Role of caspases in acetaminophen-induced liver injury

• Published in: Life sciences (1973) 2006-03, Vol.78 (15), p.1670-1676
• Main Authors: Jaeschke, Hartmut, Cover, Cathleen, Bajt, Mary Lynn
• Format: Article
• Language: English
• Subjects: Acetaminophen; Acetaminophen - adverse effects; Amino Acid Chloromethyl Ketones - pharmacology; Analgesics, Non-Narcotic - adverse effects; Animals; Caspase Inhibitors; Caspases - metabolism; Chemical and Drug Induced Liver Injury; Cysteine Proteinase Inhibitors - pharmacology; Dimethyl Sulfoxide - pharmacology; Dose-Response Relationship, Drug; Drug hepatotoxicity; Drug-induced apoptosis; Liver Diseases - enzymology; Liver Diseases - prevention & control; Male; Mice; Mice, Inbred Strains; Oncotic necrosis; Solvents - pharmacology
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2005.07.003

The mode of cell death after acetaminophen (AAP) overdose is controversially discussed. A recent study reported a protective effect of the pancaspase inhibitor Z-VAD-fmk against AAP toxicity in vivo but the mechanism of protection remained unclear. Therefore, the objective of this investigation was to assess if Z-VAD-fmk or the low doses of dimethyl sulfoxide (DMSO) used as solvent were responsible for the protection. Treatment with 10 mg/kg Z-VAD-fmk or diluted DMSO (0.25 ml/kg) for 15 min before but not 2.5 h after AAP prevented the oxidant stress (hepatic glutathione disulfide content; nitrotyrosine staining), DNA fragmentation (anti-histone ELISA, TUNEL assay) and liver injury (plasma ALT activities) at 6 h after administration of 300 mg/kg AAP. Even a lower dose (0.1 ml/kg) of DMSO was partially effective. DMSO pretreatment also attenuated the initial decline in hepatic glutathione levels. On the other hand, 10 μM Z-VAD-fmk was unable to prevent AAP-induced cell death in primary cultured mouse hepatocytes. We conclude that Z-VAD-fmk does not protect against AAP-induced liver injury and, therefore, caspases are not involved in the mechanism of AAP-induced liver injury. In contrast, the protection in vivo is caused by the diluted DMSO, which is used to solubilize the inhibitor Z-VAD-fmk. The results emphasize that even very low doses of DMSO, which are generally necessary to dissolve water-insoluble inhibitors, can have a profound impact on the toxicity of drugs and chemicals when metabolic activation is a critical aspect of the mechanism of cell injury.