Arsenite induces apoptosis in hepatocytes through an enhancement of the activation of Jun N-terminal kinase and p38 mitogen-activated protein kinase caused by partial hepatectomy.

To investigate the effects of arsenite on cell proliferation and the signal transduction in hapatocytes in vivo, rats received a single injection of sodium arsenite immediately after partial hepatectomy. Characteristic DNA fragmentation was observed at 4h after the arsenite-injection in partially hepatectomized liver, while it was not detected either in the control (partial hepatectomy only) or arsenite-injected normal (without partial hepatectomy) liver. The effect of the arsenite-injection on the activation of extracellular signal-regulated kinase (ERK) was not observed in the normal or the partially hepatectomized liver. The activity of p38 mitogen-activated protein kinase (MAPK) markedly increased after 15min to 2h after the arsenite-injection in partially hepatectomized liver while no or a less increase was observed in the arsenite-injected normal or the control, respectively. The Jun N-terminal kinase (JNK) was activated to a maximal level, about six-fold the maximum of the control, at 15min after the injection with partial hepatectomy. The arsenite-injection markedly increased the phosphorylated forms of c-Jun and ATF-2 and the protein levels of c-Jun, p53 and p21(WAF1/CIP1) in the partially hepatectomized liver. These results suggested that arsenite induced apoptosis in the hepatocytes in vivo, through the enhancement of the activation of JNK and p38 MAPK caused by partial hepatectomy and the p53-dependent p21(WAF1/CIP1) protein expression.