Protective effect of caffeic acid phenethyl ester against carbon tetrachloride-induced hepatotoxicity in mice

This study was designed to investigate the protective effects of the phenethyl ester of caffeic acid (CAPE) against carbon tetrachoride (CCl4)-induced hepatotoxicities in mice. Pretreatment with CAPE prior to administration of CCl4 significantly prevented the increases in serum alanine, aspartate aminotransferase and alkaline phosphatase activities, hepatic lipid peroxidation formation, and depletion of glutathione content. In addition, CAPE prevented CCl4-induced apoptosis and necrosis, as indicated by liver histopathology and DNA laddering studies. To determine whether the Fas/Fas ligand (FasL) pathway is involved in CCl4-induced acute liver injury, Fas and FasL proteins and caspase-3 and -8 activities were tested by western blotting and ELISA. CAPE markedly decreased CCl4-induced Fas/FasL protein expression levels and, in turn, attenuated CCl4-induced caspase-3 and -8 activities in mouse liver. Moreover, the effect of CAPE on CYP2E1, the major isozyme involved in CCl4 bioactivation, was investigated. Treatment with CAPE significantly decreased the CYP2E1-dependent hydroxylation of aniline. In addition, CAPE attenuated the CCl4-mediated depletion of antioxidant enzyme (catalase, superoxide dismutase and glutathione-S-transferase) activities. These findings suggest that the protective effects of CAPE against CCl4-induced acute liver injury may involve its ability to block CYP2El-mediated CCl4 bioactivation and to protect against Fas/FasL-mediated apoptosis.