Evaluation of Acetamiprid Mediated Oxidative Stress and Pathological Changes in Male Rats: Ameliorative Effect of Curcumin

Present study was undertaken to evaluate the acetamiprid-mediated toxicity and possible protective effect of curcumin in rats. Rats were divided into seven different groups. They received curcumin (100 mg/kg, b.wt. p.o.) and acetamiprid (26.25 and 105 mg/kg b.wt., p.o.) alone and in their combinations for period of 28 days. Lipid peroxidation and antioxidant enzyme activities were determined in liver, kidney and brain and cellular changes histopathologically. Study shows that administration of acetamiprid caused a significant induction in oxidative damage in liver, kidney and brain as evidenced by increased level of lipid peroxidation (LPO) and altered activities of reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR). Co-administration of curcumin with acetamiprid significantly decreased LPO, caused marked restoration in the non-enzymatic (GSH) and enzymatic antioxidants system (CAT, SOD and, GR) and protected from acetamiprid-mediated structural alterations of liver, kidney and brain. The results of present study indicates that curcumin ameliorate the acetamiprid-induced toxic damage to vital organ mediated via oxidative stress.

     

Ellagic acid protects hepatocytes from damage by inhibiting mitochondrial production of reactive oxygen species

The aim of this experiment is to investigate the antioxidative and antiapoptotic roles of ellagic (EA) acid in in vitro and in in vivo experiment. We measured protective properties of EA against oxidative stress-induced hepatocyte damage in vitro and Concanavalin (ConA)-induced liver damage in vivo. EA, a potent antioxidant, exhibited protective properties against oxidative stress-induced hepatocyte damage by preventing vitamin k3 (VK3)-induced reactive oxygen species (ROS) productions, apoptotic and necrotic cellular damage and mitochondrial depolarization, which is a main cause of ROS production. EA also protects against cell death and elevation of glutathione (GSH), alanine transaminase (ALT) and asparatate transaminase (AST) in Con A-induced fulminant liver damage in mice. These results show that antioxidant and cytoprotective properties of EA prevent liver damage induced by various type of oxidative stress.     

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.     

Curcumin alleviates lipopolysaccharide induced sepsis and liver failure by suppression of oxidative stress-related inflammation via PI3K/AKT and NF-κB related signaling

In many liver disorders, oxidative stress-related inflammation and apoptosis are important pathogenic components, finally resulting in acute liver failure. Erythropoietin and its analogues are well known to influence the interaction between apoptosis and inflammation in brain and kidney. The study is to clarify the effect of curcumin, a natural plant phenolic food additive, on lipopolysaccharides (LPS)-induced acute liver injury of mice with endotoxemia and associated molecular mechanism from inflammation, apoptosis and oxidative stress levels. And curcumin, lowered serum cytokines, including Interleukin 1beta (IL-1β), Interleukin 6 (IL-6) and tumor necrosis factor (TNF-α), and improved liver apoptosis through suppressing phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and inhibiting Cyclic AMP-responsive element-binding protein (CREB)/Caspase expression, and decreased oxidative stress-associated protein expression, mainly involving 2E1 isoform of cytochrome P450/nuclear factor E2-related factor 2/reactive oxygen species (CYP2E/Nrf2/ROS) signaling pathway, as well as liver nitric oxide (NO) production in LPS-induced mice. Moreover, curcumin regulated serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP), accelerated liver antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GSH-px) levels, and inhibited activation of the mitogen-activated protein kinases/c-Jun NH2-terminal kinase (P38/JNK) cascade in the livers of LPS-induced rats. Thus, curcumin treatment attenuates LPS-induced PI3K/AKT and CYP2E/Nrf2/ROS signaling and liver injury. Strategies to inhibit inflammation and apoptosis signaling may provide alternatives to the current clinical approaches to improve oxidative responses of endotoxemia.     

Modulation of pentylenetetrazole-induced seizures and oxidative stress parameters by sodium valproate in the absence and presence of N-acetylcysteine

In view of a role of oxidative stress in epilepsy and the evidence for the involvement of peroxidative injury in sodium valproate (SVP)-induced adverse effects on liver and kidneys, we investigated whether the combination of SVP with N-acetylcysteine (NAC), an antioxidant, may help us to achieve maximal efficacy in terms of seizure control, with minimal toxicity on liver and kidneys. Pentylenetetrazole (PTZ)-induced seizures were used to evaluate the anticonvulsant effect of drugs. Biochemical estimations included the determination of oxidative stress markers like thiobarbituric acid-reactive substances in brain tissue and glutathione (GSH) levels in liver and kidney tissues. Aspartate aminotransferase and alanine aminotransferase concentrations in the serum were also determined to assess liver function. In our study, NAC exhibited a nondose-dependent anticonvulsant effect. The concurrent administration of NAC with SVP significantly prolonged the latency to jerks, myoclonus and clonic generalized seizures. No significant oxidative stress was evident in brain tissue following PTZ-induced seizures, though an elevation of serum transaminase enzymes was seen. SVP at the dose studied did not produce any significant oxidative stress on the liver and kidneys, while treatment with NAC elevated liver and kidney GSH levels. The concurrent administration of NAC with SVP had beneficial effects on liver and kidney cells.     

Correlation of oxidative status with BMI and lung function in COPD

OBJECTIVES: The imbalance in oxidative status together with nutrition depletion and low body weight play a vital role in the pathogenesis and severity of chronic obstructive pulmonary disease (COPD). The study was undertaken to ascertain if a relationship existed between oxidative status and BMI in COPD. In addition, association of oxidative status and BMI with lung function of the disease was also examined. MATERIALS AND METHODS: In 202 COPD patients and 136 healthy controls plasma lipid peroxidation (LPO), reduced glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT) activities, BMI and FEV(1)% predicted were looked for interactions. RESULTS: The patients had increased LPO (p=0.006) and decreased antioxidants (GSH, p=0.005; GPx, p=0.035 and CAT, p=0.008, respectively). Of note are the correlations of oxidative stress markers with BMI and FEV(1)% predicted in the patients. LPO inversely and GSH, GPx, and CAT positively correlated with both BMI (p=0.007, p<0.001, p=0.045 and p=0.009, respectively), and FEV(1)% of predicted (LPO, p=0.001; GSH, p<0.001; GPx, p=0.043 and CAT, p<0.001) in the patients. Further, a positive correlation existed between BMI and FEV(1)% predicted (p=0.016) in COPD. CONCLUSION: The intimate relationship of oxidative status with BMI and lung function, and the direct correlation between BMI and FEV(1) may potentiate severity of the disease.     

Ovariectomy induces oxidative stress and impairs bone antioxidant system in adult rats

BACKGROUND: There is increasing evidence suggesting the role of free radicals in bone resorption and bone loss. Ovariectomized rats have been used as the animal model for the study of osteoporosis. Oxidative stress due to reactive oxygen species (ROS) can cause oxidative damage to cells. Cells have a number of defense mechanisms to protect themselves from the toxicity of ROS. Even though, there are studies portraying the role of free radicals in bone loss, the defense mechanism adapted by bone in ovariectomized animals remains obscure. We investigated the impact of ovariectomy (OVX) on the bone antioxidant system in rats. METHODS: Sixty days after bilateral OVX, the rats were killed and the femora were removed, the tissue homogenates were made and used for the estimation of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S transferase (GST), lipid peroxidation (LPO) and hydrogen peroxide (H(2)O(2)). RESULTS: The levels of LPO and H(2)O(2) were increased and enzymatic antioxidants like SOD, GPx, GST were decreased in ovariectomized animals when compared to sham-operated control rats. The calculated correlation coefficient demonstrated strong correlation (0.905) between the production of H(2)O(2) and LPO in the femur bone. A strong inverse (-0.945) correlation was observed between H(2)O(2) production and SOD activity. CONCLUSIONS: OVX induces oxidative stress in the femur bone of rats.     

Glutathione level and glutathione-dependent enzyme activities in blood serum of patients with gastrointestinal tract tumors

ObjectivesGlutathione (GSH) and enzymes cooperating with it – glutathione peroxidase (GSHPx), glutathione S-transferase (GST) and glutathione reductase (GSHR) – play crucial role in cell defence against reactive oxygen species (ROS), which are implicated in tumor disease. The aim of this study was to determine if neoplastic diseases of gastrointestinal tract may influence blood GSH level and its dependent enzyme activity.Design and methodsBlood serum was obtained before and after surgery from patients with gastric, liver and colorectal cancers, and colorectal cancer liver metastases. Lipid peroxidation and GSH levels, and GSH-dependent enzyme activities were determined by means of spectrophotometric methods.ResultsIncreased level of lipid peroxidation and significant differences in GSH level and GSHPx, GST and GSHR activities were observed in serum taken before and after surgery from patients with gastrointestinal tract tumors compared to those in control serum (from healthy blood donors).ConclusionsIncrease of lipid peroxidation and changes in GSH level and related enzyme activities, suggest oxidative stress in serum of patients with gastrointestinal tract tumor causes, which probably arise as a result of enormous production of ROS in the system. These alterations reflect the presence of functional defence mechanism against oxidative stress related firmly to the glutathione metabolism.     

Nitric oxide synthase expression in hypertension induced by inhibition of glutathione synthase

Induction of chronic oxidative stress by glutathione (GSH) depletion has been shown to cause hypertension in normal rats. This was accompanied by and perhaps in part due to inactivation and sequestration of NO by reactive oxygen species (ROS), leading to diminished NO bioavailability. This study was designed to examine renal histology, nitric oxide synthase (NOS) isotype expression, and nitrotyrosine distribution in this model. Sprague-Dawley rats were subjected to oxidative stress by administration of the GSH synthase inhibitor buthionine sulfoximine (BSO; 30 mM/l in drinking water) for 2 weeks. The controls were given tap water. Blood pressure, renal histology, tissue expression of endothelial and inducible NOS (eNOS and iNOS) and nitrotyrosine, tissue GSH content, and urinary excretion of NO metabolites (NOx) were examined. The BSO-treated group showed a 3-fold decrease in tissue GSH content, a marked elevation in blood pressure, and a significant reduction in the urinary excretion of NOx. Histological examination of kidneys revealed no significant abnormalities in either group. In addition, no significant differences were observed in either intensities or localizations of eNOS and iNOS in the kidney. However, the BSO-treated group exhibited intense accumulation in the renal tissue of nitrotyrosine, which is the footprint of NO oxidation by ROS. These observations suggest that oxidative stress-induced hypertension is not caused by either structural abnormality of or depressed NOS expression by the kidney in this model. Instead, it is associated with and perhaps partially related to enhanced renal NO inactivation by ROS and diminished NO bioavailability.     

Amelioration of carcinogen-induced toxicity in mice by administration of a potentized homeopathic drug, natrum sulphuricum 200

To examine if a potentized homeopathic drug, Natrum Sulphuricum 200 (Nat Sulph-200) has protective potentials against hepatocarcinogenesis, liver tumors were induced in mice through chronic feeding of P-dimethylaminoazobenzene (p-DAB; initiator of hepatocarcinogenesis) and phenobarbital (PB; promoter). Mice were divided into five sub-groups: fed normal low protein diet (Gr. I, normal control); fed normal low protein plus alcohol-200 (vehicle of the homeopathic remedy) (Gr. II); fed diet mixed with 0.06% p-DAB plus 0.05% PB (Gr. III); fed diet and carcinogens like Gr.III, plus alcohol 200 (positive control for drug fed mice) (Gr. IV) and fed diet and carcinogens like Gr. III, plus Natrum Sulphuiricum-200 (Gr. V; drug fed). Mice were sacrificed at day 7, 15, 30, 60, 90 and day 120 for study of cytogenetical endpoints like chromosome aberrations (CA), micronuclei (MN), mitotic index (MI) and sperm head anomaly (SHA) and biochemical toxicity parameters like aspartate amino transferase (AST), alanine amino transferase (ALT), acid (AcP) and alkaline (AlkP) phosphatases, lipid peroxidation (LPO) and reduced glutathione (GSH) content. Less number of liver tumors were observed in Gr. V (drug fed) mice. Administration of Nat Sulph 200 reduced genomic damage, activities of AcP, AlkP, AST, ALT, LPO and increased GSH content. Therefore, independent replication of the study by others is encouraged.     

Octacosanol attenuates disrupted hepatic reactive oxygen species metabolism associated with acute liver injury progression in rats intoxicated with carbon tetrachloride

We examined whether octacosanol, the main component of policosanol, attenuates disrupted hepatic reactive oxygen species metabolism associated with acute liver injury progression in rats intoxicated with carbon tetrachloride (CCl(4)). In rats intoxicated with CCl(4) (1 ml/kg, i.p.), the activities of serum transaminases increased 6 h after intoxication and further increased at 24 h. In the liver of CCl(4)-intoxicated rats, increases in lipid peroxide (LPO) concentration and myeloperoxidase activity and decreases in superoxixde dismutase activity and reduced glutathione (GSH) concentration occurred 6 h after intoxication and these changes were enhanced with an increase in xanthine oxidase activity and a decrease in catalase activity at 24 h. Octacosanol (10, 50 or 100 mg/kg) administered orally to CCl(4)-intoxicated rats at 6 h after intoxication attenuated the increased activities of serum transaminases and the increased hepatic myeloperoxidase and xanthine oxidase activities and LPO concentration and the decreased hepatic superoxide dismutase and catalase activities and GSH concentration found at 24 h after intoxication dose-dependently. Octacosanol (50 or 100 mg/kg) administered to untreated rats decreased the hepatic LPO concentration and increased the hepatic GSH concentration. These results indicate that octacosanol attenuates disrupted hepatic reactive oxygen species metabolism associated with acute liver injury progression in CCl(4)-intoxicated rats.     

Modification of renal oxidative stress and lipid peroxidation in streptozotocin-induced diabetic rats treated with extracts from Gongronema latifolium leaves

BACKGROUND: Gongronema latifolium is a tropical plant traditionally used in controlling weight gain in lactating women, as well as diabetic and overall health management. In this experiment, the aqueous and ethanolic extracts were tested to evaluate their effect on renal oxidative stress and lipid peroxidation in non-diabetic and streptozotocin-induced diabetic rats. METHODS: Diabetes was induced in male Wistar rats by intraperitoneal (i.p.) injection of streptozotocin (STZ) (65 mg/kg). The rats were divided into non-diabetic (18) and STZ-induced diabetic (18) rats, and both groups subdivided according to their treatments: aqueous extract (100 mg/kg), ethanolic extract (100 mg/kg) and control (saline solution). Aqueous and ethanolic extracts were administered by gavage in 12-h cycles over a 14-day period. RESULTS: The results indicated that the ethanolic extract significantly normalized catalase (CAT) activity (p<0.01), increased glutathione peroxidase (GPx) activity (p<0.05), and reduced reactive oxygen species (ROS) concentrations (p<0.001). It also nonsignificantly normalized superoxide dismutase (SOD) activity, increased GSH/GSSG ratio and reduced malondialdehyde (MDA) concentrations in the diabetic kidney. The aqueous extract had no effect on the superoxide dismutase activity in the diabetic animals and caused a nonsignificant increase in catalase activity. CONCLUSIONS: The ethanolic extract appeared to be more effective in reducing oxidative stress, lipid peroxidation, and increasing the GSH/GSSG ratio, thus confirming the ethnopharmacological use of G. latifolium in ameliorating the oxidative stress found in diabetics and indicating promise of possible use in lessening morbidity in affected individuals.     

新诊断2型糖尿病患者氧化应激状况及短期胰岛素泵强化治疗的影响

【目的】观察初诊2型糖尿病（T2DM）患者体内氧化应激改变及短期持续皮下胰岛素输注（CSII）治疗对患者氧化应激状况的影响。[方法]60例初诊T2DM患者接受为期2周的CSII治疗,于治疗前、后分别测定血清活性氧活力（ROS）、丙二醛（MDA）、谷胱甘肽（GSH）、超氧化物歧化酶（SOD）,同时测定T2DM患者空腹胰岛素水平,采用稳态模型计算胰岛β细胞功能（HOMA-β）。【结果】①T2DM患者ROS、MDA明显增高,GSH、SOD明显降低。②ROS、MDA与HOMA—β呈负相关,GSH、SOD与HOMA—β呈正相关。③CSII治疗2周后,ROS、MDA明显降低,GSH、SOD明显增高,同时HOMA-β亦明显增高。[结论]T2DM患者体内氧化应激明显增强。短期CSII除迅速降低血糖外,还具有降低T2DM患者氧化应激水平,保护胰岛口细胞功能。     

Leptin attenuates oxidative stress and neuronal apoptosis in hyperglycemic condition

One of the main pathological mechanisms of neurotoxicity in diabetic situation is oxidative stress promoted by hyperglycemia. It has been shown that leptin has neuroprotective effects and may provide neuronal survival signals. This study was designed to reveal the possible neuroprotective effects of leptin in hyperglycemic conditions. Pheochromocytoma (PC12) cell viability was assessed via the MTT test. Cellular reactive oxygen species (ROS) generation was determined by DCFH‐DA analysis. The malondialdehyde (MDA) and glutathione (GSH) levels were measured in high‐glucose‐treated PC12 cells with and without leptin cotreatment. Western blotting was performed to measure apoptosis markers (Cleaved caspase‐3 and Bax/Bcl2 ratio). Elevation of glucose levels (100 mmol/L) consecutively increased intracellular ROS and MDA level, and apoptosis in PC12 cells after 24 h leptin administration (12 and 24 nmol/L) decreased the high‐glucose‐induced cell toxicity, caspase‐3 activation, and Bax/Bcl‐2 ratio. Also, cotreatment with leptin (12 and 24 nmol/L) significantly reduced oxidative damage to PC12 cells in high‐glucose condition, as reflected by the diminution in MDA and ROS levels and the increase in GSH content. Our finding demonstrates that leptin has protective effects against hyperglycemia‐induced neural damage. This could be related to the attenuation of oxidative stress and neural apoptosis.     

Antioxidant and protective effects of Amrit Nectar tablets on adriamycin- and cisplatin-induced toxicities

OBJECTIVES: Maharishi herbal food supplements have been shown to inhibit the growth of mammary tumors and reduce free radical-mediated injuries. The purpose of this investigation is to evaluate the effects of aqueous and alcoholic extracts of Amrit Nectar tablets on rat liver microsomal lipid peroxidation and compare to other antioxidants. The protective effects of dietary Amrit Nectar tablets (MA-7; containing 38 herbs) on cisplatin-induced changes in glutathione (GSH) and glutathione-S-transferase (GST) activity in rat liver and kidney, and Adriamycin (Pharmacia S.p.A, Milan, Italy)-induced mortalities in mice were also investigated. RESULTS: Both aqueous and alcoholic extracts of MA-7 were more potent than other antioxidants tested under our experimental conditions. Adriamycin (15 mg/kg, intraperitoneally) caused 60% mortality during the period of 4 weeks in CDF1 mice. Dietary MA-7 (0.7%) treatment decreased the mortality to 20%. Dietary MA-7 (0.7%) supplementation with cisplatin treatment reversed the effects of cisplatin on liver and kidney GSH and GST activity. CONCLUSIONS: These results indicate that MA-7 is a powerful antioxidant. MA-7 supplementation with Adriamycin and cisplatin treatment may protect against their toxicities.     

Effects of shikonin on the development of ovarian follicles and female germline stem cells

ObjectiveTo investigate the effects and potential mechanism of action of shikonin (SHK) on the development of ovarian follicles and female germline stem cells (FGSCs).MethodsFemale Kunming adult mice were administered SHK (0, 20 and 50 mg/kg) by oral gavage. Cultures of FGSCs were treated with SHK 32 μmol/l for 24 h. The ovarian index in mouse ovaries was calculated. Numbers of primordial, primary and atretic follicles were counted. Germline stem cell markers and apoptosis were examined. Levels of glutathione (GSH), superoxide dismutase (SOD) and reactive oxygen species (ROS) were measured.ResultsBoth doses of SHK significantly decreased the ovarian index, the numbers of primordial follicles, primary follicles and antral follicles in mice. SHK significantly increased the numbers of atretic follicles and atretic corpora lutea. SHK promoted apoptosis in vivo and in vitro. SHK significantly decreased the levels of the germline stem cell markers. SHK significantly lowered GSH levels and the activity of SOD in the peripheral blood from mice, whereas SHK significantly elevated cellular ROS content in FGSCs.ConclusionsThese current results suggested that follicular development and FGSCs were suppressed by SHK through the induction of apoptosis and oxidative stress might be involved in this pathological process.     

Antioxidant cuttlefish collagen hydrolysate against ethyl carbamate-induced oxidative damage

Ethyl carbamate (EC) has been associated with the generation of reactive oxygen species (ROS) and depletion of glutathione (GSH), leading to a decline in cell viability. In this study, we found that the cuttlefish collagen hydrolysate (CCH) exhibited high antioxidant activity in scavenging hydroxyl radicals (IC₅₀ = 0.697 mg mL⁻¹), which was also effective in combating EC-induced oxidative damage in liver hepatocellular carcinoma HepG2 cells. The expression of genes related to oxidative stress response could be regulated by CCH to mitigate EC-induced oxidative stress. Pathway analysis confirmed that the protective ability of CCH could be related to ferroptosis and glutathione metabolism. Therefore, CCH could reduce the decline in cell viability by alleviating GSH depletion, and prevent EC-induced oxidative damage. Moreover, protective effect of CCH could be realized by upregulating the heme oxygenase-1 to achieve the preventation of cell sensitization. Considering these effects, CCH has potential for use in food to prevent oxidative stress.

Collagen hydrolysate against EC-induced oxidative damage.     

Analgesics and glutathione

A growing body of evidence indicates that glutathione (GSH) plays a vitally important role in cellular function. It detoxifies toxic metabolites of drugs and reactive oxygen species and regulates gene expression, apoptosis, and transmembrane transport of organic solutes. The maintenance of GSH homeostasis is essential for the organism to perform its many functions. The turnover of GSH is a dynamic process, and large quantities of GSH are synthesized per day from its precursor amino acids cysteine, glutamic acid, and glycine. Toxic doses of paracetamol deplete intracellular GSH and result in cell death by a combination of mechanisms, leading to necrosis and apoptosis, mainly in the liver. In clinical situations characterized by low GSH, the risk of toxicity from therapeutic doses of paracetamol may conceivably be increased. This toxicity has been reported in chronic alcoholics who have low intrahepatic GSH and who may have an induced enzyme system that generates the toxic metabolite of paracetamol. Considering the large number of alcoholics in our population and the widespread use of paracetamol, this must be a rare and essentially unpredictable occurrence. Except for anecdotal reports, there is no convincing evidence that other populations in which low GSH has been observed-such as patients with human immunodeficiency virus (HIV) infection or chronic hepatitis C, malnourished patients, and patients with cirrhosis-are at higher risk of experiencing adverse events from paracetamol.     

Ascorbic acid and alpha-tocopherol protect anticancer drug cisplatin induced nephrotoxicity in mice: a comparative study

BACKGROUND: Oxidative stress, resulting from an imbalance between prooxidant and antioxidant systems in favor of the former, largely contributes to immune system deregulation and complications observed in end-stage renal disease (ESRD) and patients treated with hemodialysis. Reactive oxygen species and free radicals are involved in the nephrotoxicity induced by a synthetic anticancer drug cisplatin. METHODS: A comparative study on the nephroprotective effects of antioxidant vitamins (250 and 500 mg/kg, p.o.), vitamin C (ascorbic acid) and vitamin E (alpha-tocopherol), was evaluated using cisplatin (10 mg/kg body wt, i.p.) induced oxidative renal damage in mice. Urea and creatinine in serum were estimated for the renal function. Antioxidant status was estimated in kidney homogenate. RESULTS: We found that both vitamins at 500 mg/kg significantly (P<0.01) protected the nephrotoxicity induced by cisplatin. The cisplatin induced increase of urea and creatinine concentrations were reduced in the vitamins plus cisplatin (250 and 500 mg/kg, p.o.)-treated groups. However the cisplatin induced decline of renal antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities were increased only in the 500 mg/kg vitamins treated groups. Both vitamins at 250 and 500 mg/kg could increase the concentration of reduced glutathione (GSH) and protected the increase of cisplatin induced lipid peroxidation. CONCLUSIONS: Higher doses of vitamins are effective to protect oxidative renal damage and vitamin C is the better nephroprotective agent than vitamin E. The protection is mediated partially by preventing the decline of renal antioxidant status.     

Covalent binding of metabolites of acetaminophen to kidney protein and depletion of renal glutathione

Experiments in CD-1 mice and Sprague-Dawley rats were carried out to determine the extent to which biochemical changes described previously for acute acetaminophen-induced hepatotoxicity might be applicable to the kidney. After intraperitoneal injection of acetaminophen, tissue glutathione and covalent binding of tritiated metabolites of acetaminophen to tissue protein were measured for liver, kidney cortex and kidney papilla. Glutathione was reduced more in mice than in rats, and more in liver than in kidney, without appearance of oxidized glutathione in either tissue. Covalent binding was likewise greater in mice than in rats and greater in liver than in kidney. The determination of covalent binding was extremely sensitive to the trace radiochemical impurities of the labeled drug. With prior administration of 3-methyl-cholanthrene, the induced changes were far greater in liver than in kidney, suggesting that the formation of a reactive metabolite from acetaminophen occurred in each organ by slightly different mechanisms. At doses less than those associated with demonstrable acute toxicity, the duration of covalent binding to protein was longer for renal papilla than for renal cortex or for liver. The results may be applicable to the pathogenesis of both acute and chronic nephrotoxicity.