Nickel-mediated inhibition in the glutathione-dependent protection against lipid peroxidation

Glutathione protects liver microsomes against the rapid onset of lipid peroxidation via a sulfhydryl dependent heat labile factor known as free radical reductase. The administration of nickel to mice resulted in an inhibition in the activity of free radical reductase, and enhanced lipid peroxidation and the activity of glutathione S-transferase in a dose dependent manner. The pretreatment of cyclam, a known specific chelator of nickel restored free radical reductase and glutathione S-transferase activities and alleviated nickel mediated enhancement of lipid peroxidation. Our results indicate that nickel-mediated inhibition in free radical reductase activity and activation of glutathione S-transferase may be due to the interaction of nickel with sensitive-SH groups located on these proteins.     

Plasma lipid peroxidation and erythrocyte antioxidants status in workers exposed to nickel

The objectives were to investigate the plasma lipid peroxidation and erythrocyte antioxidants status in workers exposed to nickel. The study groups comprised 69 nickel plating workers and 50 office workers residing in the same city, but away from the place of work of the study group subjects, considered as control group. Urinary nickel concentration was determined by graphite furnace atomic absorption spectrophotometry. The plasma lipid peroxidation and erythrocyte antioxidants were measured by spectrophotmetric methods. The plasma lipid peroxidation level was significantly increased in nickel-platers and their helpers as compared with controls. Erythrocyte antioxidants were significantly decreased in the nickel-platers compared with the controls. The level of plasma lipid peroxidation was positively and erythrocyte antioxidants were negatively and significantly correlated with the urine nickel levels. Multiple regression analysis assessed the oxidative stress associated with nickel and other potential confounding factors such as body mass index, the consumption of green vegetables, coffee, tea, smoking and alcohol consumption. Analysis showed that the lifestyle confounding factors: the consumption of green vegetables, smoking and alcohol, were not significantly associated with oxidative stress. The exposure to nickel, body mass index and coffee consumption were significantly associated with oxidative stress. The results show that the increased plasma lipid peroxidation and decreased erythrocyte antioxidants levels observed in nickel-exposed workers could be used as biomarkers of oxidative stress.     

Plasma lipid peroxidation and erythrocyte antioxidants status in workers exposed to nickel

The objectives were to investigate the plasma lipid peroxidation and erythrocyte antioxidants status in workers exposed to nickel. The study groups comprised 69 nickel plating workers and 50 office workers residing in the same city, but away from the place of work of the study group subjects, considered as control group. Urinary nickel concentration was determined by graphite furnace atomic absorption spectrophotometry. The plasma lipid peroxidation and erythrocyte antioxidants were measured by spectrophotmetric methods. The plasma lipid peroxidation level was significantly increased in nickel-platers and their helpers as compared with controls. Erythrocyte antioxidants were significantly decreased in the nickel-platers compared with the controls. The level of plasma lipid peroxidation was positively and erythrocyte antioxidants were negatively and significantly correlated with the urine nickel levels. Multiple regression analysis assessed the oxidative stress associated with nickel and other potential confounding factors such as body mass index, the consumption of green vegetables, coffee, tea, smoking and alcohol consumption. Analysis showed that the lifestyle confounding factors: the consumption of green vegetables, smoking and alcohol, were not significantly associated with oxidative stress. The exposure to nickel, body mass index and coffee consumption were significantly associated with oxidative stress. The results show that the increased plasma lipid peroxidation and decreased erythrocyte antioxidants levels observed in nickel-exposed workers could be used as biomarkers of oxidative stress.     

Protective role of zinc in nickel induced hepatotoxicity in rats

This study was planned to determine the protective role of zinc, if any, in attenuating the toxicity induced by nickel sulfate in rat liver. Female Sprague Dawley (SD) rats received either nickel alone in the dose of 800 mg/l in drinking water, zinc alone in the dose of 227 mg/l in drinking water, and nickel plus zinc or drinking water alone for a total duration of eight weeks. The effects of different treatments were studied on various parameters in rat liver which include antioxidant enzymes, levels of nickel and zinc and histoarchitecture at the light microscopic level. Further, the activities of hepatic marker enzymes AST and ALT were also studied in rat serum. Nickel treatment to the normal control animals, resulted in a significant increase in lipid peroxidation and enzyme activities of catalase and glutathione-S-transferase. On the contrary, nickel treatment to normal rats caused a significant inhibition in the levels of reduced glutathione. Superoxide dismutase activity was found to be decreased which however was not significant. Interestingly, when Zn was supplemented to nickel treated rats, the activities of catalase, and glutathione-S-transferase and the levels of GSH and lipid peroxidation came back to within normal limits. Activities of serum AST and ALT were increased significantly following nickel treatment to normal rats. Simultaneous zinc administration to nickel treated rats tended to restore the altered levels of AST and ALT. Normal control and zinc treated animals revealed normal histology of liver. On the other hand, nickel treated animals showed alterations in normal hepatic histoarchitecture which comprise of vacuolization of the hepatocytes and dilatation of sinusoids as well as increase in the number of bi-nucleated cells. Administration of zinc to nickel treated rats resulted in marked improvement in the structure of hepatocytes, thus emphasizing the protective potential of zinc in restoring the altered hepatic histoarchitecture. The nickel administration to normal rats indicated increased concentrations of nickel and decreased concentrations of zinc. However, zinc effectively brought the altered levels of nickel and zinc to within normal range. The study concludes that zinc has the potential in alleviating the toxic effects of nickel in rat liver because of its property to induce metallothionein (S-rich protein) as a free radical scavenger, or its indirect action in reducing the levels of oxygen reactive species.     

Protective role of <Emphasis Type="SmallCaps">l</Emphasis>-ascorbic acid on antioxidant defense system in erythrocytes of albino rats exposed to nickel sulfate

In this experimental study, we investigated whether l-ascorbic acid has any influence on the blood antioxidant defense system, lipid peroxidation and hematological parameters of the albino rats exposed to nickel sulfate(NiSO₄).Twenty four adult rats were divided into four groups of six animals in each group. The control rats were untreated and comprised Group I. Group II rats were administered nickel sulfate (2.0 mg/100 g b.wt.; intraperitonially, i.p.). Group II rats were treated orally l-ascorbic acid (50 mg/100 g b.wt.) and Group IV rats were given both nickel sulfate and l-ascorbic acid simultaneously on alternate days until the tenth dose. The hematological parameters were assessed: red blood corpuscle counts, packed cell volume %, hemoglobin concentration, white blood corpuscle counts and platelets count decreased significantly and clotting time increased significantly in nickel treated rats. We also observed increase malondialdehyde (MDA) and decrease glutathione level (GSH) in erythrocytes of nickel treated rats. The activities of erythrocyte antioxidant enzymes like superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were significantly increased in rats treated with nickel sulfate. Simultaneously treatment of l-ascorbic acid exhibited a possible protective role on the toxic effect of nickel sulfate on the hematological values, erythrocyte MDA and GSH concentrations as well as antioxidant enzymatic defense system.     

Effect of nickel on oxygen free radical metabolism

The effect of nickel on superoxide dismutase activity (SOD), as well as on rate of hydroxydopamine oxidation, was studied in vitro since lipid peroxidation has been implicated in cell damage by nickel, whose toxicity and carcinogenicity are well established. Nickel strongly inhibits SOD activity. The degree of inhibition is directly proportion to the nickel concentration (tested range 0.066 to 0.33 microgram/mL in the reaction mixture); to the substrate concentration (tested range 0.4 x 10 4M to 1.1 x 10 4M 6-hydroxydopamine); and to reaction mixture. Autoxidation of 6-hydroxydopamine was increased by nickel concentrations higher than 15 micrograms/mL. The combination of excessive oxygen free radical production and inhibition of their elimination by inhibition of SOD activity may contribute to the nickel toxicity that has been reported in industrial accidents, as well as to the high incidence of cancer occurring in nickel workers. It may also contribute to many complications in uremic patients, in whom increased serum nickel levels were reported to be in a similar range to those inhibiting SOD.     

Ames test evaluation of two commercially available zero-valent nickel compounds

Zero-valent nickel compounds are organometallic chemicals that are used in synthetic applications and may also occur as intermediates in nickel-catalyzed hydrogenation reactions used in food processing. Few studies have been performed on their possible genotoxic actions. We have tested two commercially available examples of this class of compounds. Solubility and stability were examined. Mutagenicity testing did not confirm a previous report that bis(1,5-cyclooctadiene)nickel is positive in the Ames assay. No stimulation of lipid peroxidation was observed in studies of bovine erythrocytes exposed in vitro. Our results do not indicate that zero-valent nickel compounds have genotoxic effects.     

Beneficial role of naringin, a flavanoid on nickel induced nephrotoxicity in rats

This study was conducted to investigate the beneficial role of naringin on nickel induced nephrotoxicity. Nickel (Ni) (20 mg/kg body weight (b.w.) was administered intraperitoneally (i.p.) for 20 days. Naringin was administered orally (20, 40 and 80 mg/kg b.w.) with i.p. administration of Ni. Ni administration increased the levels of serum urea, uric acid and creatinine with a significant decrease in creatinine clearance and decreased levels of urea, uric acid and creatinine in urine. The levels of lipid peroxidation markers and nickel concentration in blood and kidney were also increased. While, the activities of enzymic and non-enzymic antioxidants were decreased. Treatment with naringin attenuated the alterations in the renal and urine markers, decreasing lipid peroxidation markers, increasing the antioxidant cascade and decreasing the nickel concentration in blood and kidney. All these changes were supported by histopathological observations. These findings demonstrate that naringin exerts a protective effect against nickel toxicity.     

Cytosolic factors which affect microsomal lipid peroxidation in lung and liver

Studies were carried out to determine the effects of lung and liver cytosol on pulmonary and hepatic mierosomal lipid peroxidation, to determine the cytosolic concentrations of various substances which affect lipid peroxidation, and to determine which of these substances is responsible for the effects of the cytosol on lipid peroxidation. Lung cytosol inhibits both enzymatic (NADPH-induced) and nonenzymatic (Fe²⁺-induced) lung microsomal lipid peroxidation. In contrast, liver cytosol stimulates lipid peroxidation in hepatic microsomes during incubation alone, enhances Fe²⁺-stimulated lipid peroxidation, and has no effect on the NADPH-induced response. Substances which are known to be involved in inhibition of lipid peroxidation, including glutathione, glutathione reductase, glutathione peroxidase, and superoxide dismutase, are found in greater concentrations in liver cytosol than in lung cytosol. However, ascorbate is found in approximately equal concentrations in pulmonary and hepatic cytosol. Most of the effects of the cytosol on lipid peroxidation seem to be due to ascorbate and glutathione. For example, ascorbate, in concentrations found in lung cytosol, inhibits lung microsomal lipid peroxidation to about the same extent as the cytosol. The effects of liver cytosol on hepatic microsomal lipid peroxidation can be duplicated by concentrations of ascorbate and glutathione normally found in the cytosol; i.e., ascorbate stimulates and glutathione inhibits lipid peroxidation with the net effect being similar to that of liver cytosol. The results indicate that ascorbate has opposite effects on pulmonary and hepatic microsomal lipid peroxidation and suggest that ascorbate plays a major role in protecting pulmonary tissue against the harmful effects of lipid peroxidation.     

Enhancement of lipid peroxidation in rat liver on acute exposure to styrene and acrylamide a consequence of glutathione depletion

Lipid peroxidation, glutathione level and activity of glutathione-S-transferase were studied in liver and brain of rats 4 and 3 h after a single i.p. administration of 0, 25, 75, 100 mg/kg acrylamide or 0, 50, 100, 200, 600 mg/kg styrene, respectively. In liver both acrylamide and styrene caused an increase in lipid peroxidation and decrease in glutathione contents and activity of glutathione-S-transferase in a dose dependent manner, while in brain only acrylamide produced a decrease in glutathione content. The decrease in glutathione content was not always associated with increase of lipid peroxidation. The enhancement of lipid peroxidation occurred only when glutathione contents were depleted to certain critical levels. No effect of acrylamide or styrene was seen on lipid peroxidation under in vitro conditions. The addition of glutathione in the incubation mixture significantly inhibited the rate of lipid peroxidation of liver homogenates of acrylamide and styrene treated animals.The results suggest that enhancement of lipid peroxidation in liver on exposure to acrylamide or styrene is a consequence of depletion of glutathione to certain critical levels. The inhibition of glutathione-S-transferase activity by acrylamide and styrene suggests that detoxication of these neurotoxic compounds could be suppressed following acute exposure.     

Cisplatin induced nephrotoxicity and the modulating effect of glutathione ester

The objective of this study was to assess the therapeutic advantage of glutathione ester along with cisplatin. Comparisons were made with renal reduced glutathione, enzymatic antioxidants, and lipid peroxidation levels. Cisplatin caused differential toxic effects on renal antioxidants and lipid peroxidation. However administration of glutathione ester modulates the toxic effects of cisplatin observed in renal antioxidants and lipid peroxidation. The finding that glutathione ester co-administration along with cisplatin is more effective and advantageous in protecting against the nephrotoxicity of cisplatin when it was given alone.     

Antioxidative-related enzyme activity in Alyssum markgrafii shoot cultures as affected by nickel level

Shoot cultures of rare Balkan hyperaccumulating species Alyssum markgrafii were subjected to high nickel concentrations of 1, 3, 5, and 8?mM. The effects of graded nickel concentrations on toxicity, pigments, and several components of plant antioxidative defense system were characterized. Toxic effects of excess nickel were observed through slower growth and biomass decrease, together with increased reactive oxygen species (ROS) production and lipid peroxidation. Nickel exposure decreased chlorophyll a, b, total chlorophyll as well as carotenoid concentration. Addition of sodium benzoate, potent ROS scavenger, showed concentration-dependent disturbing effect on nickel hyperaccumulation, lowering the content of accumulated nickel in A. markgrafii shoots. General reducing power represented by low molecular weight antioxidants and phenols was inversely correlated with nickel concentration. Among the investigated antioxidative enzymes, POD seems to play important role in ROS level regulation upon excessive nickel in medium.     

Lipid peroxidation in higher plants : the role of glutathione reductase

To study the role of glutathione reductase in lipid peroxidation, bean leaves (Phaseolus vulgaris) cv Fori were treated with the herbicide acifluorfen-sodium (sodium 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid). Acifluorfen is a potent inducer of lipid peroxidation. In beans, decrease of acid-soluble SH-compounds and lipid peroxidation, measured as ethane evolution, were the toxic events after treatment of leaves with acifluorfen. As a primary response to peroxidation, increased production of antioxidants, such as vitamin C and glutathione, was found. This was followed by elevation of glutathione reductase activity. Enhanced activity of the enzyme prevented both further decline of acid-soluble SH-compounds and lipid peroxidation. Increased production of antioxidants and elevated activity of antioxidative enzymes, like glutathione reductase, seem to be a general strategy to limit toxic peroxidation in plants.     

Effect of thiols on lipid peroxidation in rat liver microsomes

The stimulatory or inhibitory effects of various thiol compounds on in vitro lipid peroxidation by iron-ascorbate in rat liver microsomes were determined. Glutathione had no measurable pro-oxidant capacity, in contrast, it protected against lipid peroxidation. N-Acetyl l-cysteine and S-methyl-glutathione had no effect on in vitro lipid peroxidation. l-Cysteine stimulated lipid peroxidation and also of d-penicillamine and dl-dithiothreitol the pre-oxidant capacity predominated the anti-oxidant capacity. Cysteamine afforded a pronounced protection against in vitro lipid peroxidation. In contrast to the labile character of the glutathione dependent protection, the protection by cysteamine was not affected by heat-pretreatment of the liver microsomes or alkylating protein sulfhydryl groups by N-ethyl maleimide. Again in contrast to glutathione, the protection against in vitro microsomal lipid peroxidation by cysteamine was not reduced after in vivo lipid peroxidation induced by CC14. This suggests that even after the process of lipid peroxidation has been started, administration of cysteamine might still be beneficial.     

Efficacy of caffeic acid in preventing nickel induced oxidative damage in liver of rats

Nickel (Ni), a major environmental pollutant, is known for its wide toxic manifestations. In the present study caffeic acid (CA), one of the most commonly occurring phenolic acids in fruits, grains and dietary supplements, was evaluated for its protective effect against the Ni induced oxidative damage in liver. In this investigation, Ni (20 mg/kg body weight) was administered intraperitoneally for 20 days to induce toxicity. CA was administered orally (15, 30 and 60 mg/kg body weight) for 20 days with intraperitoneal administration of Ni. Ni induced liver damage was clearly shown by the increased activities of serum hepatic enzymes namely aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) along with increased elevation of lipid peroxidation indices (thiobarbituric reactive acid substances (TBARS) and lipid hydroperoxides). The toxic effect of Ni was also indicated by significantly decreased levels of enzymatic (superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx) and glutathione S-transferase (GST)) and non-enzymatic antioxidants (glutathione (GSH), vitamin C and vitamin E). CA administered at a dose of 60 mg/kg body weight significantly reversed the activities of hepatic marker enzymes to their near normal levels when compared with other two doses. In addition, CA significantly reduced lipid peroxidation and restored the levels of antioxidant defense in the liver. All these changes were supported by histological observations. The results indicate that CA may be beneficial in ameliorating the Ni induced oxidative damage in the liver of rats.     

Modulation of radiation-induced alteration in the antioxidant status of mice by naringin

The alteration in the antioxidant status and lipid peroxidation was investigated in Swiss albino mice treated with 2 mg/kg b.wt. naringin, a citrus flavoglycoside, before exposure to 0.5, 1, 2, 3, and 4 Gy gamma radiation. Lipid peroxidation, glutathione, glutathione peroxidase, catalase and superoxide dismutase were determined in the liver and small intestine of mice treated or not with naringin at 0.5, 1, 2, 4 and 8 h post-irradiation. Whole-body irradiation of mice caused a dose-dependent elevation in the lipid peroxidation while a dose-dependent depletion was observed for glutathione, glutathione peroxidase, superoxide dismutase and catalase in both liver as well as small intestine. Treatment of mice with 2 mg/kg b. wt. naringin inhibited the radiation-induced elevation in the lipid peroxidation as well as depletion of glutathione, glutathione peroxidase, superoxide dismutase and catalase in liver and small intestine. Radiation-induced lipid peroxidation increased with time, which was greatest at 2 h post-irradiation and declined thereafter in the liver and small intestine. Similarly, a maximum decline in the glutathione glutathione peroxidase, and superoxide dismutase was observed at 1 h, while catalase showed a maximum decline at 2 h post-irradiation. Our study demonstrates that naringin protects mouse liver and intestine against the radiation-induced damage by elevating the antioxidant status and reducing the lipid peroxidation.     

Lipid peroxidation and haemoglobin degradation in red blood cells exposed to t-butyl hydroperoxide. Effects of the hexose monophosphate shunt as mediated by glutathione and ascorbate.

Lipid peroxidation and haemoglobin degradation were the two extremes of a spectrum of oxidative damage in red cells exposed to t-butyl hydroperoxide. The exact position in this spectrum depended on the availability of glucose and the ligand state of haemoglobin. In red cells containing oxy- or carbonmono-oxy-haemoglobin, hexose monophosphate-shunt activity was mainly responsible for metabolism of t-butyl hydroperoxide; haem groups were the main scavengers in red cells containing methaemoglobin. Glutathione, via glutathione peroxidase, accounted for nearly all of the hydroperoxide metabolizing activity of the hexose monophosphate shunt. Glucose protection against lipid peroxidation was almost entirely mediated by glutathione, whereas glucose protection of haemoglobin was only partly mediated by glutathione. Physiological concentrations of intracellular or extracellular ascorbate had no effect on consumption of t-butyl hydroperoxide or oxidation of haemoglobin. Ascorbate was mainly involved in scavenging chain-propagating species involved in lipid peroxidation. The protective effect of intracellular ascorbate against lipid peroxidation was about 100% glucose-dependent and about 50% glutathione-dependent. Extracellular ascorbate functioned largely without a requirement for glucose metabolism, although some synergistic effects between extracellular ascorbate and glutathione were observed. Lipid peroxidation was not dependent on the rate or completion of t-butyl hydroperoxide consumption but rather on the route of consumption. Lipid peroxidation appears to depend on the balance between the presence of initiators of lipid peroxidation (oxyhaemoglobin and low concentrations of methaemoglobin) and terminators of lipid peroxidation (glutathione, ascorbate, high concentrations of methaemoglobin).     

Age-related peculiarities of antioxidant system functioning in the blood of ostriches

The intensity of lipid peroxidation, activity of some enzymes antioxidant system - superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, amount of recovered glutathione and ceruloplasmin in the blood serum of ostriches in a period from 6- to 60-month age were first investigated. The increase of concentration of lipid peroxidation products is accompanied by the decline of amount of general lipids in the ostriches blood. Every life cycle period of ostriches is characterized by the indexes of functioning of the antioxidant system and intensity of accumulation intermediate lipid peroxidation products inherent in it. The pubescence period and intensive oviposition are characterized by the increase of products lipid peroxidation concentration and decrease of antioxidant enzymes activity, which can testify to the exhaustion of protective possibilities of enzymatic link of antioxidant defence.     

Glutathione, lipid peroxidation and regulation of cytochrome P-450 activity

Depletion of hepatic glutathione leads to an increase in lipid peroxidation and depression of cytochrome P-450-catalyzed metabolism of the azo dye carcinogen, N,N-dimethyl-4-aminoazobenzene. This contributes to the marked decrease in biliary excretion of N-demethylated metabolites of the dye. Parallel time courses are seen for decreased hepatic glutathione, enhanced lipid peroxidation and depressed excretion of dye metabolites. In vitro metabolism of DAB by hepatic 10,000 g supernatant fractions is depressed by iron only after glutathione depletion. In view of the iron requirement for microsomal lipid peroxidation, it is proposed that glutathione depletion leads to an increase in the intracellular iron available for activation of lipid peroxidation. In this way, glutathione may contribute to the regulation of cytochrome P-450 activity.     

Acorus calamus extracts and nickel chloride: prevention of oxidative damage and hyperproliferation response in rat kidney

Nickel, a major environmental pollutant, is known for its clastogenic, toxic, and carcinogenic potential. In this article, we report the effect of Acorus calamus on nickel chloride (NiCl2)-induced renal oxidative stress, toxicity, and cell proliferation response in male Wistar rats. NiCl2 (250 micromol/kg body weight/mL) enhanced reduced renal glutathione content (GSH), glutathione- S-transferase (GST), glutathione reductase (GR), lipid peroxidation (LPO), H2O2 generation, blood urea nitrogen (BUN), and serum creatinine with a concomitant decrease in the activity of glutathione peroxidase (GPx) (p < 0.001). NiCl2 administration also dose-dependently induced the renal ornithine decarboxylase (ODC) activity several-fold as compared to salinetreated control rats. Similarly, renal DNA synthesis, which is measured in terms of [3H] thymidine incorporation in DNA, was elevated following NiCl2 treatment. Prophylactic treatment of rats with A. calamus (100 and 200 mg/kg body weight po) daily for 1 wk resulted in the diminution of NiCl2- mediated damage, as evident from the downregulation of glutathione content, GST, GR, LPO, H2O2 generation, BUN, serum creatinine, DNA synthesis (p < 0.001), and ODC activity (p < 0.01) with concomitant restoration of GPx activity. These results clearly demonstrate the role of oxidative stress and its relation to renal disfunctioning and suggest a protective effect of A. calamus on NiCl2-induced nephrotoxicity in a rat experimental model.