Etoposide Prevents Apoptosis in Mouse Liver With D–Galactosamine/Lipopolysaccharide–Induced Fulminant Hepatic Failure Resulting in Reduction of Lethality

d–Galactosamine (GalN)/lipopolysaccharide (LPS)–induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor α (TNF–α) plays a pivotal role. We examined the effects of etoposide on GalN/LPS–induced fulminant hepatic failure. Mice were given an intraperitoneal dose of GalN (800 μg/g body weight)/LPS (100 ng/g body weight) with and without intraperitoneal etoposide (10 μg/g body weight) treatment. Liver injury was assessed biochemically and histologically. TNF–α levels in the serum, and apoptosis of hepatocytes and CPP32/caspase–3 in the liver, were determined. GalN/LPS treatment caused lethal liver injury in 87% of animals (13 of 15). The effect was associated with significant increases in TNF–α and alanine transaminase (ALT) levels in serum, the number of apoptotic hepatocytes, CPP32/caspase–3 activity, and TNF receptor 1 (TNFR1) mRNA expression in the liver. Etoposide (10 μg/g body weight) was given 3 times (at 50, 26, and 4 hours before GalN/LPS administration). Treatment of GalN/LPS–treated mice with etoposide reduced apoptosis of hepatocytes, resulting in reduction of lethality (13% [2 of 15]), while another topoisomerase II inhibitor, IRCF–193, showed no significant effect. The antilethal effect of etoposide was also confirmed in GalN/TNF–α-induced fulminant hepatic failure. Etoposide treatment reduced CPP32/caspase–3 activity in the liver, although it did not alter the serum TNF–α levels or hepatic TNFR1 mRNA expressions. In addition, etoposide treatment enhanced the mRNA and protein expression of Bcl–xL, an antiapoptotic molecule in the liver. The present findings suggest that etoposide prevents endotoxin–induced lethal liver injury by up–regulation of Bcl–xL, and that etoposide could be useful for the treatment of TNF–α-mediated liver diseases.