Effect of S-adenosylmethionine on Acetaminophen-induced Toxic Injury of Rat Hepatocytes in vitro

Acetaminophen (AAP) overdose causes severe liver injury and is the leading cause of acute liver injury in humans. The mechanisms participating in its toxic effect are glutathione depletion, oxidative stress and mitochondrial dysfunction. S-adenosylmethionine (SAMe) is the principal biological methyl donor and is also a precursor of glutathione. In our previous studies we have documented a protective action of SAMe against various toxic injuries of rat hepatocytes in primary cultures. The aim of this study was to evaluate a possible protective effect of SAMe against AAP-induced toxic injury of primary rat hepatocytes. Hepatocytes were exposed to AAP (2.5 mM) or AAP together with SAMe at the final concentrations of 5, 25 or 50 mg/l for 24 h. Incubation of hepatocytes with AAP caused a significant increase of the leakage of lactate dehydrogenase (LDH) (p p p p < 0.05). SAMe did not influence AAP-induced decrease of cellular content of glutathione. Mitochondrial respiration of harvested digitonin-permeabilized hepatocytes was measured; Complex II was more sensitive to toxic action of AAP, respiration was decreased by 20%. This decrease was completely abolished by SAMe

Liver regeneration after partial hepatectomy in rats suffering from non-alcoholic fatty liver disease

1. SUMMARY Liver regeneration after partial hepatectomy in rats suffering from non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD) is currently the most frequent chronic liver disease in economically developed countries with prevalence of about 30 %. Liver resection from different reasons is nowadays common surgical procedure. Successful recovery and renewal of liver functions depend on regenerative capacity of liver remnant. The course of liver regeneration could be profoundly influenced by concomitant liver pathological processes including NAFLD. The aim of this work has been study of early phase of liver regeneration after partial hepatectomy (PHx) in rats with nutritionally induced simple steatosis. At the beginning we introduced a model of NAFLD by a high-fat diet giving to Wistar or Sprague-Dawley rats for 3 and 6 weeks, resp. This regimen induced simple steatosis without signs of inflammation, necrosis or fibrotic changes in both strains. In the second part of our study we followed if liver regeneration after PHx in rats with NAFLD is altered. Liver regeneration was assessed by bromodeoxyuridin incorporation into DNA of hepatocytes. Regeneration of liver with simple steatosis induced by 2/3 PHx was not significantly influenced in comparison to non-steatotic liver. The only..

Studying Liver Regeneration by Means of Molecular Biology: How Far We Are in Interpreting the Findings?

Liver regeneration in mammals is a unique phenomenon attracting scientific interest for decades. It is a valuable model for basic biology research of cell cycle control as well as for clinically oriented studies of wide and heterogeneous group of liver diseases. This article provides a concise review of current knowledge about the liver regeneration, focusing mainly on rat partial hepatectomy model. The three main recognized phases of the regenerative response are described. The article also summarizes history of molecular biology approaches to the topic and finally comments on obstacles in interpreting the data obtained from large scale microarray-based gene expression analyses

The Effect of tert-Butyl Hydroperoxide-Induced Oxidative Stress on Lean and Steatotic Rat Hepatocytes In Vitro

Oxidative stress and mitochondrial dysfunction play an important role in the pathogenesis of nonalcoholic fatty liver disease and toxic liver injury. The present study was designed to evaluate the effect of exogenous inducer of oxidative stress (tert-butyl hydroperoxide, tBHP) on nonfatty and steatotic hepatocytes isolated from the liver of rats fed by standard and high-fat diet, respectively. In control steatotic hepatocytes, we found higher generation of ROS, increased lipoperoxidation, an altered redox state of glutathione, and decreased ADP-stimulated respiration using NADH-linked substrates, as compared to intact lean hepatocytes. Fatty hepatocytes exposed to tBHP exert more severe damage, lower reduced glutathione to total glutathione ratio, and higher formation of ROS and production of malondialdehyde and are more susceptible to tBHP-induced decrease in mitochondrial membrane potential. Respiratory control ratio of complex I was significantly reduced by tBHP in both lean and steatotic hepatocytes, but reduction in NADH-dependent state 3 respiration was more severe in fatty cells. In summary, our results collectively indicate that steatotic rat hepatocytes occur under conditions of enhanced oxidative stress and are more sensitive to the exogenous source of oxidative injury. This confirms the hypothesis of steatosis being the first hit sensitizing hepatocytes to further damage