Amelioration of Hepatocellular Integrity and Inhibition of Sinusoidal Oxidative Stress by N-Acetylcysteine Pretreatment in Cold Ischemia-Reperf usion Injury of Rat Liver

Nakano, Hiroshi; Boudjéma, Karim; Jaeck, Daniel; Alexandre, Eliane; Imbs, Pierre; Chenard, Marie–Pierre; Nagasaki, Hideaki; Kumada, Kaoru; Wolf, Philippe; Cinqualbre, J

doi:10.1159/000129463

Cited by 13 publications

(17 citation statements)

References 23 publications

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“…A previous study from our institution showed that the administration of N-acetylcysteine, another precursor of GSH, could not increase ATP concentrations after ischemia [22]. However, in the present study, concentrations of mitochondrial GSH and hepatic ATP 2 h after reperfusion were increased by administration of SAMe to steatotic rats.…”

Section: Discussioncontrasting

confidence: 92%

“…However, administration of SAMe significantly increased cytosolic and mitochondrial GSH concentrations after 60 min of ischemia followed by 2 h of reperfusion in steatotic rats. Administration of SAMe also decreased hepatocellular and mitochondrial oxidative stress, as shown by the cytosolic and mitochondrial GSSG/GSH ratios, which are markers of oxidative stress [16,21,22].…”

Section: Discussionmentioning

confidence: 92%

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Augmentation of Mitochondrial Reduced Glutathione by S-Adenosyl-L-Methionine Administration in Ischemia-Reperfusion Injury of the Rat Steatotic Liver Induced by Choline-Methionine-Deficient Diet

et al. 1998

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We examined whether warm ischemia-reperfusion (I/R) damage of the rat steatotic liver can be reduced by administration of S-adenosyl-L-methionine (SAMe). We examined the effect of SAMe on the mitochondrial reduced-glutathione (GSH) pool. Sixty minutes of partial left lobar vascular clamping followed by 2 h of reperfusion were employed for a model of hepatic warm ischemia. Either 5% dextrose or SAMe was injected intraperitoneally 2 h before I/R in steatotic rats (S-D5% or S-SAMe group). Serum liver enzyme concentrations 2 h after reperfusion were significantly lower in the S-SAMe group than in the S-D5% group. The cytosolic and mitochondrial GSH concentrations after I/R were significantly higher in the S-SAMe group than in the S-D5% group (p < 0.05). The cytosolic and mitochondrial oxidized-glutathione/GSH ratios after I/R were significantly greater in the S-D5% group than in the S-SAMe group (p < 0.01). The adenosine triphosphate concentration was higher in the S-SAMe group than in the S-D5% group (p = 0.0515). These results show that hepatocellular and mitochondrial oxidative stress after I/R in the steatotic liver can be reduced by administration of SAMe. The results also show that mitochondrial function and hepatocellular integrity can be restored by administration of SAMe in steatotic rats.

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Section: Discussioncontrasting

confidence: 92%

Section: Discussionmentioning

confidence: 92%

Augmentation of Mitochondrial Reduced Glutathione by S-Adenosyl-L-Methionine Administration in Ischemia-Reperfusion Injury of the Rat Steatotic Liver Induced by Choline-Methionine-Deficient Diet

et al. 1998

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“…For example, a major antioxidant function of NAC is to provide cysteine for glutathione synthesis, yet we have demonstrated that glutathione is not required for NAC-mediated inhibition of LPS activation in Kupffer cells [16]. Similar results have also been reported in a rat model of ischemia-reperfusion injury [17] and preservation injury [18]. In addition, we have provided the first data to show that NAC and ␣-tocopherol retain their inhibitory effects even when administered at points beyond the initiation of NF-B activation [19].…”

Section: Introductionsupporting

confidence: 84%

“…We have previously shown that synthesis of glutathione is not required for this effect [16] and similar data has been derived in animal models of hepatic injury [17,18]. These data suggested that oxidant stress is not a major byproduct of LPS stimulation of Kupffer cells because glutathione levels did not vary with activation and NAC was equally inhibitory when glutathione synthesis was inhibited.…”

Section: Discussionsupporting

confidence: 59%

“…Consistent with this idea this study has shown that the inhibition of protein synthesis completely prevents the effect of NAC on LPS-mediated induction of TNF-␣ mRNA. The uniformity of the cycloheximide effect, regardless of NAC concentration, argues against a passive free radical quenching by NAC suggested by Nakano et al [17,18] and suggests a more complex mechanism requiring a cellular synthetic event.…”

Section: Discussionmentioning

confidence: 78%

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Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine occurs subsequent to NF-κB translocation and requires protein synthesis

Fox

Leingang

1998

Journal of Leukocyte Biology

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Activation of the resident hepatic macrophage population, Kupffer cells, leads to production of mediators that initiate, potentiate, and modulate hepatic injury. Recent studies have shown that activation of the pluripotent transcription factor nuclear factor-B (NF-B) is an important step in the induction of inflammatory cytokines, chemokines, growth factors, cell adhesion proteins, and cytokine receptors, thus efforts have been focused to modulate its activity. A common observation in diverse experimental systems is that oxidant stress activates NF-B and antioxidant drugs prevent activation and subsequent inflammatory gene transcription. However, we have recently shown that the inhibitory effect of N-acetylcysteine (NAC) is independent of its role as a substrate of glutathione synthesis and NAC can inhibit Kupffer cell activation at points beyond the initiation of activation. The goal of this study was to characterize the mechanism for NAC-mediated inhibition of Kupffer cell activation. We show for the first time that this process requires a cellular synthetic response to prevent both NF-B and tumor necrosis factor ␣ (TNF-␣) mRNA activation. Furthermore, NACmediated inhibition occurs after degradation of IB-␣ and nuclear translocation of NF-B. These data suggest that inhibition of Kupffer cell activation by NAC is a nuclear event and offers a potential approach to modulate Kupffer cell activation during hepatic injury.

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Effect of Antioxidant Treatments on the Gut–Liver Axis Oxidative Status and Function in Bile Duct‐Ligated Rats

et al. 2007

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NAC, allopurinol, and alpha-TC, exerting a potent combined antioxidant effect on the intestine and liver in experimental obstructive jaundice, significantly prevented intestinal barrier dysfunction and liver injury. The variety of results depending on the antioxidant agent that was administered and the marker of oxidative stress that was estimated, indicates that a battery of biomarkers would be more appropriate in assessing pharmacologic responses to therapeutic interventions.

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Amelioration of Hepatocellular Integrity and Inhibition of Sinusoidal Oxidative Stress by N-Acetylcysteine Pretreatment in Cold Ischemia-Reperf usion Injury of Rat Liver

Cited by 13 publications

References 23 publications

Augmentation of Mitochondrial Reduced Glutathione by S-Adenosyl-L-Methionine Administration in Ischemia-Reperfusion Injury of the Rat Steatotic Liver Induced by Choline-Methionine-Deficient Diet

Augmentation of Mitochondrial Reduced Glutathione by S-Adenosyl-L-Methionine Administration in Ischemia-Reperfusion Injury of the Rat Steatotic Liver Induced by Choline-Methionine-Deficient Diet

Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine occurs subsequent to NF-κB translocation and requires protein synthesis

Effect of Antioxidant Treatments on the Gut–Liver Axis Oxidative Status and Function in Bile Duct‐Ligated Rats

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