Role of caspases in acetaminophen-induced liver injury.
Life Sci
; 78(15): 1670-6, 2006 Mar 06.
Article
en En
| MEDLINE
| ID: mdl-16226279
ABSTRACT
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 microM 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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Analgésicos no Narcóticos
/
Caspasas
/
Hepatopatías
/
Acetaminofén
Límite:
Animals
Idioma:
En
Revista:
Life Sci
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
HOLANDA
/
HOLLAND
/
NETHERLANDS
/
NL
/
PAISES BAJOS
/
THE NETHERLANDS