Studies on hepatic oxidative stress and antioxidant defence systems during arteether treatment of Plasmodium yoelii nigeriensis infected mice

Reactive Oxygen species play an important role in pathology during malaria infection. The status of hepatic oxidative stress and antioxidant defence indices was studied during Plasmodium yoelii nigeriensis (P. y. nigeriensis) infection in mice and arteether treatment of P. y. nigeriensis infected mice. P. y. nigeriensis infection caused a significant increase in hepatic xanthine oxidase, rate of lipid peroxidation, reduced glutathione (GSH) and glutathione reductase with progressive rise in parasitemia. This was accompanied by a significant decrease in hepatic superoxide dismutase (SOD) and catalase with increase in parasitemia. Arteether treatment (10 mg/kg body weight of mice) of infected mice from day 2 of post infection resulted in complete clearance of parasitemia on day 4 of post infection which was accompanied by restoration of all the oxidative stress and antioxidant defence indices to normal levels.     

Study on oxidative stress in patients with abdominal trauma

Reactive oxygen species have been implicated in the etiology of multiple organ dyspepsia syndrome and infection's complications in patients with trauma. But the oxidative stress and antioxidants levels in abdominal trauma have not yet been studied. Therefore, this study was planned to measure lipid peroxidation for oxidative stress and reduced glutathione, catalase and superoxide dismutase (SOD) for antioxidant levels in plasma & heamolysate of 30 patients with abdominal trauma and 30 controls. From this study we can summarize that there was an increase in oxidative stress and decrease in antioxidant levels (causing oxidative stress) on day zero in patients with abdominal trauma. This oxidative stress on day zero was not related to the development of complications. There was no significant difference in oxidative stress between patients with solitary and multiple abdominal organ injury and also between patients with hollow viscus injury and solid organ injury on day zero. From this study, we conclude that in patients with abdominal trauma there was increase in oxidative stress and decrease in antioxidant levels on day zero.     

Oxidative damage during chagasic cardiomyopathy development: role of mitochondrial oxidant release and inefficient antioxidant defense

In this study, we evaluated the oxidant status and antioxidant defense capabilities of the heart during the course of Trypanosoma cruzi infection and disease development in a murine model system. Our data show that the extent of protein carbonylation and lipid peroxidation is increased in the heart, but not the skeletal muscle, of infected mice. The level of oxidative injury biomarkers in the myocardium consistently increased with chronic disease severity. The antioxidant defense constituted by catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GSR), and reduced glutathione was increased in murine heart and skeletal tissue in response to the stress of T. cruzi infection. After the initial burst, CAT, GPx, and GSR remained unresponsive to the severity of chronic tissue damage in chagasic hearts. The cardiac level of Mn(2+) superoxide dismutase (MnSOD) was diminished in chagasic mice. Our data suggest that the host responds to acute injuries by activating antioxidant defenses that are of sufficient magnitude to scavenge the reactive oxidants in skeletal tissue. The myocardia of infected mice, however, sustain increased oxidative injuries with disease progression. We surmise that MnSOD deficiencies, resulting in the increased release of mitochondrial free radicals, lead to sustained oxidative stress that exceeds the cardiac antioxidant defense capacity and contribute to persistent oxidative damage in chagasic myocardium.     

Effects of Glutathione Modulation on Oxidative Stress and Enzymatic Antioxidant Defence in Yeast Pachysolen tannophilus

The aim of this study was to explore the relationship of intracellular glutathione with various oxidative stress markers and the stress protectant marker trehalose. In the first group of yeast cells, diethyl maleate was used for depletion of glutathione. A second group of yeast cells were incubated with amino acids constituting glutathione (GIu, Cys, Gly) to increase glutathione level. Increased level of oxidative stress marker like ROS, protein carbonyl formation and lipid peroxidation and decreased viability in glutathione-depleted cells were observed in the present study. The increased activity of antioxidant enzymes SOD and CAT in the glutathione depleted group suggests the interaction of different antioxidant defence system in Pachysolen tannophilus. Furthermore, the increased levels of trehalose in glutathione-depleted group shows that trehalose acts as a stress reducer in glutathione depleted Pachysolen tannophilus.     

Effects of coenzyme Q10 treatment on antioxidant pathways in normal and streptozotocin-induced diabetic rats

Coenzyme Q10 is an endogenous lipid soluble antioxidant. Because oxidant stress may exacerbate some complications of diabetes mellitus, this study investigated the effects of subacute treatment with exogenous coenzyme Q10 (10 mg/kg/day, i.p. for 14 days) on tissue antioxidant defenses in 30-day streptozotocin-induced diabetic Sprague-Dawley rats. Liver, kidney, brain, and heart were assayed for degree of lipid peroxidation, reduced and oxidized glutathione contents, and activities of catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. All tissues from diabetic animals exhibited increased oxidative stress and disturbances in antioxidant defense when compared with normal controls. Treatment with the lipophilic compound coenzyme Q10 reversed diabetic effects on hepatic glutathione peroxidase activity, on renal superoxide dismutase activity, on cardiac lipid peroxidation, and on oxidized glutathione concentration in brain. However, treatment with coenzyme Q10 also exacerbated the increase in cardiac catalase activity, which was already elevated by diabetes, further decreased hepatic glutathione reductase activity, augmented the increase in hepatic lipid peroxidation, and further increased glutathione peroxidase activity in the heart and brain of diabetic animals. Subacute dosing with coenzyme Q10 ameliorated some of the diabetes-induced changes in oxidative stress. However, exacerbation of several diabetes-related effects was also observed.     

Evidence that oxidative stress is increased in patients with X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a hereditary disorder of peroxisomal metabolism biochemically characterized by the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in different tissues and in biological fluids. The disease is clinically characterized by central and peripheral demyelination and adrenal insufficiency, which is closely related to the increased concentrations of these fatty acids. However, the mechanisms underlying the brain damage in X-ALD are poorly known. Considering that free radical generation is involved in various neurodegenerative disorders, like Parkinson disease, multiple sclerosis and Alzheimer's disease, in the present study we evaluated various oxidative stress parameters, namely chemiluminescence, thiobarbituric acid reactive species (TBA-RS), total radical-trapping antioxidant potential (TRAP), and total antioxidant reactivity (TAR) in plasma of X-ALD patients, as well as the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in erythrocytes and fibroblasts from these patients. It was verified a significant increase of plasma chemiluminescence and TBA-RS, reflecting induction of lipid peroxidation, as well as a decrease of plasma TAR, indicating a deficient capacity to rapidly handle an increase of reactive species. We also observed a significant increase of erythrocytes GPx activity and of catalase and SOD activities in fibroblasts from the patients studied. It is therefore proposed that oxidative stress may be involved in pathophysiology of X-ALD.     

Attenuation of TCDD-induced oxidative stress by 670 nm photobiomodulation in developmental chicken kidney

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent developmental teratogen inducing oxidative stress and sublethal changes in multiple organs, provokes developmental renal injuries. In this study, we investigated TCDD-induced biochemical changes and the therapeutic efficacy of photobiomodulation (670 nm; 4 J/cm(2)) on oxidative stress in chicken kidneys during development. Eggs were injected once prior to incubation with TCDD (2 pg/g or 200 pg/g) or sunflower oil vehicle control. Half of the eggs in each dose group were then treated with red light once per day through embryonic day 20 (E20). Upon hatching at E21, the kidneys were collected and assayed for glutathione peroxidase, glutathione reductase, catalase, superoxide dimutase, and glutathione-S-transferase activities, as well as reduced glutathione and ATP levels, and lipid peroxidation. TCDD exposure alone suppressed the activity of the antioxidant enzymes, increased lipid peroxidation, and depleted available ATP. The biochemical indicators of oxidative and energy stress in the kidney were reversed by daily phototherapy, restoring ATP and glutathione contents and increasing antioxidant enzyme activities to control levels. Photobiomodulation also normalized the level of lipid peroxidation increased by TCDD exposure. The results of this study suggest that 670 nm photobiomodulation may be useful as a noninvasive treatment for renal injury resulting from chemically induced cellular oxidative and energy stress.     

Lipid peroxidation and antioxidant defence status during larval development and metamorphosis of giant prawn,Macrobrachium rosenbergii

In the present communication we studied the involvement of reactive oxygen species and alteration in antioxidant defence status during larval development and metamorphosis of giant prawn, Macrobrachium rosenbergii. Overall results indicate that there was a decline in endogenous lipid peroxidation level during larval development. Activity of superoxide dismutase was the lowest in early larval stages (Zoea-I and II) and thereafter increased in V and VI stages, followed by a decrease in the subsequent larval stages. Catalase and glutathione peroxidase did not exhibit specific pattern of changes during development. Reduced glutathione content exhibited an incremental increase during larval progression until metamorphosis. Ascorbic acid content of the larval tissue remained unaltered during development but a sharp fall was marked in its content in the post-larvae. Hence it is concluded that early larvae face high oxidative stress as evident from the high content of thiobarbituric acid reactive substances. This may be due to direct exposure of larvae to ambient oxygen of the water as well as their low antioxidant potential. However, during development with the augmentation in antioxidant reserve of the larval tissues a diminution in the oxidative stress was recorded. Thus it is presumed that antioxidant defences play an important role in providing protection to the developing larvae from oxidative assault during larval progression and metamorphosis.     

Sialic acid and oxidizability of lipid and proteins and antioxidant status in patients with coronary artery disease

The aim of this study was to investigate the possible relationship between serum total sialic acid (TSA) concentration, recently shown to be a cardiovascular risk factor, and lipid and protein oxidation and antioxidant status and the severity of coronary artery disease (CAD) according to the obstructive vessel number in patients. The study was carried out on a total of 200 patients (142 men and 58 women) who were hospitalized for elective coronary angiographic evaluation with complaint of typical angina pectoris. According to the results of angiography, 150 patients had angiographically proven CAD (CAD group) and 50 patients had a history suggestive of angina pectoris but normal coronary angiograms (control group). The CAD group was further divided into single-, double- and triple-vessel disease groups according to the number of vessels involved. Lipid parameters were determined by routine laboratory methods. Plasma malondialdehyde (MDA) and vitamin E concentrations were determined by high-performance liquid chromatography. TSA and other oxidant and antioxidant parameters were studied spectrophotometrically. Our results demonstrated significant increases both in TSA levels and in indicators of oxidative stress in the patients with CAD compared with the controls. However, antioxidant parameters were decreased in the patients with CAD. We found strong positive correlations between TSA and plasma MDA, Delta-MDA which represents the degree of oxidative modification of apolipoprotein B-containing lipoproteins, serum protein carbonyls and apolipoprotein B and weak correlations between TSA and low density lipoprotein cholesterol, triacylglycerol, paraoxonase, glutathione peroxidase (GPx), vitamin C and vitamin E. In conclusion, TSA is related to markers of lipid and protein oxidation, paraoxonase and GPx activities, vitamin C and E levels and the severity of CAD.     

Evaluation of oxidative stress markers in neonates with intra-uterine growth retardation

Intra-uterine growth retardation (IUGR) is an abnormality of pregnancy. Neonates with IUGR weigh less than the 10th percentile for gestational age. The objective of the study was to identify the relationship between IUGR and the antioxidant status. Cord blood of 157 neonates with normal weight (control group) and 29 neonates with IUGR were included. The following parameters were determined and compared in the two groups: lipid peroxidation in the plasma, red blood cells and erythrocyte ghosts; protein and DNA damage; antioxidant enzyme activities (superoxide dismutase, catalase, glutathione peroxidase); the level of reduced glutathione; and the ferric reducing ability of the plasma. The level of lipid peroxidation was significantly higher in the IUGR group. The antioxidant enzyme activities and the levels of antioxidants were significantly lower in the IUGR group. Damage of proteins and DNA was slightly, but non-significantly, higher in the IUGR group. Neonates with IUGR seem to have significant deficiencies in antioxidant defence. IUGR is correlated with significant oxidative stress.     

Chronic hyperhomocysteinemia induces oxidative damage in the rat lung

Tissue accumulation of homocysteine occurs in classical homocystinuria, a metabolic disease characterized biochemically by cystathionine β-synthase deficiency. Vascular manifestations such as myocardial infarction, cerebral thrombosis, hepatic steatosis, and pulmonary embolism are common in this disease and poorly understood. In this study, we investigated the effect of chronic hyperhomocysteinemia on some parameters of oxidative stress (thiobarbituric acid-reactive substances, protein carbonyl content, 2',7'-dichlorofluorescein fluorescence assay, and total radical-trapping antioxidant potent) and activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in the rat lung. Reduced glutathione content and glucose 6-phosphate dehydrogenase activity, as well as nitrite levels, were also evaluated. Wistar rats received daily subcutaneous injections of Hcy (0.3-0.6 μmol/g body weight) from the 6th to the 28th days-of-age and the control group received saline. One and 12 h after the last injection, rats were killed and the lungs collected. Hyperhomocysteinemia increased lipid peroxidation and oxidative damage to protein, and disrupted antioxidant defenses (enzymatic and non-enzymatic) in the lung of rats, characterizing a reliable oxidative stress. In contrast, this amino acid did not alter nitrite levels. Our findings showed a consistent profile of oxidative stress in the lung of rats, elicited by homocysteine, which could explain, at least in part, the mechanisms involved in the lung damage that is present in some homocystinuric patients.     

The role of oxidative stress in lung injury induced by cigarette smoke

Oxidative stress is a damaging process resulting from an imbalance between excessive generation of oxidant compounds and insufficient antioxidant defence mechanisms. Oxidative stress plays a crucial role in the initiation and progression of cigarette smoke-induced lung injury, deterioration in lung functions, and development of chronic obstructive pulmonary disease (COPD). In smokers and in patients with COPD, the increased oxidant burden derives from cigarette smoke per se, and from activated inflammatory cells releasing enhanced amounts of reactive oxygen and nitrogen species (ROS, RNS, respectively). Although mild oxidative stress resulting from cigarette smoking leads to the upregulation of the antioxidative enzymes synthesis in the lungs, high levels of ROS and RNS observed in patients with COPD overwhelm the antioxidant enzymes capacities, resulting in oxidant-mediated lung injury and cell death. In addition, depletion of antioxidative systems in the systemic circulation was consistently observed in such patients. The imbalance between the generation of ROS/RNS and antioxidant capacities — the state of “oxidative stress” — is one of the major pathophysiologic hallmarks in the development of COPD. Detrimental effects of oxidative stress include impairment of membrane functions, inactivation of membrane-bound receptors and enzymes, and increased tissue permeability. In addition, oxidative stress aggravates the inflammatory processes in the lungs, and contributes to the worsening of the protease-antiprotease imbalance. Several markers of oxidative stress, such as increases in lipid peroxidation products and reductions in glutathione peroxidase activity, have been shown to be related to the reductions in pulmonary functions. In the present article we review the current knowledge about the vicious cycle of cigarette smoking, oxidative stress, and inflammation in the pathogenesis of COPD.     

Resveratrol, a red wine polyphenol, attenuates ethanol-induced oxidative stress in rat liver

The involvement of oxidative stress in the pathogenesis of alcoholic diseases in the liver has been repeatedly confirmed. Resveratrol, a natural phytoalexin present in grape skin and red wine possesses a variety of biological activities including antioxidant. This study was conducted to evaluate whether resveratrol has a preventive effect on the main indicators of hepatic oxidative status as an expression of the cellular damage caused by free radicals, and on antioxidant defence mechanism during chronic ethanol treatment. Wistar rats were treated daily with 35% ethanol solution (3 g/kg/day i.p.) during 6 weeks and fed basal diet or basal diet containing 5 g/kg resveratrol. Control rats were treated with i.p. saline and fed basal diet. Experimentally, chronic ethanol administration leads to hepatotoxicity as monitored by the increase in the level of hepatic marker enzymes and the appearance of fatty change, necrosis, fibrosis and inflammation in liver sections. Ethanol also enhanced the formation of MDA in the liver indicating an increase in lipid peroxidation, a major end-point of oxidative damage, and caused drastic alterations in antioxidant defence systems. Particularly the activities of hepatic superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were found reduced by ethanol treatment while glutathione reductase (GR) activity was unchanged. Dietary supplementation with resveratrol during ethanol treatment inhibited hepatic lipid peroxidation and ameliorated SOD, GPx and CAT activities in the liver. Conclusively, we can suggest that resveratrol could have a beneficial effect in inhibiting the oxidative damage induced by chronic ethanol administration, which was proved by the experiments that we conducted on rats.     

Status of oxidative stress and antioxidant defences during Plasmodium knowlesi infection and chloroquine treatment in Macaca mulatta.

Plasmodium knowlesi (a simian malarial parasite) infection resulted in elevation of hepatic oxidative stress in monkeys. Further, the antioxidant defence system of the host was also noticeably affected. The infected monkeys showed a marked increase in the levels of superoxide (O2-), lipid peroxidation (LPO), glutathione (GSH) and xanthine oxidase (XO), and decreased levels of superoxide dismutase (SOD) and catalase. Oral administration of chloroquine (20 mg kg body wt-1 for 3 days) to infected monkeys caused recovery trends in oxidative stress and antioxidant defences to almost normal a week after cessation of drug treatment.     

Oxidative stress and antioxidant status in patients with autoimmune liver diseases

Abstract

Objective

To estimate oxidative stress and antioxidant components during different stages of autoimmune liver diseases and assess their possible implication on disease progression.

Methods

We determined several markers of oxidative injury (isoprostane, aldehydes, protein carbonyls, 3-nitrotyrosine, and myeloperoxidase) and antioxidant components (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase) in whole blood, serum, and urine in 49 patients with autoimmune cholestatic liver diseases (AC) and 36 patients with autoimmune hepatitis (AIH) and healthy subjects matched for sex and age.

Results

Both AC and AIH patients had increased levels of all lipid and protein oxidative injury products and significantly decreased whole blood glutathione levels compared to controls. AIH patients had significantly higher levels of aldehydes and glutathione peroxidase activity and significantly lower protein carbonyl levels compared to AC patients. Protein carbonyl and isoprostane levels increased and glutathione levels decreased gradually with progression from mild fibrosis to severe fibrosis and cirrhosis in both AC and AIH patients. In addition, both cirrhotic AC and AIH patients had significantly higher protein carbonyls compared to non-cirrhotics.

Discussion

We provide novel findings in support of a major contribution of oxidant/antioxidant imbalance in the progression of liver injury in AC and AIH.     

Fungal pathogen-induced changes in the antioxidant systems of leaf peroxisomes from infected tomato plants

Peroxisomes, being one of the main organelles where reactive oxygen species (ROS) are both generated and detoxified, have been suggested to be instrumental in redox-mediated plant cell defence against oxidative stress. We studied the involvement of tomato (Lycopersicon esculentum Mill.) leaf peroxisomes in defence response to oxidative stress generated upon Botrytis cinerea Pers. infection. The peroxisomal antioxidant potential expressed as superoxide dismutase (SOD, EC 1.15.1.1), catalase (CAT, EC 1.11.1.6) and glutathione peroxidase (GSH-Px, EC 1.11.1.19) as well as the ascorbate-glutathione (AA-GSH) cycle activities was monitored. The initial infection-induced increase in SOD, CAT and GSH-Px indicating antioxidant defence activation was followed by a progressive inhibition concomitant with disease symptom development. Likewise, the activities of AA-GSH cycle enzymes: ascorbate peroxidase (APX, EC 1.11.1.11), monodehydroascorbate reductase (MDHAR, EC 1.6.5.4), dehydroascorbate reductase (DHAR, EC 1.8.5.1) and glutathione reductase (GR, EC 1.6.4.2) as well as ascorbate and glutathione concentrations and redox ratios were significantly decreased. However, the rate and timing of these events differed. Our results indicate that B. cinerea triggers significant changes in the peroxisomal antioxidant system leading to a collapse of the protective mechanism at advanced stage of infection. These changes appear to be partly the effect of pathogen-promoted leaf senescence.     

Abortion-prone mating influences placental antioxidant status and adversely affects placental and foetal development

Abstract

Oxidative stress is associated with decreased female fertility and adversely affects prenatal development. Mammalian cells have developed a network of enzymatic and non-enzymatic antioxidant defence systems to prevent oxidative stress. Little attention has been paid to the antioxidative pathways in placentas of normal and disturbed pregnancies, leaving a gap in our knowledge about the role of antioxidants in the control of foeto-placental development. The challenges in studying early human pregnancy can partly be overcome by designing animal models of abnormal pregnancy. We aimed to determine whether the antioxidant status of placentas from the CBA/J × DBA/2 abortion-prone pregnant mice differed from that of normal pregnant mice. The foetal/placental weight ratio was lower in abortion-prone matings compared with that in non-abortion-prone matings. The increased placental malondialdehyde (MDA) content, the end products of lipid peroxidation, with concomitants alterations in placental antioxidants, namely copper-zinc containing superoxide dismutase (SOD1), manganese containing (SOD2), glutathione peroxidases (GPX), glutathione reductase (GR) and catalase (CAT) activities may be involved in placental and foetal growth restriction. We show that placental oxidative stress is linked with poor prenatal development and pregnancy losses in CBA/J × DBA/2 mice matings. This animal model may be useful in the evaluation of nutritional antioxidant therapies for oxidative stress and associated prenatal developmental disorders.     

Molecular bases of the treatment of Alzheimer's disease with antioxidants: prevention of oxidative stress

Alzheimer's disease is associated with a systemic oxidative stress situation which can be followed in vivo by determining biomarkers such as plasma lipoperoxides and TBARS levels and the oxidation degree of glutathione in red blood cells. It has been observed that Alzheimer's patients show an increased level of plasma TBARS, which indicates a higher free radical oxidation of plasma unsaturated phospholipids, and an increased oxidation of red blood cells glutathione, which indicates oxidative stress in peripheral cells. This latter, glutathione oxidation, was found to correlate statistically with the cognitive status of the patients. Treatment with vitamin E resulted in an improved cognitive performance only of those patients in which the tocopherol acted as an antioxidant, according to blood indicative markers of oxidative stress. Indeed, the effect of vitamin E on Alzheimer's disease patients showed considerable variations both in its antioxidant function and in its capacity to improve cognitive functions. An important conclusion from the reported results is that epidemiological or clinical studies that aim to test the effect of antioxidant supplementation on given functions should include the determination of the antioxidant status of the patients by the measurement of blood markers of oxidative stress.     

Hypobaric hypoxia induces oxidative stress in rat brain

High altitude exposure results in decreased partial pressure of oxygen and an increased formation of reactive oxygen and nitrogen species (RONS), which causes oxidative damage to lipids, proteins and DNA. Exposure to high altitude appears to decrease the activity and effectiveness of antioxidant enzyme system. The antioxidant system is very less in brain tissue and is very much susceptible to hypoxic stress. The aim of the present study was to investigate the time dependent and region specific changes in cortex, hippocampus and striatum on oxidative stress markers on chronic exposure to hypobaric hypoxia. The rats were exposed to simulated high altitude equivalent to 6100 m in animal decompression chamber for 3 and 7 days. Results indicate an increase in oxidative stress as seen by increase in free radical production, nitric oxide level, lipid peroxidation and lactate dehydrogenase levels. The magnitude of increase in oxidative stress was more in 7 days exposure group as compared to 3 days exposure group. The antioxidant defence system such as reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and reduced/oxidized glutathione (GSH/GSSG) levels were significantly decreased in all the three regions. The observation suggests that the hippocampus is more susceptible to hypoxia than the cortex and striatum. It may be concluded that hypoxia differentially affects the antioxidant status in the cortex, hippocampus and striatum.     

Dapsone induces oxidative stress and impairs antioxidant defenses in rat liver

Dapsone (DDS) is currently used in the treatment of leprosy, malaria and in infections with Pneumocystis jirovecii and Toxoplasma gondii in AIDS patients. Adverse effects of DDS involve methemoglobinemia and hemolysis and, to a lower extent, liver damage, though the mechanism is poorly characterized. We evaluated the effect of DDS administration to male and female rats (30 mg/kg body wt, twice a day, for 4 days) on liver oxidative stress through assessment of biliary output and liver content of reduced (GSH) and oxidized (GSSG) glutathione, lipid peroxidation, and expression/activities of the main antioxidant enzymes glutathione peroxidase, superoxide dismutase, catalase and glutathione S-transferase. The influence of DDS treatment on expression/activity of the main DDS phase-II-metabolizing system, UDP-glucuronosyltransferase (UGT), was additionally evaluated. The involvement of dapsone hydroxylamine (DDS-NHOH) generation in these processes was estimated by comparing the data in male and female rats since N-hydroxylation of DDS mainly occurs in males. Our studies revealed an increase in the GSSG/GSH biliary output ratio, a sensitive indicator of oxidative stress, and in lipid peroxidation, in male but not in female rats treated with DDS. The activity of all antioxidant enzymes was significantly impaired by DDS treatment also in male rats, whereas UGT activity was not affected in any sex. Taken together, the evidence indicates that DDS induces oxidative stress in rat liver and that N-hydroxylation of DDS was the likely mediator. Impairment in the activity of enzymatic antioxidant systems, also associated with DDS-NHOH formation, constituted a key aggravating factor.