Effect of ZVAD-fmk on hepatocyte apoptosis after bile duct ligation in rat

Aim: Retention and accumulation of toxic hydrophobic bile salts within hepatocyte may cause hepatocyte toxicity by inducing apoptosis. Apoptosis is a pathway of cell death orchestrated by a family of proteases called caspases. Z-Val-Ala-Asp (OMe)-fluoromethyl ketone (ZVAD-fmk) is a cell-permeable irreversible inhibitor of caspase. The purpose of this study was to evaluate the possible effect of ZVAD-fmk on hepatocyte apoptosis after bile duct ligation in the rat. Methods: Male Sprague-Dawley rats, weighing 250-300 g, were randomized to five groups of five rats each. Group 1 underwent common bile duct ligation and simultaneous treatment with ZVAD-fmk (dissolved in dimethylsulfoxide (DMSO)). Group 2 underwent common bile duct ligation and simultaneous treatment with Z-Phe-Ala-fluoromethyl ketone (ZFA-fmk, dissolved in DMSO). Group 3 underwent sham operation and simultaneous treatment with the same amount of DMSO. Group 4 underwent sham operation and simultaneous treatment with the same amount of normal saline. Group 5 underwent common bile duct ligation without other manipulation. After three days, liver tissue was harvested for histopathologic analysis and measurements of apoptosis. Results: When compared with sham operation, common bile duct ligation significantly increased hepatocyte apoptosis (P = 0.008) and ductular proliferation (P = 0.007). ZVAD-fmk significantly diminished the increased hepatocyte apoptosis and ductular proliferation after common bile duct ligation (P = 0.008 and P = 0.007, respectively). ZFA did not show the same effects. Conclusion: Hepatocyte apoptosis and ductular proliferation significantly increased after common bile duct ligation. ZVAD-fmk effectively diminished the increased hepatocyte apoptosis and ductular proliferation after common bile duct ligation, whereas ZFA-fmk did not.