Erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serum lipid peroxidation in epileptic children with valproate and carbamazepine monotherapy

This prospective study was carried out to determine changes in the antioxidant system in epileptic children receiving long term antiepileptic drugs (AEDs). Levels of erythrocyte glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and serum lipid peroxidation were determined in 25 healthy children and 30 epileptic children who had not yet received AEDs. Sixteen patients were treated with valproic acid (VPA) and 14 with carbamazepine (CBZ); 13 months later these parameters were retested. The results showed that SOD and lipid peroxidation levels were increased but the GSH-Px levels were decreased in epileptic children on VPA therapy compared with the control group and the results before treatment. No significant differences of these parameters were found in epileptic children on CBZ therapy compared with the control group and the results before treatment, except that lipid peroxidation level was slightly higher in epileptic patients before treatment. We conclude that antioxidant systems in epileptic children on CBZ therapy are better regulated in comparison with epileptic children on VPA therapy.     

Ethanol-induced changes in lipid peroxidation and glutathione content in rat brain

The effect of acute and chronic ethanol administration on brain lipid peroxide and glutathione levels was investigated in rats. Acute ethanol administration (5 g/kg, i.p.) led to an increase in lipid peroxide levels and a decrease in glutathione levels in whole brain homogenates without cerebellum. However, there was no change in brain lipid peroxide and glutathione levels of rats chronically treated with ethanol.     

Effects of methiocarb on lipid peroxidation and glutathione level in rat tissues

Methiocarb is an N-methylcarbamate insecticide used worldwide in agriculture and health programs. The aim of this study was to investigate the possible effects of methiocarb to induce lipid peroxidation (LPO) in tissues of male Wistar rats following single and repeated oral exposures. Animals were divided into six different groups, and methiocarb was administered by orally at doses 25, 10, and 2?mg/kg body weight for 1, 5, and 28 days, respectively. Liver, kidney, brain, and testis tissues were taken from the rats for the biochemical examinations. LPO and reduced glutathione (GSH) levels were determined in the tissues. LPO was significantly increased in liver, kidney, brain, and testis after 1-, 5-, and 28-day treatments of methiocarb. GSH levels were significantly increased in the 1-day period and significantly decreased in the 5- and 28-day periods in all tissues after methiocarb administration. It is concluded that methiocarb may induce LPO and produce disturbances on the GSH levels in liver, kidney, testis, and brain of rats. This suggests that methiocarb-induced toxicity may be associated with oxidative stress to cellular membranes. Further studies are required to better understand the role of oxidative stress on methiocarb-induced toxicity.     

Effects of diethylhydroxylamine on hepatic microsomal lipid peroxidation and glutathione S-transferases

The effects of diethylhydroxylamine (DEHA), a potent free-radical scavenger, on lipid peroxidation of rat liver microsomes were investigated in vitro. DEHA strongly inhibited ascorbate-dependent nonenzymatic microsomal lipid peroxidation. DEHA also completely inhibited nonenzymatic lipid peroxidation of heat-denatured microsomes, indicating that inhibition is protein-independent. DEHA only moderately inhibited NADPH-dependent enzymatic microsomal lipid peroxidation. DEHA has been shown to exhibit antitumorogenic properties. However, it had no significant effect on hepatic glutathione S-transferase, selenium-independent glutathione peroxidase, or selenium-dependent glutathione peroxidase activity in the DEHA-treated CD-1 (lCR) Br male mouse. This suggests that the mode of action of DEHA as an antitumorogenic agent may be different from that of butylated hydroxyanisole, whose antitumor function is attributed to induction of glutathione S-transferase activity.     

Effects of cadmium on glutathione peroxidase, superoxide dismutase, and lipid peroxidation in the rat heart: a possible mechanism of cadmium cardiotoxicity

Cadmium treatment of rats maintained on a low-selenium diet produced a significant increase in specific heart weight together with histopathological changes. This increase was accompanied by a decrease in the activities of the selenoenzyme, glutathione peroxidase, and the copper-containing enzyme superoxide dismutase, together with a rise in thiobarbiturate-reactive substances in the heart. Increased dietary selenium prevented the lowering of glutathione peroxidase activity but did not influence the effect of cadmium on superoxide dismutase. The effect of cadmium on thiobarbiturate-reactive materials was markedly reduced in the rats fed high dietary selenium.     

The effects of carbamazepine and valproic acid on the erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serum lipid peroxidation in epileptic children.

Some epileptic drugs may change antioxidant enzyme activities in humans and experimental animals. Recent studies suggest that membrane lipid peroxidation may be causally involved in some forms of epilepsy, and the differences are reported in free radical scavenging enzyme levels. GSHpX, SOD, GSH are important parameters of antioxidant defence mechanisms. This study was undertaken to evaluate the effects of valproic acid and carbamazepine (CBZ) therapy on erythrocyte glutathione (GSH), glutathione peroxidase (GSHpX), superoxide dismutase (SOD) and lipid peroxidation. During the treatment with VPA or CBZ, the erythrocyte GSHpX and GSH levels of epileptic children were significantly changed as compared to those of health control subjects. The mean levels of serum lipid peroxidation and erythrocyte superoxide dismutase were not statistically different from controls. The methods used for investigation of glutathione peroxidase, superoxide dismutase, glutathione and serum lipid peroxidation were all based on spectrophotometric measurement.     

Effects of glutathione depletion, chelation and diuresis on iron nitrilotriacetate-induced lipid peroxidation in rats and mice

1. Rats and mice dosed with iron nitrilotriacetate (FeNTA) i.p. (2-12 mg Fe/kg) showed evidence of lipid peroxidation as indicated by increased exhalation of ethane and increased malondialdehyde formation in liver and kidney. 2. Buthionine sulphoximine (BSO) administered i.p. to rats and mice decreased the total glutathione (GSH) content of liver and kidney. When the rodents were pretreated i.p. with BSO prior to injection of FeNTA the increases in ethane exhalation, and in liver and kidney malondialdehyde production, were greater than with FeNTA alone, and the total GSH of liver and kidney were decreased. 3. Diuresis produced by i.p. administration of furosemide to mice substantially decreased the ethane exhalation resulting from FeNTA administration, had a lowering effect on kidney MDA, but had no significant effect on liver MDA production. 4. Similarly, desferrioxamine beta-mesylate administered i.p. to mice markedly decreased the ethane exhalation and kidney MDA production resulting from FeNTA administration.     

Effects of glutathione depletion,chelation and diuresis on iron nitrilotriacetate-induced lipid peroxidation in rats and mice

1. Rats and mice dosed with iron nitrilotriacetate (FeNTA) i.p. (2-12 mg Fe/kg) showed evidence of lipid peroxidation as indicated by increased exhalation of ethane and increased malondialdehyde formation in liver and kidney.

2. Buthionine sulphoximine (BSO) administered i.p. to rats and mice decreased the total glutathione (GSH) content of liver and kidney. When the rodents were pretreated i.p. with BSO prior to injection of FeNTA the increases in ethane exhalation, and in liver and kidney malondialdehyde production, were greater than with FeNTA alone, and the total GSH of liver and kidney were decreased.

3. Diuresis produced by i.p. administration of furosemide to mice substantially decreased the ethane exhalation resulting from FeNTA administration, had a lowering effect on kidney MDA, but had no significant effect on liver MDA production.

4. Similarly, desferrioxamine β-mesylate administered i.p. to mice markedly decreased the ethane exhalation and kidney MDA production resulting from FeNTA administration.     

The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats

Water containing 20% ethanol was given for a period of 3, 6 and 9 weeks to rats, and changes in hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferases were investigated. Lipid peroxide levels and glutathione peroxidase activities remained unchanged after 3 weeks and started to increase thereafter. Glutathione levels and glutathione transferase activities were significantly increased following ethanol consumption. These results show that chronic ethanol consumption stimulates hepatic lipid peroxidation in rats. This stimulation is not dependent on glutathione depletion and the increased glutathione peroxidase and glutathione transferase activities may reflect an adaptive change against ethanol-induced lipid peroxide toxicity.     

Drug-induced lipid peroxidation in mice—I Modulation by monooxegenase activity,glutathione and selenium status

Feeding male mice for 2 days with sucrose leads to a decrease of total liver glutathione by more than 50 per cent when compared to controls. Such animals were intoxicated with 300 mg/kg paracetamol and upon administration of inducers of the drug-metabolizing system, in vivo and vitro lipid peroxidation in these animals was largely increased as well as the susceptibility to the drug. Pretreatment of the mice with methylcholanthrene led to a 28-fold, with benzo(α)pyrene to a 22-fold, and with phenobarbital to a tenfold increase in ethane exhalation. In vivo administration of various monooxygenase inhibitors showed that all agents effectively inhibit paracetamol-induced lipid peroxidation. It is concluded that phase I metabolism of paracetamol is a prerequisite for the manifestation of drug-induced lipid peroxidation.Selenium deficiency in mice neither affected hepatic levels of glutathione nor its decrease following sucrose feeding, nor glutathione transferase, superoxide dismutase, catalase and glutathione reductase activity. Selenium-dependent glutathione peroxidase activity of selenium-deficient mice, reactive with H₂O₂ as well as with t-butylhydroperoxide, decreased to 5 per cent of the supplemented controls. A glutathione peroxidase activity, which utilized cumenehydroperoxide as a substrate but insensitive to selenium deficiency, was found. Selenium-deficient diethylmaleate-pretreated animals were much more susceptible to paracetamol-induced lipid peroxidation than controls. Supplemented diethylmaleate-pretreated animals showed no signs of lipid peroxidation if treated with 100 mg/kg aminopyrine or ethylmorphine. However, deficient animals exhibited high ethane exhalation rates, drastically increased serum transaminases, loss of hepatic glutathione and mortality upon administration of these drugs. Qualitatively similar results with lower ethane exhalation rates were observed when 125 mg/kg furosemide was administered to diethylmaleate-pretreated selenium-deficient or -adequate mice. Even administration of 200 mg/kg ethoxycoumarin in combination with diethylmaleate lead to significant lipid peroxidation in phenobarbital-induced mice.The results demonstrate that in vivo selenium-dependent glutathione peroxidase plays a predominant role within the glutathione redox couple system. The enzyme protects the liver from peroxidative damage evoked by phase I metabolism of various drug types, as long as sufficient glutathione is available. It is suggested that activated oxygen released from the microsomal monooxygenase is the species responsible for the observed lipid peroxidation accompanied by severe acute liver lesions.     

氟喹诺酮类药物对大鼠肝外组织GST、GR及GSH-Px活性的影响

目的探讨氟喹诺酮类药物对大鼠肺、脑、肾、小肠中谷胱甘肽S-转移酶、谷胱甘肽还原酶及谷胱甘肽过氧化物酶活性的影响。方法实验分为体外和体内两部份。从大鼠的肺、脑、肾、小肠制备S9,分别测定给予环丙沙星、妥氟沙星、司帕沙星前后三种谷胱甘肽相关酶的酶活性。结果体内实验和体外实验结果显示,三种药物对各组织的G ST活性较对照组均有不同程度的抑制(P<0.05),但体外实验与体内实验中各药物组与对照组的差异有所不同,且不同组织中G ST活性降低的程度也不同;药物组各组织的GR和G SH-Px活性较对照组有降低,但大多无显著性差异。结论氟喹诺酮类药物对肝外组织的G ST活性有一定的抑制作用,且对不同组织的G ST活性的抑制作用存在差别,对GR和G SH-Px活性有抑制的趋势。     

Time-course of changes in hepatic lipid peroxidation and glutathione metabolism in rats with carbon tetrachloride-induced cirrhosis

1. The aims of the present study were to assess: (i) the temporal relationships between hepatic lipid peroxidation, changes in the glutathione detoxification system and the onset/development of cirrhosis in CCl4-treated rats; and (ii) the effects of oral zinc administration on these parameters. 2. Cirrhosis was induced in 120 rats by intraperitoneal injections of CCl4 twice a week over 9 weeks. One hundred and twenty additional animals were used as controls. Both groups were further subdivided to receive either a standard diet or one supplemented with zinc. Subsets of 10 animals each were killed at weeks 1, 2, 3, 5, 7 and 9 from the start of the study. 3. Induction of cirrhosis produced a decrease in the components of the hepatic glutathione anti-oxidant system: glutathione transferase activity decreased from week 1, the concentration of reduced glutathione (GSH) decreased from week 5 and glutathione peroxidase (GPx) activity decreased from week 7. This impairment was chronologically related to an increase in free radical generation. Hepatic lipid peroxidation was significantly correlated with GPx activity (r = -0.47; P < 0.001) in CCl4-treated rats. Zinc administration did not produce any significant improvement of the hepatic glutathione system. 4. In conclusion, cirrhosis induction in rats by CCl4 administration produced a decrease in the hepatic glutathione antioxidant system that was related to an increase in free radical production. Furthermore, zinc supplementation produced a reduction in the degree of hepatic injury and a normalization of lipid peroxidation, but not an improvement of the hepatic GSH anti-oxidant system.     

Cytotoxic and cytoprotective activities of curcumin. Effects on paracetamol-induced cytotoxicity, lipid peroxidation and glutathione depletion in rat hepatocytes

The cytoprotective effect of curcumin, a natural constituent of Curcuma longa, on the cytotoxicity of paracetamol in rat hepatocytes was studied. Paracetamol was selected as a model-toxin, since it is known to be bioactivated by 3-methylcholanthrene inducible cytochromes P450 presumably to N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite which upon overdosage causes protein- and non-protein thiol-depletion, lipid peroxidation and cytotoxicity measured as LDH-leakage. At low concentrations curcumin was found to protect significantly against paracetamol-induced lipid peroxidation, without protection against paracetamol-induced LDH-leakage and without protection against paracetamol-induced GSH-depletion. At a 100 times higher concentration of curcumin the observed protective effect on lipid peroxidation was accompanied with a tendency to increase cellular GSH-depletion and LDH-leakage. No time-dependency was found as to the curcumin-induced effects: treatment of the hepatocytes 1 hr before, concomitantly or 1 hr after the addition of paracetamol to the cells had similar effects. In contrast to what was expected on the basis of previous in vivo experiments, at higher concentrations curcumin itself was found to be slightly cytotoxic. Curcumin-induced LDH-leakage was accompanied by a significant depletion of GSH. It has been concluded that the observed cytoprotective and cytotoxic activities of curcumin may be explained by a strong anti-oxidant capacity of curcumin and the capability of curcumin to conjugate with GSH. Furthermore, it has been concluded that lipid peroxidation is not playing a causal role in cell-death induced by paracetamol or by curcumin.     

Lipid peroxidation and glutathione peroxidase activity in chronic obstructive pulmonary disease exacerbation: prognostic value of malondialdehyde.

Results of recent studies have indicated that during exacerbation of chronic obstructive pulmonary disease (COPD), antioxidant capacity is lower and the levels of lipid peroxidation products are higher than those in age-matched healthy subjects. The aim of this study was to assess the time course of changes in oxidant stress during the treatment of exacerbation of COPD. For this purpose, we measured erythrocyte glutathione peroxidase (GPx) activity and serum levels of the lipid peroxidation product malondialdehyde (MDA) in 18 male patients with acute exacerbation of COPD. Fifteen healthy non-smokers having no history of lung disease served as control subjects. Mean erythrocyte GPx values of patients were 45.54 +/- 9.04 u/gHb on admission and had increased to 72.77 +/- 9.68 by the tenth day of treatment, but still remained lower than those of healthy subjects (83.13 +/- 10.91) (p=0.007). Serum MDA values in patients were Vol. 12, No. 1, 2001 significantly higher (2.68 +/- 1.28 nmol/ml) than those in control subjects (1.04 +/- 0.36 nmol/ml) (p=0.000) and returned to normal values by the tenth day of treatment (1.08 +/- 0.36 nmol/ml) (p=0.766). Erythrocyte GPx values in patients who were current smokers (39.87 +/- 3.82 u/gHb) were lower than those in ex-smokers (49.15 +/- 9.67 u/gHb) (p=0.021). Moreover, serum MDA values in patients who were current smokers (3.32 +/- 1.18 nmol/ml) were higher than those in ex-smokers (1.66 +/- 0.60 nmol/ml) (p=0.007). The results show that oxidative stress in patients with acute exacerbation of COPD is related to higher MDA levels that return to normal conditions during the course of treatment. In conclusion, the results suggest that MDA levels can serve as a marker of prognosis and of the success of treatment of the exacerbation of COPD.     

Effects of cadmium treatment on selenium-dependent and selenium independent glutathione peroxidase activities and lipid peroxidation in the kidney and liver of rats maintained on various levels of dietary selenium

Rats fed a basal, low-selenium diet, or this diet supplemented with 0.1 ppm and 1.0 ppm selenium and treated with cadmium, showed significant reductions in the activity of the selenoenzyme glutathione peroxidase in kidney and liver. Cadmium treatment resulted in a significant increase in the activity of selenium-independent glutathione peroxidase activity in the liver of selenium-supplemented rats. Selenium-independent glutathion peroxidase activity was significantly reduced in the kidney of rats fed the basal low-selenium diet. There was no significant increase in lipid peroxidation in any of the groups studied. Cadmium concentrations in the kidney and liver of these animals ranged from about 250 to 700 g Cd/g tissue, dry weight.Supported by NIEHS Center Grant ES-00159 and a Grant from the Selenium-Tellurium Development Association     

Effect of garlic on the hepatic glutathione S-transferase and glutathione peroxidase activity in rat

It was attempted to observe the effect of garlic on the hepatic glutathione s-transferase and glutathione peroxidase activity in this study. Glutathione s-transferase (EC 2.5.1.18) are thought to play a physiological role in initiating the detoxication of potential alkylating agents, inclnding pharmacologically active compounds. Glutathione peroxidase (EC 1.11.1.9) might play an important role in the protection of cellular structures against oxidative challenge. The activities of glutathione s-transferase and glutathione peroxidase in rat liver were increased by the treatment of garlic juice. Allicin fraction, heat-treated allicin fraction and garlic butanol fraction markedly inhibited glutathione s-transferase activityin vitro, whereas glutathione peroxidase activity was significantly increased in heat-treated allicin fraction and garlic butanol fraction.     

Endrin-induced depletion of glutathione and inhibition of glutathione peroxidase activity in rats

1. Recent studies have shown that endrin induces lipid peroxidation and may produce toxicity through an oxidative stress. We have therefore examined the effect of endrin administration to rats on glutathione content and the activities of glutathione metabolizing enzymes. 2. The oral administration of endrin resulted in dose- and time-dependent decreases in hepatic and renal glutathione content with maximum depletion (90%) occurring in liver at approximately 24 hr post-treatment. 3. Decreases in glutathione content were also observed in lung, brain, spleen and heart. 4. Endrin (4 mg/kg) decreased selenium dependent glutathione peroxidase activity in liver and kidney by 64 and 50%, respectively, while small increases were observed in the activities of glutathione reductase and glutathione S-transferase. 5. The toxicity of endrin may be at least in part related to oxidative tissue damage associated with depletion of glutathione and inhibition of glutathione peroxidase activity.     

甘草酸二铵对大鼠心肌缺血再灌注损伤脂质过氧化及心肌酶活性的影响

目的:观察甘草酸二铵(DG)对大鼠心肌缺血再灌注损伤脂质过氧化及心肌酶活性的影响。方法:雄性wistar大鼠30只,随机分为假手术组、缺血再灌注组和DG20mg·kg-1组。每组10只。采用在体大鼠心肌缺血30min再灌注60min损伤模型,再灌注60min后分别用比色法测定心肌丙二醛(MDA)含量、超氧化物歧化酶(SOD)、三磷酸腺苷酶(ATP酶)、血清磷酸肌酸激酶(CPK)和乳酸脱氢酶(LDH)水平,并用酶组织化学方法检测心肌组织琥珀酸脱氢酶(SDH)的活性。结果:DG能显著降低心肌组织中MDA含量和SDH的活性(P<0.05,P<0.01),提高SOD和ATP酶活性(P<0.05,P<0.01),并减少心肌CPK和LDH的释放(P<0.05,P<0.01)。结论:DG具有保护大鼠心肌缺血再灌注损伤的作用,其作用机理可能与其降低心肌脂质过氧化,增强心肌细胞SOD、SDH和ATP酶活性有关。     

Ricin-induced hepatic lipid peroxidation, glutathione depletion, and DNA single-strand breaks in mice.

The ability of ricin, the glycoprotein toxin from the castor bean (Ricinus communis), to stimulate oxidative stress was investigated. Following the i.p. administration of 25 micrograms ricin/kg or the vehicle to female CF-1 mice, the effects of ricin on hepatic lipid peroxidation, nonprotein sulfhydryl (reduced glutathione) content and DNA single-strand breaks were determined at 0, 12, 24, 36, 48 and 72 hr post-treatment. Hepatic lipid peroxidation significantly increased 3.4-, 3.8-, and 3.0-fold relative to control values at 24, 36, and 48 hr post-treatment, respectively. Hepatic nonprotein sulfhydryl concentrations decreased significantly to approximately 51%, 61% and 65% of control values, at 24, 36, and 48 hr, respectively. The incidence of hepatic DNA single-strand breaks increased by 2.9-, 2.8-, and 2.4-fold relative to the zero time values at 24, 36, and 48 hr after treatment with ricin, respectively. No significant differences were observed in either lipid peroxidation or nonprotein sulfhydryl concentrations at 12 or 27 hr post-treatment. Decreases in liver and intestinal weight to body weight ratios were observed in ricin-treated animals, while no changes were observed in spleen and kidney weight to body weight ratios. These results indicate that in the liver of mice, ricin induces an oxidative stress which is maximal at approximately 36 hr post-treatment.     

Effects of melatonin on the levels of antioxidants and lipid peroxidation products in rats treated with ammonium acetate

The antioxidant potential of melatonin (MLT) on hyperammonemia (induced by ammonium acetate treatment) were studied in rats. The levels of circulatory ammonia, urea and non-protein nitrogen increased significantly in ammonium acetate treated rats and decreased significantly in rats treated with melatonin and ammonium acetate. In brain tissues, the same pattern of alterations across groups was observed in the levels of thiobarbituric acid reactive substances and lipid profile variables (free fatty acids, triglycerides, phospholipids, and cholesterol). Further, enzymatic (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymatic (reduced glutathione) antioxidants in brain tissues decreased significantly in ammonium acetate treated rats and increased significantly in rats treated with melatonin and ammonium acetate. These biochemical alterations could be due to the ability of melatonin to (i) scavenge a variety of radicals and reactive oxygen species (ii) induce antioxidative enzymes which reduce steady state levels of reactive oxygen species and (iii) stabilize cell membranes which assist them in reducing oxidative damage and thus could prevent oxidative stress in rats.