PubMed · 4583705
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R Williams. 1973. Hepatic encephalopathy.. https://pubmed.ncbi.nlm.nih.gov/4583705/
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Paracetamol, in toxic doses, is associated with extensive liver damage. This represents one of the common causes of morbidity and mortality in drug poisoning cases. This study was undertaken to investigate the possible potentiation of the hepatoprotective action of N-acetylcysteine (NAC) by cimetidine (CMD), an inhibitor of hepatic microsomal oxidative enzymes. The effects of NAC, cimetidine and the two in combination, administered 2 h post-paracetamol dose, on mortality, plasma glutamic oxaloacetic (GOT) and glutamic pyruvic (GPT) transaminase activities and hepatic reduced glutathione (GSH) levels were investigated in mice 24 h after treatment with a single oral dose of paracetamol (400 mg/kg). Both NAC and cimetidine caused a partial improvement of survival rate, plasma GOT and GPT activities. In addition, they prevented the depletion of hepatic GSH contents. However, concomitant administration of NAC and cimetidine produced a 100% survival rate and a marked reduction in plasma GOT and GPT activities to within the normal range, while significantly raising hepatic GSH concentrations to values close to those measured in saline-treated control animals. It is therefore concluded that cimetidine and N-acetylcysteine may have an additive hepatoprotective action in the treatment of paracetamol overdose.
Western blot analysis of conditioned media from hepatocytes exposed to H2O2 revealed that a 28 kDa protein was released dose-dependently in response to 1-10 mM H2O2. The 28 kDa protein was present in freshly isolated hepatocytes and exhibited cross-reactivity towards an antibody against CINC/gro. The intracellular amount of the protein decreased in parallel to the H2O2-induced release into the medium. The CINC-related protein was absent in media harvested after 1 h of treatment. The delivery of CINC-related protein correlated with the extent of cell damage as judged from lactate dehydrogenase leakage. Likewise, exposure of hepatocytes to 10-50 mM acetaminophen resulted in a dose-dependent release of the CINC-related protein after 24 h of culture. In contrast, monomeric CINC (molecular weight approximately 6.5 kDa) but not the 28 kDa CINC-related protein was released by lipopolysaccharide (LPS)-stimulated Kupffer cells. The amount of monomeric CINC liberated by Kupffer cells was diminished upon acetaminophen-treatment. Also, the release of tumor necrosis factor-alpha by hepatocytes was reduced after exposure to high acetaminophen doses (40-50 mM). In contrast to this finding, TNF-alpha release from hepatocyte cultures was not affected after H2O2 treatment. These data suggest that damaged hepatocytes release proinflammatory cytokines which may aggravate liver injury through activation of neutrophils and monocytes. The results indicate that the appearance of the CINC-related protein is due to impairment of plasma membrane integrity as the consequence of massive cell damage. In addition, APAP inhibited the release of monomeric CINC from LPS-activated Kupffer cells and of TNF-alpha from hepatocytes even at concentrations that were not sufficient to affect cell viability.
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