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PubMed1989

Trypanothione reductase from Trypanosoma cruzi. Catalytic properties of the enzyme and inhibition studies with trypanocidal compounds.

Trypanothione reductase of Trypanosoma cruzi is a key enzyme in the antioxidant metabolism of the parasite. Here we report on the enzymic and pharmacological properties of trypanothione reductase using glutathionylspermidine disulfide as a substrate. 1. Both pH optimum (7.5) and the ionic strength optimum (at 30 mM) are unusually narrow for this enzyme. 40 mM Hepes, 1 mM EDTA, pH 7.5 was chosen as a standard assay buffer because in this system the kcat/Km ratio had the highest values for both natural substrates, glutathionylspermidine disulfide (2.65 x 10(6) M-1 s-1) and trypanothione disulfide (4.63 x 10(6) M-1 s-1). 2. Using the standardized assay, trypanothione reductase and the phylogenetically related host enzyme, human glutathione reductase, were studied as targets of inhibitors. Both enzymes, in their NADPH-reduced forms, were irreversibly modified by the cytostatic agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Nifurtimox, the drug used in the treatment of Chagas' disease, is a stronger inhibitor of glutathione reductase (Ki = 40 microM) than of trypanothione reductase (IC50 = 200 microM). 3. Of the newly synthesized trypanocidal compounds [Henderson, G. B., Ulrich, P., Fairlamb, A. H., Rosenberg, I., Pereira, M., Sela, M. & Cerami, A. (1988) Proc. Natl Acad. Sci., 85, 5374-5378] a nitrofuran derivative, 2-(5-nitro-2-furanylmethylidene)-N,N'-[1,4-piperazinediylbis (1,3-propanediyl)]bishydrazinecarboximidamide tetrahydrobromide, was found to be a better inhibitor for trypanothione reductase (Ki = 0.5 microM) than for glutathione reductase (IC50 = 10 microM). A naphthoquinone derivative, 2,3-bis[3-(2-amidinohydrazono)-butyl]-1,4-naphthoquinone dihydrochloride, turned out to be both an inhibitor (IC50 = 1 microM) and an NADPH-oxidation-inducing substrate (Km = 14 microM). This effect was not observed with human glutathione reductase. Such compounds which lead to oxidative stress by more than one mechanism in the parasite are promising starting points for drug design based on the three-dimensional structures of glutathione and trypanothione reductases.

Animals↗

PubMed1998

Trace metals and variations of antioxidant enzymes in Arctic bivalve populations.

In the framework of an INTAS project, arctic populations of the clam Macoma balthica were collected from seven stations (Mezen, Khaypudyr, Pechora 3, Pechora 5, Dvina, Keret 1, and Keret 2) in the White Sea and Pechora Sea. The main objectives of this research were to define baseline concentrations of trace metals (As, Cd, Cr, Cu, Fe, Mn, Pb, Zn) in M. balthica and to evaluate antioxidant responses as biomarkers of anthropogenic stress in these organisms. The antioxidant parameters examined included the levels of glutathione and the activities of several glutathione-dependent and antioxidant enzymes: glyoxalase I and glyoxalase II (EC 4.4.1.5 and EC 3.1.2.6), glutathione S-transferases (EC 2.5.1.18), glutathione reductase (EC 1.6.4.2), glutathione peroxidases (EC1.11.1.9 and EC 2.5.1.18, respectively, for Se-dependent and Se-independent forms), superoxide dismutase (SOD, EC 1.15.1.1), and catalase (EC 1.11.1.6). Organisms revealed enhanced concentrations of lead in both Keret stations, Khaypudyr, and Mezen, and high levels of copper in Keret and cadmium in Khaypudyr. At the biochemical level, organisms from Pechora 3, Pechora 5, and Dvina were not statistically different, whereas those from Mezen and Khaypudyr exhibited higher activities of superoxide dismutase, glutathione peroxidase, and glyoxalase II. Catalase levels were lower in Mezen and Khaypudyr. More heterogeneous were the responses of glyoxalase I and glutathione S-transferases, while no significant differences among the stations were observed for glutathione reductase. Multiple regression analyses revealed significant positive relationships between the main antioxidant enzymes (glutathione peroxidases, superoxide dismutase, glyoxalase I, and glyoxalase II), and confirmed the exception of catalase, which, when significant, was negatively correlated with the other parameters. The results support the suitability of antioxidant responses as biomarkers of pollutant exposure and/or toxicity for arctic biomonitoring programs even though only moderately polluted sites were sampled.

Alkyl and Aryl Transferases↗

PubMed1992

Effects of organophosphorus insecticide phosphomidon on antioxidant defence components of human erythrocyte and plasma.

Effect of organophosphorus insecticide, phosphomidon (250 and 500 ppm) on human erythrocyte and plasma were studied in vitro to get insight into the cellular antioxidant defence mechanism and malondialdehyde formation. The antioxidant defence system of erythrocyte was altered as evident by depression of glutathione reductase, glucose 6 phosphate dehydrogenase, whereas the level of reduced glutathione, glutathione peroxidase, glutathione-S-transferase, superoxidedismutase and catalase were stimulated. In the case of plasma fraction, glutathione reductase, glutathione peroxidase, glutathione-s-transferase, glucose-6-phosphate dehydrogenase, superoxide dismutase and levels of reduced glutathione were significantly depressed and the malondialdehyde formation and catalase activity were elevated indicating the less adaptive response of plasma to protect it from oxidative damage.

Adult↗

PubMed1978

Assimilatory sulfate reduction in an Escherichia coli mutant lacking thioredoxin activity.

An investigation of sulfate reduction in B tsnC*7004, a mutant of Escherichia coli lacking thioredoxin, is reported. Although thioredoxin is indispensable for the adenosine 3'-phosphate 5'-phosphosulfate (PAPS) sulfotransferase reaction under the usual conditions of assay in extracts of wild-type cells, the mutant grew as well as the wild type on sulfate, indicating that sulfate reduction is not rate limiting for growth. Another cofactor for the PAPS sulfotransferase reaction was found in extracts of the mutant that is absent from wild type cells. This cofactor was indistinguishable from thioredoxin in molecular weight but had a slightly different isoelectric point, allowing a separation of the two types of molecules by isoelectric focusing. Whereas electrons from nicotinamide adenine dinucleotide phosphate, reduced form, could be transferred via thioredoxin reductase or via glutathione and glutathione reductase to reduce thioredoxin in extracts of wild-type cells, electrons from nicotinamide adenine dinucleotide, reduced form, could only be transferred to the cofactor of the mutant via glutathione and glutathione reductase. All of the other available mutants blocked in sulfate reduction in E. coli contained normal levels of thioredoxin. The "PAPS reductase" mutant is shown to be blocked in the PAPS sulfotransferase reaction. We conclude that the cofactor found in mutant B tsnC*7004 is probably a mutated thioredoxin with an amino acid substitution that alters the isoelectric point and the reactivity with thioredoxin reductase.

Bacterial Proteins↗

PubMed2004

Modulation of the redox state of tubulin by the glutathione/glutaredoxin reductase system.

Alterations in the redox status of proteins have been implicated in the pathology of several neurodegenerative diseases. We report that peroxynitrite-induced disulfides in porcine brain tubulin are repaired by the glutaredoxin reductase system composed of glutathione reductase, human or Escherichia coli glutaredoxin, reduced glutathione, and NADPH. Reduction of disulfide bonds between the alpha- and beta-tubulin subunits by the glutathione reductase system was assessed by Western blot. Tubulin cysteine oxidation and reduction was quantitated by monitoring the incorporation of 5-iodoacetamido-fluorescein, a thiol-specific labeling reagent. Tubulin disulfide bond reduction by the glutaredoxin reductase system restored tubulin polymerization activity that was lost following peroxynitrite addition. In support of redox modulations of tubulin by glutathione, thiol-disulfide exchange between tubulin and oxidized glutathione was detected and quantitated by HPLC. In addition, glutathionylation of tubulin was detected by dot blot using an anti-GSH antibody.

Animals↗

PubMed2001

Effect of methoxychlor on antioxidant system of goat epididymal sperm in vitro.

AIM: To evaluate the effect of methoxychlor on the antioxidant system of goat epididymal sperm. METHODS: Epididymis of adult goat was obtained from local slaughter houses and sperm were collected by chopping the epididymis in modified Ringer' s phosphate solution (RPS). After several washings, the sperm samples were dispersed in RPS and incubated with methoxychlor (1 micromol/L, 10 micromol/L and 100 micromol/L) and methoxychlor + vitamin C (100 micromol/L each) for 3 h at 32 degrees C. After incubation, the sperm motility and viability were assessed. An aliquot of sperm sample was homogenized, centrifuged and used for the assay of superoxide dismutase, glutathione peroxidase, glutathione reductase and lipid peroxidation. RESULTS: In methoxychlor-incubated sperm and in sperm co-incubated with methoxychlor and vitamin C, the sperm motility and viability showed no significant changes as compared to the corresponding controls. In methoxychlor-incubated sperm the activity of superoxide dismutase, glutathione reductase and glutathione peroxidase were decreased while lipid peroxidation was increased in a dose-dependent manner. Co-incubation of sperm with methoxychlor and vitamin C showed no changes in the activity of superoxide dismutase, glutathione reductase and glutathione peroxidase and in the level of lipid peroxidation. CONCLUSION: Methoxychlor induced oxidative stress in epididymal sperm of goats by decreasing the levels of antioxidant enzymes. Co-incubation of sperm with methoxychlor and vitamin C, a natural antioxidant, reversed the effect of methoxychlor.

Animals↗

PubMed1992

Rat colonic antioxidant status: interaction of dietary fats with 1,2-dimethylhydrazine challenge.

The polyunsaturated fatty acid composition of dietary fat has been associated with increased oxidant stress in tissues. We previously showed that antioxidant mechanisms in colon mucosa are affected by dietary fat. In this study, the colonic antioxidant response to treatment with the colon-specific carcinogen 1,2-dimethylhydrazine (DMH) was determined. Sprague-Dawley rats were fed one of four AIN-76A-based diets with varied fat content. The basal diet contained 5% corn oil, the menhaden oil diet contained 19% menhaden oil and 1% corn oil, the corn oil diet contained 20% corn oil and the beef tallow diet contained 19% beef tallow and 1% corn oil. Animals were given one or two intraperitoneal injections of either DMH (20 mg/kg) or 1 mmol/L EDTA. Homogenates of colon mucosa were assayed to determine activity of catalase, glutathione peroxidase, total superoxide dismutase, manganese superoxide dismutase, glutathione reductase and glutathione-S-transferase, as well as total glutathione concentration, thiobarbituric acid-reacting substances and nuclear aberrations. Total glutathione concentration was greater in rats fed all diets following two injections of DMH, whereas glutathione reductase activity remained unchanged relative to controls. Lipid peroxidation was highest in the group fed menhaden oil; nuclear aberrations were greatest in the corn oil-fed group. In conclusion, both type and amount of dietary fat modified the response of colon tissue to genotoxic challenge, but none of the diets seemed more protective than the others.

1,2-Dimethylhydrazine↗

PubMed1994

Modifications of the anti-oxidant metabolism during proliferation and differentiation of colon tumor cell lines.

The anti-oxidant metabolism was studied at different times after sub-culture in 2 colon cell lines previously characterized for their growth and differentiation properties. The HT29 cell line is mainly composed of proliferative and undifferentiative cells, while the derived 5-fluorouracil (FUra)-adapted cells undergo growth-dependent differentiation, which is complete at post-confluence. In the 2 cell lines, all the anti-oxidant parameters studied appeared to be related to proliferation, with increased activity of superoxide dismutase (SOD) 1 and 2, catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GSR), and glutathione transferase (GST), and decreased glucose-6-phosphate dehydrogenase (G6PD) activity and glutathione content, in parallel with slowing down of proliferation. At post-confluence, these metabolic parameters remained stable, except for GPX activity, which continued to increase, and CAT activity, which decreased. The amounts of SOD1, SOD2 and CAT immunoreactive proteins, estimated by Western blotting, appeared to be correlated to their respective enzymatic activities. SOD1, CAT and GST activity and glutathione content, which remained at similar levels in the 2 cell lines for all times studied, appeared unrelated to the differentiation process. GSR and GPX activity, which was lower in FUra-adapted than in parental cells only at post-confluence, could be considered as markers of differentiated cells. The higher SOD2 and lower G6PD activity observed in FUra-resistant cell in comparison with parental cells at all times after sub-culture could be characteristic both of differentiative and of differentiated cells. Interestingly, cytogenetics have previously indicated that deletions of the long arm of chromosome 6, which carry the gene for SOD2, were frequently observed in parental but not in FUra-adapted cells. These results demonstrate that modifications of the anti-oxidant metabolism occur in relation with proliferation and differentiation, and suggest a particular role for SOD2 in these cellular processes.

Antioxidants↗

PubMed1995

Plasmodium berghei: implication of intracellular glutathione and its related enzyme in chloroquine resistance in vivo.

Glutathione (GSH) plays a critical role in the detoxication and the protection of cells against oxidative stress. In the present study we examined the relationship between the intracellular GSH levels as well as glutathione S-transferase (GST), glutathione reductase (GR), and glutathione peroxidase (GPx) activities and how they relate to Plasmodium berghei resistance to chloroquine. Resistant strains (CQR30 and CQR60) were selected in vivo from a sensitive strain (NK65). Marked increases in GSH levels and GST activity within resistant parasites were observed, compared to sensitive parasites. On the other hand, GR and GPx activities were similar in sensitive and resistant parasites. Treatment with chloroquine did not influence the intracellular level of GSH, but it was found to significantly decrease GR activity. Intracellular depletion of GSH, by a nontoxic concentration of buthionine sulfoximine (BSO), significantly sensitized the resistant parasites to chloroquine. These results suggest that the P. berghei resistance results from altered GSH and GST levels and activity, respectively, which enable the detoxification of chloroquine in resistant parasites.

Animals↗

PubMed2005

Role of selenium on antioxidant capacity in methomyl-treated mice.

Methomyl carbamate is a pesticide widely used in the control of insects. The present work aims at studying the effect of selenium on the antioxidant system of methomyl-treated mice. Swiss albino mice were intraperitoneally administered a single dose of methomyl (7 mg/Kg body weight). Mice of another group were injected with sodium selenite (5 pmole/Kg b.wt.) 7 days before methomyl intoxication. After 24 hours, methomyl exposure resulted in significant increase in lactic dehydrogenase activity (LDH). The antioxidant capacity of hepatic cells in terms of the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione-S-transferase (GST) and glutathione (GSH) content was diminished. It appears that methomyl exerts its toxic effect via peroxidative damage to hepatic, renal and splenic cell membranes. Also, methomyl induced DNA damage in these organs as detected by alkaline filter elution technique. The distribution of methomyl in different organs of mice was detected by HPLC. Selenium administration prior to methomyl injection produced pronounced protective action against methomyl effects. It is observed that selenium enhances the endogenous antioxidant capacity of the cells by increasing the activities of SOD, CAT, GR and GST as well as increasing GSH content. The activity of LDH was decreased in blood and the damage of DNA was suppressed comparable to controls. In conclusion, the adverse effects of methomyl in mice could be ameliorated by selenium.

Animals↗

PubMed2005

Modulatory effect of cadmium exposure on deltamethrin-induced oxidative stress in Channa punctata Bloch.

The modulatory effect of cadmium pretreatment (0.2 mg/kg b.w. i.p.) on deltamethrin-induced oxidative stress and alterations of antioxidants was studied in freshwater fish Channa punctata Bloch. Lipid peroxidation (LPO) was measured as one of the indicators of oxidative stress. Activities of glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were also studied in liver, kidney, and gills. Levels of reduced glutathione (GSH) were measured in various tissues. Fish pretreated with cadmium and subsequently exposed to deltamethrin showed significantly reduced LPO values when compared with deltamethrin-exposed fish. Conversely, in the kidney, a potentiation response was observed. Deltamethrin exposure in fish resulted in significant alteration in activities of glutathione-dependent antioxidant enzymes. In the cadmium preexposed fish, which were subsequently exposed to deltamethrin, antioxidant enzymes showed a tendency toward normalization over deltamethrin-only exposed fish in liver and gills. GSH also showed a similar pattern in liver and gills but in kidney it remained elevated. Cadmium alone had no significant effect on various parameters at the concentration used in this study. When metallothionein (MT) induction was studied, only liver showed an MT-like protein band in sodium dodecylsulfate-polyacrylamide gel electrophoresis analysis. These results demonstrate a modulatory role of cadmium on the oxidative stress and other related parameters in liver and gills. These findings are important in the context of exposure to a mixture of pollutants in aquatic environment.

Animals↗

PubMed1996

Studies on the effects of monosodium glutamate (MSG) on oxidative stress in erythrocytes of adult male mice.

Subcutaneous administration of monosodium glutamate (MSG) to normal adult male mice for 6 days at dose levels of 4 and 8 mg/g body weight caused a significant increase in erythrocyte glucose content accompanied by increased lipid peroxidation. The levels of total glutathione and protein-bound glutathione were significantly increased in the erythrocytes, whereas non-protein glutathione was significantly decreased. The administration of 4 and 8 mg/g body weight of MSG significantly increased the activities of glutathione reductase (GR), glutathione-S-transferase (GST) and glutathione peroxidase (GPX). It was observed that MSG, above 4 mg/g body weight, produced oxidative stress which was counteracted by the body by maintaining the level of glutathione, which was done by increasing the activity of its metabolizing enzymes.

Animals↗

PubMed2005

Changes in activities of superoxide dismutase, nitric oxide synthase, glutathione-dependent enzymes and the incidence of apoptosis in sheep corpus luteum during the estrous cycle.

Anti-oxidative enzymes play a role in protecting cells from oxidative stress-induced cell death. The present study was conducted to evaluate whether the anti-oxidant and pro-oxidant enzymatic capacities of the sheep corpus luteum (CL) are correlated with steroidogenic and structural status of the gland during the estrous cycle. Steroidogenic activity, apoptosis and superoxide dismutase (SOD1 and SOD2), nitric oxide synthase (NOS), glutathione peroxidase (GPX), glutathione reductase (GSR) and glutathione S-transferase (GST) activities were determined in the CL at specific developmental stages of the luteal phase. The intensity of apoptotic DNA fragmentation, characteristic of physiological cell death, was much greater in CL at late luteal phase than at early and mid-luteal phase, concomitantly with the diminution in the plasma progesterone concentrations from mid-to late luteal phase. SOD1 and GPX activities increased from early to mid-luteal phase, and increased further at late luteal phase. SOD2 and GST activities were not different between early and mid-luteal phase, but increased at late luteal phase. GSR activity was not different between any luteal phase examined. NOS activity decreased from early to mid- and late luteal phase. These results show that the activities of SOD1, SOD2, NOS, GPX, GSR and GST in the sheep CL are subject to major changes during the estrous cycle, and that the anti-oxidant and pro-oxidant enzymatic capacities of luteal cells are not correlated with cell steroidogenic status and integrity during the late luteal phase.

Animals↗

PubMed2005

Lipid peroxidation and antioxidant enzymes in synovial fluid of patients with primary and secondary osteoarthritis of the knee joint.

OBJECTIVE: Osteoarthritis of the knee (KOA) is a common, age-related, joint disorder associated with loss of articular cartilage, osteophyte formation, sub-chodral bone change and synovitis. Recent studies have shown that reactive oxygen species (ROS) may participate in the initiation and progression of KOA. This study examines potential changes in the activities of antioxidant enzymes (superoxide dismutase, both isoenzymes zinc-copper superoxide dismutase and manganese superoxide dismutase) and glutathione transformation enzymes (glutathione peroxidase, glutathione reductase and glutathione-S-transferase) in synovial fluid of KOA patients, and estimates their relationship to the degree of lipid peroxidation in synovial fluid evaluated by malondialdehyde concentration, synovial fluid viscosity, type and duration of KOA. DESIGN: Synovial fluid samples obtained by transdermal arthrocentesis from 41 patients with KOA (23 had primary KOA and 18 had secondary KOA) and 22 control subjects were analyzed. Activities of antioxidant enzymes were analysed with the use of kinetic method, MDA concentration was measured fluorometrically by the Ohkawa method, and synovial fluid viscosity was measured using a cone-late viscometer Brookfield DV-II+ and a test by Ropes. RESULTS: Patients with KOA had significantly increased activities of all enzymes when compared to the control subjects for both KOA subgroups. The synovial fluid viscosity was significantly decreased and the synovial fluid test by Ropes was abnormal in KOA patients, mainly in the secondary KOA subgroup. The activities of all antioxidant enzymes were significantly negatively correlated with synovial fluid viscosity and duration of KOA. CONCLUSIONS: Patients with KOA display abnormal antioxidant status of synovial fluid with increased activities of antioxidant enzymes and decreased synovial fluid viscosity. Furthermore, synovial fluid viscosity, and activity of GR can be used to distinguish the primary from the secondary type of KOA.

Adult↗

PubMed1998

Effect of propofol on oxidative stress in an in vitro model of anoxia-reoxygenation in the rat brain.

Propofol, an intravenous anaesthetic, is similar in chemical structure to the active nucleus of antioxidant substances such as alpha-tocopherol (vitamin E). The present study was designed to test whether propofol had antioxidant effects in an in vitro model of anoxia-reoxygenation in slices of rat brain. We used seven experimental groups: (1) control oxygenated tissue; (2) tissue subjected to anoxia for 20 min and reoxygenation for 3 h; and tissues processed as described and incubated with (3) Intralipid (commercial solvent for propofol), or propofol at a concentration of (4) 10 micromol/l, (5) 50 micromol/l, (6) 150 micromol/l or (7) 300 micromol/l. The production of lipid peroxides was quantified as thiobarbituric acid reactive substances (TBARS); tissular glutathione production and the activities of glutathione peroxidase (GSHpx), glutathione reductase (GSSGrd) and glutathione transferase (GSHtf) were also measured. Reoxygenation led to tissular oxidative stress, which was curtailed by propofol. The anaesthetic led to a 47% reduction in TBARS, a 165% increase in the reperfusion-inhibiting glutathione content, a 47% decrease in GSHpx activity, and an 87% increase in GSHtf activity. Intralipid had no effect on any of the parameters studied here. We conclude that propofol has a clear antioxidant effect in rat brain tissue subjected to anoxia-reoxygenation.

Animals↗

PubMed2003

Chronic cold exposure affects the antioxidant defense system in various rat tissues.

BACKGROUND: Chronic exposure to stress alters the normal body homeostasis and, hence, leads to the development of various human pathologies, which might involve alterations in the antioxidant defense system. We studied the effect of chronic cold exposure on oxidative stress and antioxidant defense system in various rat tissues. METHODS: Male albino rats (Wistar strain), 2-3 months old, were exposed to 3 weeks of cold treatment. Antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) were measured in addition to the antioxidants, ascorbic acid (AsA) and glutathione (GSH), and the prooxidants, lipid peroxides (LPO) and xanthine oxidase (XOD), in brain, heart, kidney, liver and small intestine using standard protocols. RESULTS: Chronic cold exposure resulted in a significant increase in LPO in all the tissues studied while XOD was increased in the brain and intestine. Total SOD activity was significantly decreased in all the tissues, whereas CAT activity was significantly increased in the kidney and decreased in heart, liver and intestine in the animals exposed to cold. GPx activity was increased only in the brain and intestine of stressed rats. Chronic cold exposure resulted in significant decrease in GR activity in heart, liver and intestine. GST activity was increased (except heart) and GSH was significantly decreased in all the tissues in treated rats. AsA was increased in kidney and intestine but decreased in heart of stressed animals. CONCLUSIONS: The observed changes in the antioxidant defense system are tissue specific, but it is evident that chronic exposure to cold leads to oxidative stress by displacing the prooxidant-antioxidant balance of this defense system by increasing the prooxidants while depleting the antioxidant capacities.

Animals↗

PubMed2001

Biomarkers of exposure and effect in flounder (Platichthys flesus) exposed to sediments of the Adriatic sea.

The modifications of several biomarkers were investigated in flounder (Platichthys flesus) when exposed in the laboratory to sediment samples collected from the Northern Adriatic Sea. Besides clean sand used as a control substrate, fish were exposed to sediments sampled offshore the delta of the Po River, the harbour of Trieste, and from the industrial harbour of Venice (Porto Marghera). After six days of exposure, the enzyme activities ethoxyresorufin-O-deethylase (EROD), UDP glucuronyltransferase (UDPGT), glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx), were assayed in fish liver. In addition, the contents of reduced glutathione (GSH), nonprotein thiols (SH), total sugars and extractable lipids were also determined in hepatic tissue, as well as the number of micronucleated hepatocytes and biliary concentrations of fluorescent aromatic compounds (FAC). Despite some variability within treatment groups, differences among exposed organisms were evident and consistent with known contaminant levels of sampled areas. Microsomal activities (EROD, UD-PGT) and FAC levels were the most sensitive exposure indicators. Variations in the other biomarkers showed only tendencies which although not statistically significant were generally consistent with the contamination pattern.

Animals↗

PubMed2001

Dose response of carboplatin-induced hearing loss in rats: antioxidant defense system.

Carboplatin, a platinum-containing anticancer drug, is currently being used against a variety of cancers. However, a single high dose of carboplatin is ototoxic in cancer patients. This is the first study to show carboplatin-induced hearing loss in a rat model. Male Wistar rats were divided into five groups and treated as follows: (1) control (saline, intraperitoneally (i.p.)); (2) carboplatin (64 mg/kg, i.p.); (3) carboplatin (128 mg/kg i.p.); (4) carboplatin (192 mg/kg, i.p.) and (5) carboplatin (256 mg/kg, i.p.). Animals in all groups were sedated with ketamine/xylazine and auditory brain-evoked responses (ABRs) were recorded before and 4 days after treatments. The animals were sacrificed on the fourth day and cochleae were harvested and analyzed. Carboplatin dose-dependently decreased body weight. However, at higher doses of carboplatin (192 and 256 mg/kg), there was a significant elevation of hearing threshold shifts at clicks, 4, 8, 16 and 32 kHz tone burst stimuli. The higher doses of carboplatin (192 and 256 mg/kg) significantly increased cochlear lipid peroxidation (132 and 146% of control) and depleted cochlear glutathione levels (66 and 63% of control), respectively. The antioxidant enzyme activities such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase (GST) depressed significantly at higher doses of carboplatin. The data suggest that higher doses of carboplatin (above 128 mg/kg) induce hearing loss as evidenced by significant changes in ABRs, lipid peroxidation and antioxidants in the cochlea of rats.

Animals↗