipid peroxidation and glutathione peroxidase activity along with significant decrease in the activity of glutathione, catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione-S-transferase was decreased significantly in both liver and brain at 10.5 and 12.6 mg/kg. No significant alteration in the activity of glucose-6-phosphate dehydrogenase and glutathione reductase was observed in either liver or brain at any dose. Dose-dependent histopathological changes, observed in both liver and brain are also described. A significant increase in caspase-3 activity was observed at all doses in liver and at 10.5 and 12.6 mg/kg in brain. Sodium arsenite caused DNA cleavage into fragments and manifested as "DNA laddering", a hallmark of apoptosis.     

Silibinin potentially protects arsenic-induced oxidative hepatic dysfunction in rats

Arsenic (As) compounds are reported as environmental toxicants and human carcinogens. Exposure to arsenic imposes a big health issue worldwide. Silibinin (SB) is a major flavonolignan compound of silimarin and is found in milk thistle of Silybum marianum. It has been reported that silibinin has antioxidant efficacy as metal chelators due to the orientation of its functional groups. However, it has not yet been explored in experimental animals. In view of this fact, the purpose of this study was to delineate the ameliorative role of silibinin against arsenic-induced hepatotoxicity in rats. Rats were orally treated with arsenic alone (5?mg/kg body weight (bw)/day) plus silibinin (75?mg/kg bw/day) for 4weeks. Hepatotoxicity was evaluated by the increased activities of serum hepatospecific enzymes namely aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, lactate dehydrogenase and total bilirubin along with increased elevation of lipid peroxidative markers, thiobarbituric acid reactive substances, lipid hydroperoxides, protein carbonyl content and conjugated dienes. The toxic effect of arsenic was also indicated by significantly decreased activities of membrane bound ATPases, enzymatic antioxidants like superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glucose-6-phosphate dehydrogenase along with nonenzymatic antioxidants like reduced glutathione, total sulfhydryl groups, vitamins C and E. Administration of silibinin exhibited a significant reversal of arsenic-induced toxicity in hepatic tissue. All these changes were supported by reduction of DNA damage in hepatocytes and histopathological observations of the liver. These results suggest that silibinin has a potential protective effect over arsenic-induced hepatotoxicity in rat.     

Hepatic damage caused by chronic arsenic toxicity in experimental animals

OBJECTIVE: Noncirrhotic fibrosis of the liver is common in subjects chronically consuming ground water geologically contaminated with arsenic, but the mechanism of the hepatic fibrosis is not known. Because lipid peroxidation has been implicated in the development of several other forms of hepatic fibrosis, including iron and copper overload, we have explored the roles of oxidative stress and lipid peroxidation in the causation of hepatic fibrosis in a murine model of chronic arsenic toxicity. METHODS: Male BALB/c mice were given drinking water contaminated with arsenic (3.2 mg/L) or arsenic-free (<0.01 mg/L, control) ad libitum. Mice were sacrificed at 3, 6, 9, 12, and 15 months for examination of hepatic histology and assays of hepatic reduced glutathione content, lipid peroxidation, enzymes of the antioxidant defense system, and membrane-bound sodium/potassium ATPase (Na+/K+ ATPase). RESULTS: After 12 months of arsenic feeding, the liver weights increased significantly as did serum aspartate aminotransferase and alanine aminotransferase. After 6 months of arsenic feeding, hepatic glutathione and the enzymes glucose-6-phosphate dehydrogenase and glutathione peroxidase were significantly lower than those of the control group. Hepatic catalase activity was significantly reduced at 9 months in the arsenic-fed group, while glutathione-S-transferase and glutathione reductase activities were also significantly reduced at 12 and 15 months. Plasma membrane Na+/K+ ATPase activity was reduced after 6 months while lipid peroxidation increased significantly after 6 months of arsenic feeding. Liver histology remained normal for the first 9 months, but showed fatty infiltration after 12 months of arsenic feeding. Histologic evidence of fibrosis was observed after 15 months. CONCLUSION: We have demonstrated hepatic fibrosis due to long-term arsenic toxicity in an animal model. Initial biochemical evidence of hepatic membrane damage, probably due to reduction of glutathione and antioxidant enzymes, may be seen by 6 months. Continued arsenic feeding resulted in fatty liver with serum aminotransferase and alanine aminotransferase elevated at 12 months and hepatic fibrosis at 15 months. The murine model is proposed as relevant to epidemic human toxicity in areas of arsenic contamination.     

Enhanced depletion of lens reduced glutathione Adriamycin in riboflavin-deficient rats

The anticancer drug Adriamycin has photosensitizing properties which potentially may be detrimental to lens tissue. Since reduced glutathione (GSH) serves to protect lens from photo-oxidative stress and dietary riboflavin is required by glutathione reductase to regenerate GSH, we investigated whether Adriamycin intensifies the depletion of GSH levels in rat lens during dietary riboflavin deficiency. Three-week-old rats were divided into two groups. One group was fed a diet deficient in riboflavin (less than 1 ppm) and the other group was pair-fed a control diet containing adequate riboflavin (8.5 ppm). After 6-12 weeks of dietary treatment, half the animals in each dietary group received Adriamycin (8 mg/kg/day) intraperitoneally for 3 days. After killing the rats, lenses were removed, and GSH content and glutathione reductase activity were measured in freshly prepared homogenates. To determine the extent of systemic oxidative stress and the degree of riboflavin deficiency, glucose-6-phosphate dehydrogenase and glutathione reductase activities, respectively, were measured in erythrocytes. In lens of rats fed the riboflavin-sufficient diet, treatment with Adriamycin did not diminish GSH content or alter glutathione reductase activity. In confirmation of reports by others, lenses of animals fed the riboflavin-deficient diet had diminished GSH levels, lower basal glutathione reductase activity, and elevated glutathione reductase activity coefficients compared to those of animals pair-fed the control diet. The present study shows that in riboflavin-deficient rats, Adriamycin exacerbated the depletion of GSH but did not reduce further glutathione reductase activity. The implications of these findings are that nutritional deficiencies, in particular riboflavin deprivation, may pose a potential risk to lenticular tissue following Adriamycin treatment.     

Effects of acute dimethoate administration on antioxidant status of liver and brain of experimental rats

Organophosphorus compounds may induce oxidative stress leading to generation of free radicals and alterations in antioxidant and scavengers of oxygen free radicals. The present study demonstrates effect of acute exposure of dimethoate in causation of oxidative stress in male Wistar rats. Dimethoate was administered orally at doses 45, 75 and 90 mg/kg of body weight on the basis of LD(50) for 24 h. After administration of doses, the liver and brain homogenates were analyzed for various parameters of oxidative stress. The results indicated an increase in hepatic cytochrome P450, lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase in liver and brain at 90 and 75 mg/kg doses. There were no significant changes in the levels of glucose-6-phosphate dehydrogenase activity in both liver and brain. Similarly, there were no significant changes in hepatic glutathione and glutathione-S-transferase activities. However, there was a significant increase in glutathione and glutathione-S-transferase in brain at 90 mg/kg dose only. Erythrocyte acetylcholinesterase was inhibited at all doses used. Dose-dependent histopathological changes, observed in both liver and brain, are also described.     

Changes in glutathione peroxidase system and pyridine nucleotide phosphate levels in kidneys of cephaloridine-administered rats

To elucidate the nephrotoxic mechanisms of cephaloridine (CER), changes in renal contents of glutathione (GSH), glutathione disulfide (GSSG), reduced and oxidized nicotinamide adenine dinucleotide phosphates (NADPH and NADP) and changes in renal activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase were examined for 15 days in rats that received single intravenous injections of CER in doses of 0 (control), 100 and 1,000 mg/kg body weight. Significantly different changes from the control group were observed in the 1,000 mg/kg group. The 1,000 mg/kg group showed elevations in renal NADP and NADPH contents and decrements in renal GSH content in the period of the 1st to 3rd hour after the CER-administration. Thus, the fall in renal GSH content was considered to be a cause for renal injury due to the oxygen radicals observed in the early period. After the 6th hour, the 1,000 mg/kg group showed decreases of renal glutathione peroxidase and glutathione reductase activities and increases of renal glucose-6-phosphate dehydrogenase activity as well as GSH content. Although accumulation of GSH in the kidney was clearly observed in the late period, the more highly aggravated renal injury was speculated to be due to the decreased level in the utilization of GSH according to the fall of renal glutathione peroxidase activity.     

Effect of dietary phytate on magnesium bioavailability and liver oxidant status in growing rats.

Male albino rats (initial average weight 60 g) were fed semi-synthetic diets based on casein, corn starch and sunflower oil over 21 days. All diets were supplemented with 300 mg magnesium from MgSO4x7H2O and 0,7.5 and 15 g phytic acid (PA) from sodium phytate per kg. The addition of PA to the diets resulted in a dose-dependent decrease of apparent Mg absorption and Mg concentration in the plasma and femur. Impaired Mg bioavailability due to 15 g PA/kg diet was accompanied by an increase of hepatic thiobarbituric acid reactive substances and protein carbonyls as well as by a moderate decline in liver reduced glutathione (GSH) levels. The liver homogenates of rats receiving the diets with 7.5 and 15 g PA/kg, respectively, were much more susceptible to iron-induced lipid peroxidation than those of the controls. Hepatic antioxidative enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), glucose-6-phosphate dehydrogenase (G6PDH)], alpha-tocopherol concentration and phenyl-N-tert-butylnitrone (PBN) adducts using electron spin resonance spectroscopy remained unchanged by the different dietary treatments. Under the conditions of a marginal dietary Mg supply, phytate had pro-oxidative rather than antioxidative effects in the case of liver metabolism.     

The relationship of dietary protein to metallothionein and cadmium-induced renal damage

The effect of dietary protein on the concentration of kidney metallothionein and cadmium in relationship to renal damage was investigated. Rats fed a low-protein diet accumulated significantly less cadmium in the kidney, liver, lung, and small intestine than rats fed a normal or high-protein diet. Metallothionein synthesis and/or storage was significantly reduced in rats fed the low-protein diet compared with rats fed the normal or high-protein diet. In rats fed the high-protein diet extensive proximal renal tubular necrosis was observed when kidney cadmium was below 200 μg/g wet weight and metallothionein was above 740 μg/g wet weight. Proximal tubular necrosis was slight to moderate in rats fed the normal or low-protein diet, which correlated with relatively low levels of cadmium and metallothionein in the kidney. These studies show that dietary protein affects the tissue level of both cadmium and metallothionein. The results also demonstrate that extensive renal damage can occur when the level of kidney cadmium is below the suggested critical concentration of 200 μg/g wet weight. Based on studies which show the nephrotoxic effects of cadmium-metallothionein and results of the present experiments, we suggest that the concentration of this complex in the kidney is of greater pathological importance than the level of kidney cadmium.     

Effects of aminothiols in 2-acetylaminofluorene-treated rats. II. Glutathione cycle and liver cytosolic activities

Reduced glutathione, enzymes involved in its metabolism and other cytosolic activities were evaluated in liver preparations of Wistar rats fed with a diet supplemented with 2-acetylaminofluorene (0.05%) and/or with glutathione or N-acetyl-L-cysteine (0.1%). The treatment lasted 4 cycles, each composed of 3 weeks of special diet followed by 1 week of standard diet. The carcinogen produced a considerable increase in gamma-glutamyl transpeptidase in liver homogenates at cycles III and IV, with an irreversible trend which was not discontinued even during the weeks of standard diet. Moreover, generally from cycle I, 2-acetylaminofluorene stimulated several enzyme activities in the liver cytosol, such as glutathione S-transferase, glutathione reductase, glucose 6-phosphate dehydrogenase, NADH- and NADPH-dependent diaphorases. Administration of the two aminothiols to untreated rats resulted in a significant enhancement of glutathione peroxidase, glucose 6-phosphate dehydrogenase and diaphorases. In 2-acetylaminofluorene-treated rats, both thiols further stimulated glutathione S-transferase during the last treatment cycles and attenuated gamma-glutamyl transpeptidase activity, which however was not sufficient to thoroughly counteract the liver lesions due to the massive feeding of the carcinogen. Hepatocellular glutathione was enhanced during the last cycle of treatment with 2-acetylaminofluorene, and was further increased by co-administration of exogenous glutathione.     

Effects of hyperoxia on pulmonary metabolism of newborn rats and modification by chlorphentermine

Continuous exposure of newborn rats to 95% oxygen for 3 days decreased the incorporation of thymidine into lung DNA with a return to control values after 5–7 days of exposure. In general, hyperoxia increased the activities of pulmonary glutathione peroxidase, glutathione reductase and lactic dehydrogenase without associated significant alterations in glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and pyruvate kinase. Although hyperoxygenation elevated both lung lactate and pyruvate levels, a fall in the ratio of lactate to pyruvate was noted. Daily, oral administration of 20 mg/kg chlorphentermine significantly enhanced the incorporation of thymidine into DNA throughout the course of the experiment. Whereas anorectic drug treatment decreased lactic dehydrogenase activity, increases were seen in the activities of glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, glutathione peroxidase and glutathione reductase. Under our experimental conditions, the chlorphentermine-stimulated rise in newborn lung lactate and pyruvate levels was associated with a lower ratio of lactate to pyruvate. In newborns exposed simultaneously to continuous 95% oxygen and daily chlorphentermine, this drug modified the effects seen with oxidant alone as reflected by significant stimulation in DNA synthesis, elevation in glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase as well as depression in lactic dehydrogenase and pyruvate kinase. While concurrent O₂ and chlorphentermine administration, in general, did not markedly alter glutathione reductase when compared to O₂ alone, combined treatment produced a greater rise in glutathione peroxidase. In comparison to corresponding O₂ controls, simultaneous oxidant and drug exposure increased the ratio of lactate to pyruvate and lactate levels without an associated marked change in tissue pyruvate. Our results indicate that, in simultaneous oxidant- and anorectic drug-treated newborns, the metabolic responses seen in lung, in general, resembled those produced by chlorphentermine alone and were opposite to those induced by 95% oxygen.     

Effects of diallyl tetrasulfide on cadmium-induced oxidative damage in the liver of rats

The protective efficacy of diallyl tetrasulfide (DTS) from garlic on liver injury induced by cadmium (Cd) was investigated. In this study, Cd (3 mg/kg body weight) was administered subcutaneously for 3 weeks to induce toxicity. DTS was administered orally (10, 20 and 40 mg/kg body weight) for 3 weeks with subcutaneous (sc) injection of Cd. Cd-induced liver damage was evidenced from increased activities of serum hepatic enzymes, namely aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate dehydrogenase, with significant elevation of lipid peroxidation indices (thiobarbituric acid reactive substances and hydroperoxides) and protein carbonyl groups in the liver. Rats subjected to Cd toxicity also showed a decline in the levels of total thiols, reduced glutathione (GSH), vitamin C and vitamin E, accompanied by an increased accumulation of Cd, and significantly decreased activities of superoxide dismutase, catalase (CAT), glutathione peroxidase, glutathione-S-transferase (GST), glutathione reductase, and glucose-6-phosphate dehydrogenase in the liver. Administration of DTS at 40 mg/kg body weight significantly normalised the activities of hepatic marker enzymes, compared to other doses of DTS (10 and 20 mg/kg body weight). In addition, DTS (40 mg/kg body weight) significantly reduced the accumulation of Cd and the level of lipid peroxidation, and restored the level of antioxidant defense in the liver. Histological studies also showed that administration of DTS to Cd-treated rats resulted in a marked improvement of hepatocytes morphology with mild portal inflammation. Our results suggest that DTS might play a vital role in protecting Cd-induced oxidative damage in the liver.     

Catechin prevents tamoxifen-induced oxidative stress and biochemical perturbations in mice

Natural antioxidants like catechin are now known to have a modulatory role on physiological functions and biotransformation reactions involved in the detoxification process, thereby affording protection from toxic metabolic actions of xenobiotics. Reactive oxygen intermediates have been demonstrated to play an etiological role in anticancer drug-induced toxicity. This study was performed to explore the modulatory and protective effect of catechin on the toxicity of an anticancer drug, tamoxifen (TAM) with special reference to protection against disruption of glutathione metabolizing and antioxidant enzymes. TAM treatment resulted in a significant increase in the lipid peroxidation (LPO), H(2)O(2) generation and protein carbonyl (PC) contents in the liver and kidney as compared to controls while catechin+TAM-treated group showed significant decrease in LPO levels, H(2)O(2) generation and PC contents in liver and kidney when compared with TAM-treated group. Non-enzymatic antioxidants like reduced glutathione (GSH) and low molecular antioxidants like ascorbic acid (AsA) also showed normalcy due to exogenous catechin administration. Catechin pre-treatment showed restoration in the level of cytochrome P450 (CYP) content and in the activities of glutathione metabolizing enzymes, viz., glutathione-S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) and other antioxidant enzymes such as, glucose-6-phosphate dehydrogenase (G6-PD), catalase (CAT) and superoxide dismutase (SOD) in both liver and kidney when compared to TAM-treated animals. The results of the study show that catechin supplementation might be helpful in abrogation of TAM toxicity during chemotherapy. Additionally, it makes it a prophylactic and preventive agent of anticancer drug-induced oxidative stress.     

Cardioprotective effects of Sesbania grandiflora in cigarette smoke-exposed rats

Cigarette smoke is a major risk factor of coronary heart disease, myocardial infarction, and cardiac death. It has been reported to contain large amounts of oxidants. This study was undertaken to evaluate the cardioprotective effects of Sesbania grandiflora (S. grandiflora) against cigarette smoke-induced oxidative damage in rats. Adult male Wistar-Kyoto rats were exposed to cigarette smoke for a period of 90 days and consecutively treated with S. grandiflora aqueous suspension (SGAS, 1000 mg/kg body weight per day orally) for a period of 3 weeks. Lactate dehydrogenase activity in serum and cardiac lipid peroxidation product level were significantly increased while the activities of cardiac superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase then the levels of reduced glutathione, vitamin C, and vitamin E were significantly decreased in rats exposed to cigarette smoke. Besides, copper level was elevated, whereas zinc, manganese, and selenium levels were significantly diminished in the heart of rats exposed to cigarette smoke. Treatment with SGAS restored the antioxidant status and retained the levels of micronutrients. These results suggest that chronic cigarette smoke exposure increases the oxidative stress, thereby disquieting the cardiac defense system and S. grandiflora protects the heart from the oxidative damage through its antioxidant potential.     

Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity

Dietary antioxidants protect laboratory animals against the induction of tumours by a variety of chemical carcinogens. Among possible mechanism of protection against chemical carcinogenesis could be mediated via-antioxidant-dependent induction of detoxifying enzymes. Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and is commonly used as a spice and food colouring material and exhibits antiinflammatory antitumour, and antioxidant properties. In this study we therefore investigated the effect of dietary supplementation of curcumin on the activities of antioxidant and phase II-metabolizing enzymes involved in detoxification, and production of reactive oxygen species were quantified in ddY male mice. Dietary supplementation of curcumin (2%, w/v) to male ddY mice for 30 days significantly increased the activities of glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and catalase to 189%, 179%, 189%, and 181% in liver and 143%, 134%, 167% and 115% in kidney respectively as compared with corresponding normal diet fed control (P<0.05-0.001). Parallel to these changes, curcumin feeding to mice also resulted in a considerable enhancement in the activity of phase II-metabolizing enzymes viz. glutathione S-transferase and quinone reductase to 1.7 and 1.8 times in liver and 1.1 and 1.3 times in kidney respectively as compared with corresponding normal diet fed control (P<0.05-0.01). In general, the increase in activities of antioxidant and phase II-metabolizing enzymes was more pronounced in liver as compared to kidney. The induction of such detoxifying enzymes by curcumin suggest the potential value of this compound as protective agent against chemical carcinogenesis and other forms of electrophilic toxicity. The significance of these results can be implicated in relation to cancer chemopreventive effects of curcumin against the induction of tumours in various target organs.     

Effect of Terminalia arjuna stem bark on antioxidant status in liver and kidney of alloxan diabetic rats

Free radicals and associated oxidative stress induced by alloxan are implicated in eliciting pathological changes in diabetes mellitus. Terminalia arjuna bark, an indigenous plant used in ayurvedic medicine in India, primarily as a cardiotonic is also used in treating diabetes, anemia, tumors and hypertension. The present study examined the effect of ethanolic extract (250 and 500 mg/kg body weight) of Terminalia arjuna stem bark in alloxan induced diabetic rats and its lipid peroxidation, enzymatic and nonenzymatic activity was investigated in the liver and kidney tissues. The extract produced significant (P<0.05) reduction in lipid peroxidation (LPO). The effect of oral T. arjuna at the dose of 500 mg/kg body weight was more than the 250 mg/kg body weight. The extract also causes a significant (P<0.05) increase in superoxide dismutase, catalase, glutathione peroxidase, glutathione-s-transferase glutathione reductase and glucose-6-phosphate dehydrogenase, reduced glutathione, vitamin A, vitamin C, vitamin E, total sulfhydryl groups (TSH) and non protein sulfhydryl groups (NPSH) in liver and kidney of alloxan induced diabetic rats, which clearly shows, the antioxidant property of T. arjuna bark. The result indicates that the extract exhibit the antioxidant activity through correction of oxidative stress and validates the traditional use of this plant in diabetic animals.     

Early changes in hepatic redox homeostasis following treatment with a single dose of valproic acid

Changes in reduced glutathione (GSH) and pyridine nucleotide phosphate levels as well as in the activities of the glutathione peroxidase-reductase system and glucose-6-phosphate dehydrogenase have been studied in rats after a single i.p. administration of various doses of valproic acid (VPA). GSH level decreased in a dose-dependent relation. At the end of 180 min GSH levels either returned to control limits (lower doses) or showed a tendency to normalize (higher doses). GSH loss was paralleled by the reduction in glutathione reductase activity. A significant NADPH reduction was also seen after animal exposure to high VPA doses. At the end of 180 min a maximal NADPH decrease was reached. The activities of both glutathione peroxidase and glucose-6-phosphate dehydrogenase were suppressed irrespective of whether animals were given low or high VPA doses.     

Effects of melatonin on the activity of the glutathione antioxidant system and various NADPH-generating enzymes in the liver and blood of rats with type 2 diabetes mellitus

The actions of melatonin on the activity of the glutathione antioxidant system and various NADPH-generating enzymes in rats with type 2 diabetes mellitus were studied. The development of this pathology was found to be accompanied by increases in the activities of glutathione reductase (E.C. 1.6.4.2), glutathione peroxidase (E.C. 1.11.1.9), and NADP-isocitrate dehydrogenase (NADP-IDH, E.C. 1.1.1.41), along with decreases in the activity of glucose-6-phosphate dehydrogenase (G6PDH, E.C. 1.1.1.49) in both the liver and serum as compared with animals without pathology. In addition, there was a decrease in the level of reduced glutathione. Administration of melatonin induced changes in the study parameters towards control values. This effect appeared to be linked to decreases in the loading on the glutathione antioxidant system due to the antioxidant properties of this hormone, which are associated with the features of its chemical structure which allow it to interact efficiently with free radicals to form metabolites with little or no toxicity.     

Pyridoxine mitigates cadmium induced hepatic cytotoxicity and oxidative stress

Therapeutic potential of pyridoxine (vit B6) was evaluated against cadmium induced hepatic cytotoxicity in culture and oxidative stress in rats. Nonmalignant "Chang" liver cell culture was exposed to Cd (cadmium chloride) that produced cytotoxicity in terms of increase in cell growth inhibition rate, alanine aminotransferase, lactate dehydrogenase and lipid peroxidation, which was significantly mitigated by pyridoxine in a concentration dependent manner. Acute exposure to Cd (6.5mg/kg body weight; ip once only) produced a condition of hepatic oxidative stress by substantially increasing lipid peroxidation and oxidized glutathione level along with corresponding decrease in reduced glutathione and various antioxidant enzymes, i.e., superoxide dismutase, catalase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase. Cadmium administration significantly increased the leakage of liver marker enzymes in serum, i.e., transaminases, alkaline phosphatase and lactate dehydrogenase. Therapy with pyridoxine after 3h of Cd administration decreased the release of serum transaminases, alkaline phosphatase and lactate dehydrogenase towards control. Administration of pyridoxine inhibited lipid peroxidation and formation of oxidized glutathione, increased the reduced glutathione level and restored the activities of aforesaid antioxidant enzymes towards control. The observations clearly demonstrated that pyridoxine treatment mitigates cadmium induced hepatic cytotoxicity and oxidative stress and provides evidence that it may be used clinically against Cd-induced hepatic toxicity.