Extrahepatic cholestasis will be induced by the method of common bile duct ligation. The potential effect of fluvastatin attenuating the development of cholestatic liver injury will be evaluated by the mesurements of the markers of liver injury - ALT, AST, determination of cholestasis, inflammation, oxidative stress and mitochondrial function. The project should disclose the mechanisms of potential curative effect of statins including the effect on mitochondria function and the dose- and time-dependance.

Na modelu extrabiliární cholestázy navozené podvazem choledochu bude sledován účinek podávání fluvastatinu na rozvoj jaterního poškození. K hodnocení budou použity markery jaterního poškození (ALT, AST) a cholestázy, produkce zánětlivých cytokinů, míra oxidačního stresu a funkce mitochondrií. Projekt má za cíl odhalit mechanizmus případného terapeutického účinku statinů včetně vlivu na funkci mitochondrií, závislost na použité dávce látky a době zahájení jejího podávání (počet dní od provedeného podvazu).

• MeSH
• cytokiny aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• extrahepatální cholestáza MeSH
• glutathion MeSH
• hepatitida chirurgie   MeSH
• peroxidace lipidů MeSH
• statiny aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• syndrom systémové zánětlivé reakce mortalita   MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• hepatologie
• chirurgie
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

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.

• MeSH
• alanintransaminasa krev   účinky léků   metabolismus   MeSH
• alkalická fosfatasa krev   účinky léků   metabolismus   MeSH
• aspartátaminotransferasy krev   účinky léků   metabolismus   MeSH
• bilirubin krev   metabolismus   MeSH
• gama-glutamyltransferasa krev   účinky léků   metabolismus   MeSH
• glukuronosyltransferasa účinky léků   metabolismus   MeSH
• glutathion účinky léků   metabolismus   MeSH
• indoly škodlivé účinky   MeSH
• interleukin-6 metabolismus   MeSH
• intrahepatální cholestáza farmakoterapie   metabolismus   MeSH
• játra účinky léků   patologie   MeSH
• krysa rodu rattus MeSH
• kyseliny mastné mononenasycené škodlivé účinky   MeSH
• ligace MeSH
• messenger RNA účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• statiny škodlivé účinky   MeSH
• transformující růstový faktor beta účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND AND AIM: The administration of pravastatin to patients with cholestatic liver disease has suggested the potential of the drug with regard to reducing raised plasma cholesterol and bile acid levels. Information about the mechanisms associated with this effect is lacking. Thus, the aim of the present study is to evaluate pravastatin effects on the liver bile acid and cholesterol homeostasis in healthy and cholestatic rats. METHODS: Control sham-operated and reversibly bile duct-obstructed (BDO) rats were treated with pravastatin (1 or 5 mg/kg) or the vehicle alone for 7 days after surgery. RESULTS: Lower doses of pravastatin reduced bile acid plasma concentrations in cholestatic animals. The effect was associated with reduced liver mRNA expression of Cyp7a1, Cyp8b1, Mrp2, Ugt1a1 and the increased expression of Bsep. In addition, BDO-induced increase in the liver content of cholesterol was normalized by pravastatin. The change was accompanied by the reduced liver expression of Hmg-CoA reductase, LDL receptor, and Acat2, and induced the expression of Abca1 and Mdr2. These changes corresponded with the upregulation of nuclear receptors LXRα and PPARα, and the downregulation of FXR, CAR, SREBP-2 and HNF1α. High doses of pravastatin lacked any positive effects on bile acids and cholesterol homeostasis, and blocked bile formation through the reduction of the biliary excretion of bile acids. CONCLUSIONS: Pravastatin rendered a positive reduction in BDO-induced increases in plasma bile acid concentrations and cholesterol liver content, mainly through the transcriptionally-mediated downregulation of genes involved in the synthesis of these compounds in the liver.

• MeSH
• časové faktory MeSH
• cholestáza farmakoterapie   genetika   metabolismus   MeSH
• cholesterol metabolismus   MeSH
• chronická nemoc MeSH
• homeostáza MeSH
• játra účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• membránové transportní proteiny genetika   metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• permeabilita MeSH
• potkani Wistar MeSH
• pravastatin farmakologie   MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• statiny farmakologie   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• MeSH
• hepatektomie MeSH
• játra účinky léků   patologie   chirurgie   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• regenerace jater účinky léků   fyziologie   MeSH
• S-adenosylmethionin aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH