The course of a-amanitin (a-AMA) toxicity in cultured canine and human hepatocytes is divided into 2 phases. The first phase comprises mainly functional cell impairments expressed by inhibition of protein and urea synthesis. The second stage is lethal and is characterized by ongoing necrosis and/ or apoptosis. a-AMA-induced apoptosis in human heptocyte cultures is p53- and caspase-3-dependent. Moreover, a-AMA causes increase in SOD activity, reduction of CAT activity and a significant increase in lipid peroxidation in cells, which may contribute to its severe hepatotoxicity.