Effects of Three Different Fibrates on Intrahepatic Cholestasis Experimentally Induced in Rats

Background . Activation of PPAR α modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of PPAR α agonists, fenofibrate, bezafibrate, and gemfibrozil, on acute cholestasis induced by ethinylestradiol (EE) plus chlorpromazine (CPZ) in rats. Method . 100 male albino rats (150–200 gm) were divided randomly into 10 equal groups. Control group received 1% methylcellulose vehicle; disease group received CPZ plus EE for 5 consecutive days; four groups received either ursodeoxycholic acid, fenofibrate, bezafibrate, or gemfibrozil for 7 days; 2 days before EE + CPZ, three other groups received one of the three fibrates after GW6471, a selective PPAR α antagonist in addition to EE + CPZ. The final group received GW6471 alone. Results . The three fibrates showed marked reduction ( P < 0.05) in serum levels of ALP, GGT, ALT, AST, total bile acids, bilirubin, TNF α , and IL-1 β and in hepatic malondialdehyde level as well as a significant increase in bile flow rate ( P < 0.05) in addition to improvements in histopathological parameters compared to diseased group. In groups which received GW6471, these effects were completely abolished with fenofibrate and partially blocked with bezafibrate and gemfibrozil. Conclusion . Short-term administration of fibrates to EE/CPZ-induced intrahepatic cholestatic rats exerted beneficial effects on hepatocellular damage and apoptosis. Fenofibrate anticholestatic effect was solely PPAR α dependent while other mechanisms played part in bezafibrate and gemfibrozil actions.