카드뮴 중독 흰쥐에서 간세포 세포자멸사에 관한 연구

Abstract

Background and Objectives: Cadmium (Cd) is a heavy metal of considerable environmental and occupational concern. Liver is a major target organ of Cd toxicity following repeated Cd exposures. The aim of this study was to investigate the mechanism of apoptosis on Cd-induced hepatotoxicity in animal model. Materials and Methods: Twenty-four adult male Sprague-Dawley (SD) rats were injected with a dose of Cd acetate daily (30 μmol/kg body weight, intraperitoneally). After 1, 2 and 7 days the rats were killed, and the blood and liver tissues were sampled for analysis. Biochemical analyses of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were conducted. Histopathologic, immunohistochemical and Western blot analyses for cellular damage and apoptosis of the liver were conducted. Results: Decrement of the body weight was identified slowly after 1 day. Serum AST/ALT level was increased. According to the Western blot analyses, caspase-3, -9, Bax, Bid and PARP were decreased and caspase-3, Bid and PARP were cleaved with time- and dose-dependently. Decrement of cytosolic Bax with accordingly increment of the mitochondrial Bax was identified. The mitochondrial Bax induced release of cytochrome C from mitochondria to cytosol. Bcl-2 was decreased but, caspase-8 was not shown significant changes. Histopathologic analysis? showed cytoplasmic eosinophilia with nuclear pyknosis of the hepatocytes with time lapse. Lobular disarray with ballooning degeneration was evident. Cytoplasmic expression of Bax was increased with time. Conclusions: Cd could induce loss of body weight and liver cell damage in SD rat. Cd-induced liver cell damage is associated with apoptotic pathway from activation of Bid and Bax to activation of caspase -3 and -9 through release of mitochondrial cytochrome c, and this is not associated with activation of caspase 8. These results suggest that Cd-induced liver cell apoptosis in rat may not related to the death-receptor pathway. Moreover, this apoptosis is time- and dose-dependent and associated with decrement of Bcl-2. Therefore, the mechanism of Cd-induced apoptosis in the hepatocytes of the SD rat in 7 days involved mitochondrial-dependent pathway but not death-receptor related caspase-dependent signaling.