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Deteriorating effect of fluvastatin on the cholestatic liver injury induced by bile duct ligation in rats
H. Lotková, P. Staňková, T. Roušar, O. Kučera, L. Kohoutek, S. Mičuda, E. Brčáková, G. Kolouchová, Z. Cervinková
Language English Country Slovakia
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
NS9739
MZ0
CEP Register
- MeSH
- Alanine Transaminase blood drug effects metabolism MeSH
- Alkaline Phosphatase blood drug effects metabolism MeSH
- Aspartate Aminotransferases blood drug effects metabolism MeSH
- Bilirubin blood metabolism MeSH
- gamma-Glutamyltransferase blood drug effects metabolism MeSH
- Glucuronosyltransferase drug effects metabolism MeSH
- Glutathione drug effects metabolism MeSH
- Indoles adverse effects MeSH
- Interleukin-6 metabolism MeSH
- Cholestasis, Intrahepatic drug therapy metabolism MeSH
- Liver drug effects pathology MeSH
- Rats MeSH
- Fatty Acids, Monounsaturated adverse effects MeSH
- Ligation MeSH
- RNA, Messenger drug effects metabolism MeSH
- Rats, Wistar MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects MeSH
- Transforming Growth Factor beta drug effects metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
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- $a 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.
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