Fluvastatin reduced liver injury in rat model of extrahepatic cholestasis.

Inhibitors of 3-hydroxy-3methylglutarly coenzyme A, reductase, namely statins, exert pleiotropic actions beyond lipid-lowering effects. In ex vivo and in vitro studies, statins have antioxidative and antiinflammatory effects. Herein, we sought to determine whether treatment with fluvastatin (FV) would be beneficial in a rat model of common bile duct ligation (BDL)-induced liver injury. Female rats were subjected to a sham (n=10) or BDL (n=20). Obstructive jaundice was induced in rats by the ligation and division of the common bile duct. Three days after operation, rats subjected to CBDL were randomized to receive treatment with either FV (10 mg/kg) or saline every day over a 10 days experimental period. High levels of alanine aminotransferase, aspartate aminotransferase, and gamma glutamyltransferase decreased significantly (P<0.05) in animals treated with FV with compared to saline-administrated BDL animals. Compared with sham-operated rats, CBDL rats showed significantly higher levels of total nitrite and nitrate, malondihaldehyde, tumor necrosis factor alpha, myeloperoxidase, and lower concentrations of glutathione, superoxide dismutase, and catalase in the liver tissue (P<0.001). All of these changes were significantly attenuated (P<0.05) by treatment with FV after CBDL. CBDL was associated with increased apoptosis and nuclear factor kappa beta expression in saline-treated rats. Treatment with FV also decreased these parameters. These data support the view that FV ameliorates hepatic inflammation, lipid peroxidation, and tissue injury in rats subjected to CDBL. FV warrants further evaluation as an adjunctive treatment to ameliorate liver injury from extrahepatic biliary obstruction.

The NF-kappaB inhibitors attenuate hepatic injury in bile duct ligated rats.

Cholestasis-induced liver injury during bile duct obstruction causes an inflammatory response and this inflammatory process may be an important source of tissue injury. We hypothesized that NF-kappaB inhibition would decrease liver injury in a rat model of extrahepatic biliary obstruction. A total of 40 female rats of Sprague-Dawley strain were allocated to four groups. First group was sham operated control. The second group underwent common bile duct ligation (BDL) and was monitored for 10 days. Third group of rats underwent BDL and received pyrrolidine dithiocarbomate (PDTC) at a dose of 100 mg/kg/day intraperitoneally. Fourth group underwent BDL and received sulfasalazine at a dose of 100 mg/kg b.w. Both inhibitors were administered once a day throughout last 7 days of the experimental period. Rats were terminated 10 days after sham operation or BDL. Aspartate aminotransferase, alanine aminotransferase, gamma-glutamil transpeptidase, and tumor necrosis factor-alpha levels were elevated in the BDL group as compared to the control group, while this increase was significantly decreased by treatment with PDTC and sulfasalazine (P < 0.05). Hepatic GSH, SOD and catalase levels were significantly depressed by BDL, but were elevated back to control levels in NF-kappaB inhibitor-treated BDL groups. Increases in tissue free radical and MDA levels and MPO activity due to BDL were reduced back to control levels by NF-kappaB inhibitor treatment (P < 0.05). Similarly histological damage in the BDL rats was reduced by treatments. These results indicate that inhibitors of NF-kappaB activity such as PDTB and sulfasalazine exert a therapeutic effect on cholestatic liver injury in rats with BDL through anti-inflammatory and antioxidant actions.