N-Acetyl cysteine is an early but also a late preventive agent against carbon tetrachloride-induced liver necrosis

Vallés, Elena; Castro, Clementina; Castro, J.A.

doi:10.1016/0378-4274(94)90202-x

Cited by 40 publications

(14 citation statements)

References 17 publications

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“…The results suggested that early and late protective effects of NAC might be attributable to its prior conversion to cysteine and GSH. [25] Ethanol treatment resulted in steatosis, inflammatory infiltrates, occasional foci of necrosis, elevated ALT, accumulation of MDA and hydroxynonenal protein adducts, decreased antioxidant capacity, and increased antibody titers toward serum hydroxyethyl radical, MDA and hydroxynonenal adducts. NAC treatment increased cytosolic antioxidant capacity, abolished ethanol-induced lipid peroxidation, and inhibited the formation of antibodies toward hydroxynonenal and hydroxyethyl radical adducts.…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotective and antioxidant activity of N-acetyl cysteine in carbamazepine-administered rats

2014

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Objectives:The present study evaluates the hepatoprotective activity of N-acetyl cysteine (NAC) against carbamazepine (CBZ)-induced hepatotoxicity.Materials and Methods:Rats were treated with CBZ (50 mg/kg p.o.) and CBZ supplemented with NAC 50, 100 and 200 mg/kg for 45 days, after which blood samples were collected and subjected to liver function tests. Animals were killed, liver was separated, weighed and the levels of antioxidants and liver enzymes were estimated. In addition, histopathological investigation was also performed.Results:Serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate (SGOT) transaminase, alkaline phosphatase (ALP), bilirubin, lipid peroxidation, absolute and relative liver weights were significantly (P < 0.05) elevated, whereas serum levels of albumin, total protein and body weight were decreased in the CBZ-treated animals. CBZ also produced vacuolar degeneration, centrilobular congestion and hepatic necrosis as evidenced from histopathological report. NAC significantly reduced the levels of serum transaminase, ALP, bilirubin and liver weight and increased the levels of total protein, albumin and body weight.Conclusion:It was observed that NAC increased the glutathione (GSH) content, reduced lipid peroxidation and reversed the CBZ-induced histopathological abnormalities. CBZ-induced hepatotoxicity may be due its toxic epoxide metabolite-induced oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Hepatoprotective and antioxidant activity of N-acetyl cysteine in carbamazepine-administered rats

2014

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“…It is particularly toxic to the liver, where it causes hepatocellular degeneration, centrilobular necrosis 1,2 and impairs different enzymatic systems. 3 The generation of free radicals appears to be pivotal in CCl 4 hepatotoxicity: CCl 4 is metabolized by cytochrome P-450 to produce the trichloromethyl radical, which initiates a cascade of free radical reactions resulting in an increase of lipid peroxidation and a reduction in some enzyme activities.…”

Section: Introductionmentioning

confidence: 99%

Oxidative preconditioning affords protection against carbon tetrachloride‐induced glycogen depletion and oxidative stress in rats

Candelario‐Jalil

Mohammed-Al-Dalain

Fernández

et al. 2001

J of Applied Toxicology

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The rectal insufflation of a judicious dose of ozone, selected from that used in clinical practice, is able to promote oxidative preconditioning or oxidative stress tolerance preventing the hepatocellular damage mediated by free radicals. In order to evaluate the effects of ozone oxidative preconditioning on carbon tetrachloride-mediated hepatotoxicity, the following experimental protocol was designed: group 1 (negative control, sunflower oil i.p.); group 2 (CCl(4) in sunflower oil, 1 ml kg(-1) i.p.); group 3 (15 ozone-oxygen pretreatments at a dose of 1 mg kg(-1) via rectal insufflation + CCl(4) as in group 2); group 4 (ozone control group, 15 ozone-oxygen pretreatments + sunflower oil i.p.). Ozone pretreatment prevented glycogen depletion (as demonstrated by biochemical and histopathological findings) and avoided lactate overproduction associated with the hepatotoxic effects of CCl(4). The administration of CCl(4) increased lipid peroxidation (as measured by thiobarbituric acid-reactive substances) and uric acid levels and inhibited superoxide dismutase activity. All these deleterious effects induced by CCl(4) were prevented by ozone pretreatment. The administration of ozone without CCl(4) (ozone control group) did not produce any changes in the evaluated parameters. Our results showed that ozone treatment, in our experimental conditions, was able to prevent anaerobic glycolysis and oxidative stress induced by CCl(4).

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“…[31][32][33][34] Given in a similar regimen as the glutathione monoethylester 1 hour after phorone and 1 hour before ␣CD95 treatment, none of the following agents restored sensitivity toward CD95-mediated liver injury: N-acetyl cysteine (1,000 mg/kg), free glutathione (0.5 mmol/kg), ␣-tocopherol (200 mg/kg), butyl-hydroxytoluene (200 mg/kg), or catalase (10 6 U/kg). These observations provide evidence that oxidative stress is an unlikely cause for interruption of apoptotic signaling, and that it was the reduced concentration of intracellular glutathione that mediated protection from ␣CD95-induced liver injury.…”

Section: Hepatoprotection By Phorone Pretreatment In Cd95-mediatedmentioning

confidence: 99%

CD95-mediated murine hepatic apoptosis requires an intact glutathione status

et al. 1999

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Agonistic engagement of the cytokine receptor CD95 in mice leads to activation of hepatic caspases, followed by massive hepatocyte apoptosis, acute liver failure, and death. This mechanism of cell death is thought to be associated with several human liver disorders. Because hepatic glutathione represents the major defense against toxic liver injury, we investigated its role in CD95-mediated liver failure, which represents a model for hyperinflammatory organ destruction. As a tool for modulating the liver glutathione status of mice in vivo, we used the GSH transferase substrate, phorone, which rapidly depleted hepatic glutathione in a dose-dependent manner. When GSH was depleted, CD95-initiated hepatic caspase-3-like activity and DNA fragmentation were completely blocked, and animals were protected from liver injury dosedependently as assessed by histological examination and determination of liver enzymes in plasma. Conversely, repletion of hepatic glutathione by treatment with the permeable glutathione monoethylester restored susceptibility of GSH-depleted mice toward CD95-mediated liver injury. In contrast, the antioxidants, GSH, N-acetyl cysteine, ␣-tocopherol, butyl-hydroxytoluene, and catalase failed to do so. Animals treated once with phorone survived for more than 3 months after an otherwise lethal injection of the activating anti-CD95 antibody. We investigated the thiol sensitivity of recombinant caspase-3 in vitro and observed that its activity was dependent on the presence of a reducing agent such as GSH, while GSSG attenuated proteolytic activity. Based on our finding that CD95-mediated hepatocyte apoptosis requires an intact intracellular glutathione status, we propose that the activation of apoptosis-executing caspases is controlled by reduced glutathione. (HEPATOLOGY 1999;30:177-185.)The cytokine receptor CD95 (synonyms: APO-1/Fas) belongs to the tumor necrosis factor (TNF)/nerve growth factor receptor superfamily. The death receptors in this family share the death domain, i.e., a conserved intracellular motive that transduces the apoptotic signal via activation of intracellular cysteine proteases, the caspases. 1 CD95 is expressed by lymphoid and nonlymphoid cells and is regarded as a principal trigger for apoptotic cell death of hepatocytes. 2,3 In human as well as murine liver, TNF-R1 and CD95 are independent triggers of apoptosis, and the application of the activating anti-CD95 antibody (␣CD95) in mice leads to lethal liver destruction within hours as a result of massive apoptosis of hepatocytes. 4,5 There is growing evidence for the involvement of CD95 in the physiological regulation of hepatocyte turnover, as well as in the pathophysiology of several liver diseases such as viral hepatitis, transplant rejection, and hepatitis caused by inflammatory stimuli. [6][7][8] Similar to cells of immune-privileged sites, tumor cells display an elevated expression of the CD95 ligand (CD95L) and a concomitant dysfunction of CD95, which, for instance, renders hepatocellular carcinomas resistant toward attac...

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N-Acetyl cysteine is an early but also a late preventive agent against carbon tetrachloride-induced liver necrosis

Cited by 40 publications

References 17 publications

Hepatoprotective and antioxidant activity of N-acetyl cysteine in carbamazepine-administered rats

Hepatoprotective and antioxidant activity of N-acetyl cysteine in carbamazepine-administered rats

Oxidative preconditioning affords protection against carbon tetrachloride‐induced glycogen depletion and oxidative stress in rats

CD95-mediated murine hepatic apoptosis requires an intact glutathione status

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