MECHANISM OF GALACTOSAMINE-INDUCED HEPATOCYTE APOPTOSIS

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Details of galactosamine (GalN)-induced apoptosis in mouse hepatocytes were investigated. In the primary hepatocyte cultures treated with GalN,DNA-fragmentation was detected prior to LDH-release from cells to culture medium, and apoptosis was followed by necrosis in the high dose group (20mM). Hepatocyte apoptosis was also induced in mice at 24 hr after GalN-treatment (3mg/kg), and apoptosis was also followed by necrosis in this case.Immediately after GalN-treatment, an intracellular Ca^<2+>-concentration arose sharply in the primary hepatocyte cultures. In addition, CPZ (Ca^<2+>-calmodulin antagonist) and VR (Ca^<2+>-channel blocker) effectively suppressed hepatocyte apoptosis both in in vitro and in vivo systems when they were administered before GalN-treatment, and this suggests that a rapid increase in intracellular Ca^<2+>-concentration may play an important role in the development of GalN-induced hepatocyte apoptosis. Now we are trying to elucidate why GalN-treatment induces a rapid Ca^<2+>-influx into hepatocytes. On the other hand, hepatocyte necrosis was not suppressed by CPZ- and VR-treatment. Moreover, Fas and p53 had no relation to the induction of apoptosis by GalN.The mechanism of GalN-induced hapatocyte apoptosis seems to be different from those of T-2 toxin-induced lymphocytic apoptosis and of 5-azacytidine-induced neuronnal apoptosis which were also examined in the present project from the comparative viewpoints.