Studies on paraquat-induced oxidative stress in rat liver

Oxidative injury of liver was studied 20 hr after a single oral administration of 150 mg/kg paraquat (PQ) to rats. PQ exerted no effect on cytosolic superoxide dismutase (SOD) activity but increased mitochondrial SOD activity by 14%. The level of GSH was decreased by 30%, and GSH/GSSG ratio was diminished almost twice. The correlation between the enhancement of mitochondrial SOD activity and the diminution of GSH level by PQ implicates O2- in the liver toxicity of the drug. Mitochondrial aconitase activity was slightly decreased (by 9%) while cytosolic aconitase activity was not affected. The results cast additional light on the responses of both aconitases to oxidative stress.     

Hippophae rhamnoides attenuates nicotine-induced oxidative stress in rat liver

The effects of vitamin E and Hippophae rhamnoides L. (Elaeagnaceae) extract (HRe-1) on nicotine-induced oxidative stress in rat liver were investigated. Four groups, eight rats each, were used in this study, and the supplementation period was 3 weeks. The groups were: nicotine (0.5?mg/kg/day, intraperitoneal (i.p.)); nicotine plus vitamin E (75?mg/kg/day, intragastric (i.g.)); nicotine plus HRe-1 (250?mg/kg/day, i.g.); and the control group. The malondialdehyde and nitric oxide levels, glutathione peroxidase, glutathione S-transferase, glutathione reductase, superoxide dismutase, and total and non-enzymatic superoxide scavenger activities were measured spectrophotometrically in supernatants of the tissue homogenates. Nicotine increased the malondialdehyde level in liver tissue compared with control. This nicotine-induced increase in lipid peroxidation was prevented by both vitamin E and HRe-1. Superoxide dismutase activity was higher in the nicotine plus vitamin E-supplemented group compared with nicotine and control groups. Glutathione reductase activity was higher in the nicotine group compared with the control group. However, glutathione peroxidase activity in the control group was higher than the levels in the nicotine, and the nicotine plus HRe-1 supplemented groups. The nitric oxide level was higher in the nicotine group compared with all other groups. Total and non-enzymatic superoxide scavenger activities and glutathione S-transferase activity were not affected by any of the treatments. Our results suggest that Hippophae rhamnoides extract as well as vitamin E can protect the liver against nicotine-induced oxidative stress.     

Effects of exogenous metallothionein against thallium-induced oxidative stress in rat liver

Metallothionein (MT) is a low-molecular weight sulfur-rich protein that plays role in metal homeostasis/detoxification and radical scavenging. The following study investigated the ability of exogenous MT to protect against oxidative damage induced by thallium (TI) in rat liver. Male Wistar rats were divided into four groups; a control and three experimental groups. The control group received physiological saline. Group 1 animals were injected with thallium acetate intraperitoneally (i.p.) at a single dose of LD₅₀ (32 mg/kg). In group 2 and group 3, metallothionein I was administrated once at two different doses (1 or 2.5 mg/kg i.p., respectively) 1 h before TI intoxication. Levels of endogenous antioxidants, oxidative stress markers were measured and histopathological examinations were performed 4 days after TI administration. TI accumulation in liver decreased related to the dose of MT. Mostly all of the alterations in the levels antioxidants restored to normal levels in MT administrated animals. H₂O₂ levels and lipid peroxidation decreased, integrity of hepatocytes and membranous structures inside the cells were preserved. The toxic effects of TI were modulated in MT administrated animals particularly at the dose of 2.5 mg/kg. These findings suggest an active role of exogenous MT against TI-induced oxidative stress in rat liver.     

Quercetin protects rat liver against lead-induced oxidative stress and apoptosis

Quercetin, a flavonoid, effectively improved the lead-induced histology changes including structure damage and leukocyte infiltration in rat liver. The present study was designed to explore the protective mechanism of quercetin against lead-induced hepatic injury. We found that quercetin markedly decreased the MDA and H(2)O(2) levels and lowered the GSH/GSSG ratio in the liver of lead-treated rat. Moreover, quercetin markedly restored Cu/Zn-SOD, Mn-SOD, CAT and GPx activities and upregulated mRNA expression levels of these proteins in the liver of lead-treated rat. Western blot analysis showed that quercetin significantly inhibited apoptosis by modulating the ratio of Bax to Bcl-2 expression and suppressing the expression of phosphorylated JNK1/2 and cleaved caspase-3 in the liver of lead-treated rat. In conclusion, these data suggest that quercetin protects the rat liver from lead-induced injury by attenuating lipid peroxidation, renewing the activities of antioxidant enzymes and inhibiting apoptosis.     

Protective role of melatonin in cyclosporine A-induced oxidative stress in rat liver

Cyclosporine A (CsA) is the most widely used immunosuppressive drug for preventing graft rejection and autoimmune disease. However, the therapeutic treatment induces several side effects such as nephrotoxicity, cardiotoxicity, hypertension and hepatotoxicity. Among possible mechanisms of CsA-induced hepatic damage, oxidative stress has been suggested. Melatonin (Mel) has been successfully used as a potent antioxidant against many pathophysiological states. This experimental study was performed to test, during CsA treatment, the alterations of some heat shock proteins (HSP) and the Mel antioxidant properties against CsA-induced injury. Rats were divided into four groups, which were treated respectively with olive oil, Mel alone, CsA and CsA plus Mel for 30 days. At the end of the treatments, the animals were killed and hepatic tissue was treated for morphological (haematoxylin-eosin), biochemical (reduced glutathione, GSH and malondialdehyde, MDA) and immunohistochemical (HSP60, HSP72, GRP75 and MT) analyses. The results indicate that CsA-induced hepatotoxicity was characterised by morphological alterations in tissue architecture, changes in GSH and MDA levels and increase in stress protein expression. In conclusion, our data suggest that the imbalance between production of free oxygen radicals and antioxidant defence systems, due to CsA administration, is a mechanism responsible for oxidative stress. Moreover, we show that Mel plays a protective action against CsA-induced oxidative stress, as supported by biochemical and immunohistochemical results.     

Nitrofurazone: kinetics and oxidative stress in the singlepass isolated perfused rat liver

The disposition of the antibiotic nitrofurazone was studied in the singlepass isolated perfused rat liver. Both the effects of the steady-state level of drug and the composition of the perfusate were evaluated. The higher level (120 micrograms/ml) of nitrofurazone in a perfusion medium lacking the glutathione (GSH) precursors, glycine, glutamic acid and cysteine, caused a marked increase in bile flow (from 1.01 +/- 0.07 to 2.33 +/- 1.07 microliters/min/g), massive biliary efflux of glutathione disulfide (GSSG) (from 0.55 +/- 0.07 to 60.6 +/- 25.4 nmol/min/g) and a sharp decline in the caval efflux of GSH (to undetectable levels) and the tissue level of GSH (from 5.74 +/- 0.20 to 2.68 +/- 0.13 mumol/g). Even after the drug was discontinued, these parameters were not restored to control levels. The lower level (30 micrograms/ml) of nitrofurazone with or without amino acid supplementation and the higher level with supplementation induced less dramatic effects. Using [35S]methionine, a new conjugated metabolite of nitrofurazone and glutathione was detected. The data suggest that the toxicity of the reactive oxygen species generated by the redox cycling of the nitro group and the reactive metabolites generated by further reduction of nitrofurazone can be mitigated by adequate glutathione levels, but that livers lacking sufficient glutathione to scavenge these reactive species may be damaged.     

Effect of sweet grass extract against oxidative stress in rat liver and serum

Ethanol metabolism is accompanied by generation of free radicals which can damage the cell components. However, sweet grass is a source of coumarin and its derivatives have emerged as a promising group of antioxidant compounds. The aim of this study has been to investigate the influence of sweet grass on oxidative stress formation in the liver and serum of rats intoxicated with ethanol. Alcohol intoxication led to a decrease in the superoxide dismutase, catalase, glutathione peroxidase and reductase activity in the blood serum as well as in the liver, but not in the glutathione reductase activity. The decrease in the antioxidant abilities of the examined tissues after ethanol intoxication resulted in enhanced lipid peroxidation measured as malondialdehyde and 4-hydroxynonenal levels. The metabolic consequence of oxidative modifications of lipids was damage of the liver cells membrane and an increase in its permeability appeared as a leakage of alanine aminotransferase and aspartate aminotransferase into the blood. Administration of sweet grass to the ethanol-intoxicated rats remarkably prevented the significant increase in concentrations of all measured lipid peroxidation products as well as the damage of the liver cell membrane. These results indicate beneficial antioxidant effect of the sweet grass on the liver of rats intoxicated with ethanol.     

High fat diet aggravates arsenic induced oxidative stress in rat heart and liver

Arsenic is a well known global groundwater contaminant. Exposure of human body to arsenic causes various hazardous effects via oxidative stress. Nutrition is an important susceptible factor which can affect arsenic toxicity by several plausible mechanisms. Development of modern civilization led to alteration in the lifestyle as well as food habits of the people both in urban and rural areas which led to increased use of junk food containing high level of fat. The present study was aimed at investigating the effect of high fat diet on heart and liver tissues of rats when they were co-treated with arsenic. This study was established by elucidating heart weight to body weight ratio as well as analysis of the various functional markers, oxidative stress biomarkers and also the activity of the antioxidant enzymes. Histological analysis confirmed the biochemical investigations. From this study it can be concluded that high fat diet increased arsenic induced oxidative stress.     

Perchlorate-induced oxidative stress in isolated liver mitochondria

As a new threat to environment all through the world, perchlorate (ClO₄ ^?) was predominantly a thyrotoxin, and its toxic manifestations in non-thyroid were also documented. To date, little is known about the effect of ClO₄ ^? on cell and organelle. To reveal the toxicity of ClO₄ ^? on living organism in-depth, mitochondria isolated from liver of Carassius auratus were incubated with different concentrations of ClO₄ ^?. The results demonstrated that ClO₄ ^?-induced mitochondrial oxidative stress, and subsequently caused a gradual opening of permeability transition pore leading to mitochondrial swelling and lipid peroxidative membrane damage. ClO₄ ^? has a conspicuous inhibition of electron transport chain activity which largely correlated to complexes I and IV. The investigations clearly demonstrated the oxidative stress of ClO₄ ^? in mitochondria, may well reveal cytotoxic effects in vitro that merit further investigation.     

Phenotypic anchoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver.

Toxicogenomics provides the ability to examine in greater detail the underlying molecular events that precede and accompany toxicity, thus allowing prediction of adverse events at much earlier times compared to classical toxicological end points. Acetaminophen (APAP) is a pharmaceutical that has similar metabolic and toxic responses in rodents and humans. Recent gene expression profiling studies with APAP found an oxidative stress signature at a subtoxic dose that we hypothesized can be phenotypically anchored to conventional biomarkers of oxidative stress. Liver tissue was obtained from experimental animals used to generate microarray data, where male rats were given APAP at subtoxic (150 mg/kg) or overtly toxic (1500 and 2000 mg/kg) doses and sacrificed at 6, 24, or 48 h. Oxidative stress in liver was evaluated by a diverse panel of markers that included assessing expression of base excision repair (BER) genes, quantifying oxidative lesions in genomic DNA, and evaluating protein and lipid oxidation. A subtoxic dose of APAP produced significant accumulation of nitrotyrosine protein adducts. Both subtoxic and toxic doses caused a significant increase in 8-hydroxy-deoxyguanosine (8-OH-dG) as well as a significant decrease in glutathione (GSH) content. Only toxic doses of APAP significantly induced expression levels of BER genes. None of the doses examined resulted in a significant increase in the number of abasic sites or in the amount of lipid peroxidation. The accumulation of nitrotyrosine and 8-OH-dG adducts along with reduced GSH content in the liver phenotypically anchors the oxidative stress gene expression signature observed with a subtoxic dose of APAP, lending support to the validity of gene expression studies as a sensitive and biologically meaningful end point in toxicology.     

Evaluation of oxidative stress during apoptosis and necrosis caused by D-galactosamine in rat liver

Eighteen and twenty-four hours after intraperitoneal administration of D-galactosamine (1g/kg body weight) to rats, the activity of caspase-3-like protease in the liver increased significantly compared with that in the control group given saline. Histological examinations including the in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method found apoptotic hepatocytes 18 hr after the administration of D-galactosamine. Caspase-3 activity was barely detectable in the plasma of control rats, but increased significantly 24 hr after drug administration along with a dramatic increase in glutamate-oxaloacetate transaminase (GOT). These results indicated that D-galactosamine causes apoptosis in the liver by activating caspase-3, which is released to the plasma by secondary necrosis. The concentration of lipid hydroperoxides in the liver increased significantly 24 hr after D-galactosamine administration. In contrast, the concentration of vitamin C in the liver decreased significantly 18 and 24 hr after D-galactosamine administration. These results suggest that D-galactosamine induces severe oxidative stress in the liver, leading to extensive necrosis.     

No evidence of intracellular oxidative stress during ischemia-reperfusion damage in rat liver in vivo.

The role of the intracellular generation of reactive oxygen species in the pathogenesis of ischemia-reperfusion damage of the liver was investigated in two in vivo rat models. Global hepatic ischemia was produced in the left and median lobes for 90 min followed by 60 min reperfusion to the total organ (model A) or only to the ischemic lobes (model B). Although both regimens caused significant rises in serum transaminases, this rise was higher in model B. In neither model was intracellular hydrogen peroxide production nor increased glutathione disulfide in bile found. The activities of various antioxidant enzymes were not affected by ischemia or ischemia-reperfusion. In conclusion, oxygen-free radicals are unlikely to be produced in the cells of rat liver during ischemia-reperfusion.     

Role of oxidative stress in alcohol-induced liver injury

Reactive oxygen species (ROS) are highly reactive molecules that are naturally generated in small amounts during the body’s metabolic reactions and can react with and damage complex cellular molecules such as lipids, proteins, or DNA. Acute and chronic ethanol treatments increase the production of ROS, lower cellular antioxidant levels, and enhance oxidative stress in many tissues, especially the liver. Ethanol-induced oxidative stress plays a major role in the mechanisms by which ethanol produces liver injury. Many pathways play a key role in how ethanol induces oxidative stress. This review summarizes some of the leading pathways and discusses the evidence for their contribution to alcohol-induced liver injury. Special emphasis is placed on CYP2E1, which is induced by alcohol and is reactive in metabolizing and activating many hepatotoxins, including ethanol, to reactive products, and in generating ROS.     

Cypermethrin-induced oxidative stress in rat brain and liver is prevented by vitamin E or allopurinol

Considering that the involvement of reactive oxygen species (ROS) has been implicated in the toxicity of various pesticides, this study was designed to investigate the possibility of oxidative stress induction by cypermethrin, a Type II pyrethroid. Either single (170 mg/kg) or repeated (75 mg/kg per day for 5 days) oral administration of cypermethrin was found to produce significant oxidative stress in cerebral and hepatic tissues of rats, as was evident by the elevation of the level of thiobarbituric acid reactive substances (TBARS) in both tissues, either 4 or 24 h after treatment. Much higher changes were observed in liver, increasing from a level of 60% at 4 h up to nearly 4 times the control at 24 h for single dose. Reduced levels (up to 20%) of total glutathione (total GSH), and elevation of conjugated dienes ( approximately 60% in liver by single dose at 4 h) also indicated the presence of an oxidative insult. Glutathione-S-transferase (GST) activity, however, did not differ from control values for any dose or at any time point in cerebral and hepatic tissues. Pretreatment of rats with allopurinol (100 mg/kg, ip) or Vitamin E (100 mg/kg per day, ig, for 3 days and a dose of 40 mg/kg on the 4th day) provided significant protection against the elevation of TBARS levels in cerebral and hepatic tissues, induced by single high dose of oral cypermethrin administration within 4 h. Thus, the results suggest that cypermethrin exposure of rats results in free radical-mediated tissue damage, as indicated by elevated cerebral and hepatic lipid peroxidation, which was prevented by allopurinol and Vitamin E.     

Protective effects of Iranian Achillea wilhelmsii essential oil on acetaminophen-induced oxidative stress in rat liver

Abstract

Context: Achillea wilhelmsii C. Koch (Asteraceae) is widely used in Iranian traditional medicine.

Objective: This in vivo study evaluates the hepatoprotective role of Iranian A. wilhelmsii oils against acetaminophen-induced oxidative damages in rats.

Materials and methods: The animals were divided into five groups: in negative control and control groups, the DMSO and 500?mg/kg acetaminophen were i.p. injected, respectively. In treatment groups, 100 and 200?mg/kg oils and 10?mg/kg BHT were given i.p. immediately after acetaminophen administration. Then, the hepatic oxidative/antioxidant parameters such as lipid peroxidation (LP), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and ferric reducing ability of plasma (FRAP) were measured in time intervals (2, 4, 8, 16, and 24?h) after administrations confirmed by histophatological consideration at 24?h.

Results: The results indicated that acetaminophen caused a significant elevation in SOD activity (8–24?h) and LP and FRAP levels (4?h) paralleled with significant decline in GSH level (4 and 8?h). The apparent oxidative injury was associated with evident hepatic necrosis confirmed in histological examination. The presences of A. wilhelmsii oils (100 and 200?mg/kg) with acetaminophen mitigated significantly the rise in SOD, LP, and FRAP levels and restored the GSH compared with the group treated with acetaminophen. These were confirmed by histological examination indicating the hepatic necrosis reversal by the oils.

Discussion and conclusion: It can be concluded that concomitant administration of A. wilhelmsii oils with acetaminophen may be useful in reversing the drug hepatotoxicity.     

Halothane induces oxidative stress and NF-kappaB activation in rat liver: protective effect of propofol

We investigated the effects of propofol on markers of oxidative stress, nuclear factor kappa B (NF-kappaB) activation and inducible nitric oxide synthase (iNOS) expression in liver of rats treated with halothane under hypoxic conditions. Male Wistar rats received halothane 1%/oxygen 14%, oxygen 14%/propofol 60 mg kg(-1) i.p., or halothane 1%/oxygen 14%/propofol 60 mg kg(-1) i.p. Morphological examination showed complete loss of architecture with massive necrosis of parenchyma in the halothane group, while only minor histological abnormalities were observed in rats receiving halothane plus propofol. The cytosolic concentration of TBARS and the hydroperoxide-initiated chemiluminescence increased significantly in the liver of animals from the halothane group (+62% and +40% versus controls, respectively), and this increase was abolished by propofol administration. Halothane induced a marked activation of NF-kappaB (+180%), and resulted in a significant decrease of the nonphosphorylated form of the inhibitor IkappaBalpha (-53%), while phosphorylated IkappaBalpha protein level was markedly increased (+146%). Propofol administration lowered these effects to +30% (NF-kappaB), -26% (nonphosphorylated IkappaBalpha), and +56% (phosphorylated IkappaBalpha). The increase of iNOS protein level (+59%) induced by halothane was significantly reduced to +22% by additional administration of propofol. Results obtained show that administration of propofol inhibits oxidative stress, NF-kappaB nuclear traslocation and iNOS overexpression in liver of rats receiving halothane. Propofol treatment, by inhibiting the NF-kappaB signal transduction pathway, might block the production of noxious mediators involved in the development of halothane-induced injury.     

非酒精性脂肪性肝病与氧化应激

非酒精性脂肪性肝病常与肥胖、2型糖尿病和高血压等代谢综合征并存,其与氧化应激的关系越来越受到关注.本文综述非酒精性脂肪性肝病的发病机制、氧化应激及其相关抗氧化剂的研究.     

The effect of acute oxidative stress on the ultrastructure of the perfused rat liver

Ageing and liver disease are associated with ultrastructural changes in the hepatic sinusoid. Because of the possibility that reactive oxygen species could mediate these processes, we examined the effect of acute oxidative stress on the ultrastructure of the intact liver. Rat livers were perfused ex vivo, in situ with hydrogen peroxide via the portal vein. The livers were then fixed and the ultrastructure of the liver tissue examined with transmission and scanning electron microscopy. The effects of hydrogen peroxide were largely confined to the perisinusoidal areas. The sinusoidal endothelial cells became swollen and more porous, with large gaps replacing sieve plates. The space of Disse showed an increase in volume and the density of hepatocyte projections decreased. Kupffer cell activation was noted. Little or no ultrastructural change was observed within the hepatocytes. Oxidative stress delivered via the portal vein dramatically alters the ultrastructure of the perisinusoidal regions of the liver. This process may contribute to the pathogenesis of disease and age-related changes in the liver.