PURPOSE: In the following, the cellular and molecular mechanism of cytotoxicity induced by prodrug dacarbazine toward the isolated rat hepatocytes was studied. METHOD: Accelerated cytotoxicity screening technique (ACMS) was used to perform this study. RESULT: Addition of dacarbazine to isolated rat hepatocytes resulted in reactive oxygen species (ROS) formation, and lysosomal membrane leakiness before hepatocyte lysis occurred. Hepatocyte ROS generation was inhibited by desferoxamine (a ferric chelator). Cytotoxicity was prevented by antioxidants or ROS scavengers (mannitol or dimethylsulfoxide), cytochorome P450 inhibitors (phenylimidazole, diphenyliodonium chloride, 4-methylpyrazole, and benzylimidazole). In addition to lysosomal damage, dacarbazine caused hepatocyte protease activation and cell proteolysis. CONCLUSION: Dacarbazine cytotoxicity is associated with ROS (H(2)O(2), O(2)(*-) ) generation. It is suggested that H(2)O(2) could cross the lysosomal membrane, react with lysosomal Fe(2+) to form hydroxyl radical (Haber-Weiss reaction) which is the major cause of lysosomal membrane leakiness, proteases, and other digestive enzymes' release and finally the cell death.
PURPOSE: In the following, the cellular and molecular mechanism of cytotoxicity induced by prodrug dacarbazine toward the isolated rat hepatocytes was studied. METHOD: Accelerated cytotoxicity screening technique (ACMS) was used to perform this study. RESULT: Addition of dacarbazine to isolated rat hepatocytes resulted in reactive oxygen species (ROS) formation, and lysosomal membrane leakiness before hepatocyte lysis occurred. Hepatocyte ROS generation was inhibited by desferoxamine (a ferric chelator). Cytotoxicity was prevented by antioxidants or ROS scavengers (mannitol or dimethylsulfoxide), cytochorome P450 inhibitors (phenylimidazole, diphenyliodonium chloride, 4-methylpyrazole, and benzylimidazole). In addition to lysosomal damage, dacarbazine caused hepatocyte protease activation and cell proteolysis. CONCLUSION:Dacarbazinecytotoxicity is associated with ROS (H(2)O(2), O(2)(*-) ) generation. It is suggested that H(2)O(2) could cross the lysosomal membrane, react with lysosomal Fe(2+) to form hydroxyl radical (Haber-Weiss reaction) which is the major cause of lysosomal membrane leakiness, proteases, and other digestive enzymes' release and finally the cell death.
Authors: Ahmad Salimi; Mehrdad Vaghar-Moussavi; Enayatollah Seydi; Jalal Pourahmad Journal: Environ Sci Pollut Res Int Date: 2016-01-22 Impact factor: 4.223
Authors: H O Lawal; A Terrell; H A Lam; C Djapri; J Jang; R Hadi; L Roberts; V Shahi; M-T Chou; T Biedermann; B Huang; G M Lawless; N T Maidment; D E Krantz Journal: Mol Psychiatry Date: 2012-12-11 Impact factor: 15.992