Hepatic Antioxidant System Research Articles

Interaction of exercise training and chronic ethanol ingestion on hepatic and plasma antioxidant system in rat.

This study was undertaken in order to investigate the interactive effects of exercise training and chronic ethanol consumption on the antioxidant system in rat liver and plasma. Fisher-344 rats were treated in separate groups as follows: sedentary control (SC); exercise training (ET) for 6.5 weeks; ethanol 20% (2.0 g kg-1, p.o.) for 6.5 weeks; and ET and ethanol administration. In liver, ET significantly decreased the malondialdehyde (MDA) level (73% of SC). Chronic ethanol significantly increased catalase (CAT) activity and MDA levels (126% and 135% of SC), respectively, and also depleted the reduced glutathione (GSH) level and the reduced to oxidized glutathione (GSH/GSSG) ratio (81% and 38% of SC), respectively. Exercise training plus ethanol significantly increased CAT and glutathione reductase (GR) activity (126% and 118% of SC), respectively, and decreased the MDA level (67% of SC). In plasma, ethanol significantly enhanced CAT activity and MDA levels (173% and 221% of SC), respectively. Ethanol ingestion also increased the CAT/superoxide dismutase (SOD) ratio (216% of SC) in plasma. Training plus ethanol ingestion significantly increased CAT activity and MDA levels (208% and 148% of SC), respectively, and increased CAT/SOD and glutathione peroxidase (GSH-Px)/SOD ratios (279% and 142% of SC), respectively. The data indicate that the combination of exercise and ethanol ingestion resulted in an enhanced hepatic CAT and GR activity to eliminate H2O2 and to maintain endogenous GSH levels. Thus, training ameliorated the ethanol-induced oxidative injury in the liver. The ratio of CAT/SOD in plasma increased twofold due to chronic ethanol intake and threefold due to the combination, which may be used as an index of oxidative stress.

Interaction of Exercise Training and Chronic Ethanol Ingestion on Hepatic and Plasma Antioxidant System in Rat

Interaction of Exercise Training and Chronic Ethanol Ingestion on Hepatic and Plasma Antioxidant System in Rat

Interaction of exercise and ethanol on hepatic and plasma antioxidant system in rat

This study was undertaken in order to determine the effects of exercise and ethanol consumption on antioxidant system in rat liver and plasma. Male Fisher-344 rats were treated as follows: (1) sedentary control (SC); (2) acute exercise (AE); (3) ethanol 20% (1.6 g/kg, p.o.); and (4) AE and ethanol administration. Animals were sacrificed and plasma and liver were isolated and analyzed for antioxidant enzyme, glutathione and lipid peroxidation. In liver, AE significantly elevated SOD and GSH-Px activity and slightly increased MDA level. Ethanol significantly decreased SOD, CAT, and GR activity (69, 74, and 77% of SC) respectively, and also depleted GSSG level (61% of SC) in liver. AE plus ethanol significantly decreased SOD activity 976% of SC), GSH and GSSG levels (85 and 72% of SC) in liver. In plasma, AE significantly enhanced GR activity (173% of SC). Ethanol decreased CAT, GSH-Px, and GR activity (41, 75 and 57% of SC) respectively and lowered MDA level (80% of SC) in plasma. AE plus ethanol significantly decreased CAT and GSH-Px activity (7% and 45% of SC) and increased SOD activity (160% of SC) in plasma. The data indicate that the combination of AE and ethanol ameliorated the changes in hepatic antioxidant enzyme activities, and enhanced the depletion of hepatic glutathione. The ratios of CAT/SOD, GSH-Px/SOD and GR/GSH-Px in plasma almost doubled due to acute exercise whereas CAT/SOD ratio decreased 20-fold due to alcohol consumption which may be used as an index of exercise and alcohol-induced oxidative stress.

Evaluation of hepatic antioxidant systems after intravenous administration of polymeric nanoparticles

We have investigated the modifications of the levels of intracellular markers of the oxidative stress in hepatocytes, after single or repeated injections of poly(isobutyl cyanoacrylate) (PIBCA) and polystyrene (PS) nanoparticles. Nanoparticles were administered intravenously at single doses of 20 and 100 mg kg −1 for 14 days. Levels of reduced (GSH) and oxidized (GSSG) glutathione, Superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CT) and the peroxidation of membrane lipids were measured. Single and repeated administration of PIBCA and PS nanoparticles induced a transient depletion of GSH and GSSG levels, a transient inhibition of SOD activity and a slight increase in CT activity. However, GPx activity was not modified and lipid peroxidation was not observed, suggesting that hepatocytes are not strongly affected by these modifications. Since nanoparticles do not distribute in hepatocytes, oxidative species could proceed from hepatic macrophages, activated after nanoparticle phagocytosis. It is unlikely that poly(alkyl cyanoacrylate) degradation products might be responsible for the oxidative attack because non-biodegradable PS nanoparticles induced the same effect. Uptake of polymeric nanoparticles by Kupffer cells in the liver induce modifications in hepatocyte antioxidant systems, probably due to the production of radical oxygen species. However, the depletion in glutathione was not great enough to initiate hepatocyte damage, since no changes in lipid peroxidation and reversible alterations were observed. This is an important factor to be considered in the use of polymeric nanoparticles as drug carriers.

Variations of hepatic antioxidant systems and DNA ploidy in rats aged 2 to 8 months

Oxygen-reactive species are by-products of biological redox reactions and are involved in the development and aging processes. In order to test whether the time-dependent changes in the hepatic antioxidant defense are related to changes in DNA ploidy, we studied in rats, aged 2–8 months, the enzymes and metabolites related to the primary cell defense against oxidative stress, as well as the distribution of DNA into the cell cycle phases. Catalase and glutathione peroxidase, together with glutathione reductase and mitochondrial superoxide dismutase, underwent progressive and significant time course increases. Although no temporal changes were observed in the concentration of protein thiol groups and malondialdehyde in rats in the same age period, glutathione redox state, detected by the GSH/GSSG ratio decreased significantly to 41% ( P < 0.001) of the initial value. DNA content was assayed by flow cytometry in isolated hepatocytes, and changes in DNA ploidy and distribution in the cell cycle phases were determined. A sharp decrease in diploid population from rats aged 1–8 months (92.9% → 11.1%) and a pronounced increase in hepatocyte polyploid populations in the same age period (2.6% → 87.3%) were observed. However, liver cell population involved in S phase (DNA synthesis) was unchanged. These results indicate that the cell defense mechanisms against oxygen toxicity increased in liver of rats from 2–8 months in order to suppress the oxidative imbalance. During the 6-month period of a rat's life (2–8 months), the significant alterations of GSH/GSSG ratio to a more oxidative state have no influence on the proliferating capacity of the cells.

Schisandrin B protects against carbon tetrachloride toxicity by enhancing the mitochondrial glutathione redox status in mouse liver

Previous studies in our laboratory have demonstrated the effect of Schisandrin B (Sch B), an active ingredient of the fruit of Schisandra chinensis, on enhancing the hepatic glutathione antioxidant system in mice, as evidenced by the hepatoprotection against carbon tetrachloride (CCl 4) toxicity. In the present study, the mechanism involved in the hepatoprotection afforded by Sch B treatment was investigated. Treating female Balb/c mice with 1,3-bis(2-chloroethyl)-l-nitrosourea, an inhibitor of glutathione reductase (GRD), at a dose of 2 mmol/kg (i.p.) did not abrogate the hepatoprotective action of Sch B in CCl 4-treated mice. The result indicates that the increased activity of hepatic GRD is not ascribable to the hepatoprotective action of Sch B. In control mice, the same Sch B treatment regimen caused an enhancement in hepatic mitochondrial glutathione redox status, as indicated by the significant increase and decrease in reduced and oxidized glutathione levels, respectively. While the CCl 4 intoxication greatly impaired mitochondrial glutathione redox status, the beneficial effect of Sch B treatment became more evident after CCl 4 challenge. Our results strongly suggest that the mechanism of hepatoprotection afforded by Sch B treatment may involve the enhancement of mitochondrial glutathione redox status.

Effect of schisandrin B on hepatic glutathione antioxidant system in mice: protection against carbon tetrachloride toxicity.

Pretreating female Balb/c mice with schisandrin B (Sch B) at increasing daily doses (1-4 mmol/kg) for 3 days caused dose-dependent increases in hepatic glutathione S-transferase (GST) and glutathione reductase (GRD) activities. However, the activities of glucose-6-phosphate dehydrogenase (G6PDH), Se-glutathione peroxidase (GPX), and gamma-glutamylcysteine synthetase (GCS) were down-regulated to varying degrees in a dose-dependent manner. While there were biphasic changes in hepatic reduced glutathione (GSH) level as well as susceptibility of hepatic tissue homogenates to in vitro peroxide-induced GSH depletion, a gradual decrease in hepatic malondialdehyde content was observed. The beneficial effect of Sch B on the hepatic GSH anti-oxidant system became more evident after CCl4 challenge. The same Sch B pretreatment regimen caused a dose-dependent protection against carbon tetrachloride (CCl4)-induced hepatotoxicity. The hepatoprotection was associated with significant enhancement in hepatic GSH status, as indicated by the substantial increase in tissue GSH levels and the corresponding decrease in susceptibility of tissue homogenates to GSH depletion. Where the activities of GST and GRD were increased linearly over non-CCl4 control values, there was also a gradual elevation in G6PDH activity upon administration of increasing doses of Sch B. In contrast, GPX activity was moderately down-regulated. The ensemble of results suggests that the hepatoprotection afforded by Sch B pretreatment may mainly be attributed to the enhancement in the functioning of the hepatic GSH anti-oxidant system, possibly through stimulating the activities of GSH related enzymes.

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Following the pioneer report of Di Luzio (Physiologist 6, 169-173, 1963) concerning the prevention of the acute ethanol-induced fatty liver by antioxidants, many observations have shown that ethanol-induced liver injury may be linked, at least partly, to an oxidative stress resulting from increased free radical production and/or decreased antioxidant defence. The disturbances induced in the major hepatic enzymatic and non-enzymatic antioxidant systems following experimental acute and chronic ethanol administration are reviewed, emphasizing the important role of dietary alpha-tocopherol in modifying the induction of oxidative stress and its usual expression as increased lipid peroxidation. Adaptative increases in some elements of the hepatic antioxidant defence partly counteract the enhanced generation of prooxidant free radicals following chronic ethanol intake. By contrast, lipid peroxidation is favoured when ethanol is administered together with a fat-rich diet and/or various xenobiotics. Chronic ethanol feeding has also been reported to potentiate the oxidative stress resulting from an acute ethanol load. By generating potent chemoattractants for human neutrophils and/or by stimulating the expression of genes involved in collagen biosynthesis, liver lipid peroxidation may play an important role in the progression of steatosis to hepatitis and cirrhosis. Oxidative stress has been shown not to be restricted to the liver, but also to affect, under some experimental conditions of ethanol administration, extrahepatic tissues, such as the central nervous system, the heart and the testes. This stress can be partly prevented by vitamin E supplementation. Ethanol-induced antioxidant disturbances have also been reported in clinical studies in blood and liver biopsies. Pharmacological antioxidants could have beneficial effects in reducing the incidence of ethanol-induced changes in cellular lipids, proteins and nucleic acids. The antioxidants considered could act by reducing free radical production (e.g. chelators of redox-active iron derivatives), trapping free radicals themselves, interrupting the peroxidation process or reinforcing the natural antioxidant defence.