Epidermal growth factor attenuates α-amanitin-induced hepatotoxicity: a comparison with silibinin.

α-Amanitin, the principal toxin of Amanita phalloides, causes fulminant hepatic failure for which no antidote of proven efficacy exists. Silibinin is the agent most often used, yet its clinical benefit remains uncertain. Because epidermal growth factor receptor signalling is engaged during α-amanitin injury and epidermal growth factor (EGF) has antioxidant and cytoprotective properties, we asked whether EGF protects hepatocytes against α-amanitin. In HuH-7 cells, neither EGF (up to 20 μM) nor silibinin (up to 100 μM) was cytotoxic; in the MTT assay, which reflects metabolic activity rather than definitive viability, co-treatment did not significantly change the signal relative to 10 μM α-amanitin, whereas EGF restored superoxide dismutase, catalase and glutathione and lowered malondialdehyde in a concentration-dependent manner. In BALB/c mice, acute α-amanitin poisoning (0.75 mg/kg) was treated with EGF (750 or 1500 μg/kg), silibinin (5 mg/kg), or their combination. High-dose EGF produced the largest falls in serum AST, ALT, ALP and GGT, the lowest liver histological damage score, and the lowest hepatic caspase-3 immunopositivity; on these endpoints its effect was comparable to that of the single silibinin regimen tested and greater than the 750 μg/kg dose. Within the limits of an acute model that did not assess survival or measure signalling, EGF - particularly at the higher dose - attenuated α-amanitin hepatotoxicity in association with reduced oxidative stress and apoptosis, and merits further evaluation as a candidate treatment for amatoxin poisoning.