title: Deteriorating effect of fluvastatin on the cholestatic liver injury induced by bile duct ligation in rats.
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.
authors: Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38 Hradec Králové, Czech Republic. lotko@lfhk.cuni.cz
authors: Halka
authors: H
authors: Lotková
authors: Pavla
authors: P
authors: Staňková
authors: Tomáš
authors: T
authors: Roušar
authors: Otto
authors: O
authors: Kučera
authors: Lukáš
authors: L
authors: Kohoutek
authors: Stanislav
authors: S
authors: Mičuda
authors: Eva
authors: E
authors: Brčáková
authors: Gabriela
authors: G
authors: Kolouchová
authors: Zuzana
authors: Z
authors: Cervinková
mesh_terms: D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D001663:Bilirubin / Q000097:blood / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000188:drug therapy* / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000009:adverse effects*; D000077340:Fluvastatin; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects; D007211:Indoles / Q000009:adverse effects*; D015850:Interleukin-6 / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001219:Aspartate Aminotransferases; D001663:Bilirubin; D005229:Fatty Acids, Monounsaturated; D000077340:Fluvastatin; D014453:Glucuronosyltransferase; D005978:Glutathione; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D015850:Interleukin-6; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D005723:gamma-Glutamyltransferase; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme