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.

Department of Biological and Medical Sciences Faculty of Pharmacy in Hradec Králové Charles University Prague Heyrovského 1203 500 05 Hradec Králové Czech Republic

Department of Pharmacology Faculty of Medicine in Hradec Králové Charles University Prague Šimkova 870 500 38 Hradec Králové Czech Republic

Department of Physiology Faculty of Medicine in Hradec Králové Charles University Prague Šimkova 870 500 38 Hradec Králové Czech Republic

Department of Surgery Faculty of Health Studies University of Pardubice Průmyslová 395 532 10 Pardubice Czech Republic

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