ABSTRACT
Antiinflammatory effect of statins mediated by the reduction of cytokine IL-6 in hepatocytes have been reported. Contrary to beneficial effect, statins can increase susceptibility to mitochondrial dysfunction. Extrahepatic biliary obstruction is associated with oxidative stress, pro-inflammatory response and hepatocyte mitochondrial dysfunction. The aim of our study was to verify the effect of fluvastatin on cholestatic liver injury. Cholestasis was induced in Wistar rats by bile duct ligation. Fluvastatin (1 or 5 mg/kg) was administered after surgery and then daily for 7 days. The dose of 5 mg/kg led to the deterioration of hepatocellular injury. Despite lower production of IL-6, decrease in GSH content, rise of TGFß and inhibition of respiratory complex I in mitochondria were determined. The mRNA expressions of canalicular transporter Mdr1b and basolateral transporter Mrp3 increased in cholestatic liver. Fluvastatin administration then led to the attenuation of this change. Analogously, mRNA expression of conjugative enzyme Ugt1a1 was diminished by fluvastatin administration to cholestatic rats. We can conclude that decrease in the antioxidative status and mitochondrial dysfunction could at least in part participate on the deteriorating effect of fluvastatin. Whether these processes can be a consequence of the alteration in metabolism and transport of potentially toxic substances remains to verify.
Subject(s)
Cholestasis, Intrahepatic/drug therapy , Cholestasis, Intrahepatic/metabolism , Fatty Acids, Monounsaturated/adverse effects , Indoles/adverse effects , Interleukin-6/metabolism , Alanine Transaminase/blood , Alanine Transaminase/drug effects , Alanine Transaminase/metabolism , Alkaline Phosphatase/blood , Alkaline Phosphatase/drug effects , Alkaline Phosphatase/metabolism , Animals , Aspartate Aminotransferases/blood , Aspartate Aminotransferases/drug effects , Aspartate Aminotransferases/metabolism , Bilirubin/blood , Bilirubin/metabolism , Fluvastatin , Glucuronosyltransferase/drug effects , Glucuronosyltransferase/metabolism , Glutathione/drug effects , Glutathione/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Ligation , Liver/drug effects , Liver/pathology , Male , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Wistar , Transforming Growth Factor beta/drug effects , Transforming Growth Factor beta/metabolism , gamma-Glutamyltransferase/blood , gamma-Glutamyltransferase/drug effects , gamma-Glutamyltransferase/metabolismABSTRACT
S-adenosylmethionine (SAMe) is a key metabolite regulating growth, differentiation and death of hepatocytes. Experimentally, exogenous SAMe has been documented to attenuate hepatocarcinogenesis. The aim of our study was to evaluate the effect of SAMe on proliferation of hepatocytes that are not cancerously transformed. Partial 2/3 hepatectomy (PH) was performed in rats, control animals underwent laparotomy. SAMe was injected immediately after the surgery and then at 24 h intervals for two days at 10 or 40 mg/kg. The animals were sacrificed 24, 48 and 72 h after operation and the intensity of liver regeneration was evaluated. SAMe treatment at 10 mg/kg was associated with decrease in the synthesis of liver DNA 48 h after PH, however, it was not reflected in DNA content. SAMe treatment at 40 mg/kg led to the reduction of DNA synthesis 72 h after PH followed by the diminution of DNA content. The results have documented the inhibition of the liver regeneration by SAMe that may be mediated by the suppression of liver fat accumulation. Cell GSH level correlating with the growth rate was not affected by SAMe. Prevention from the decrease in the intracellular content of SAMe, as a factor attenuating regeneration remains to be verified.