Etoposide prevents apoptosis in mouse liver with D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure resulting in reduction of lethality

Hepatology. 2001 Jun;33(6):1441-50. doi: 10.1053/jhep.2001.24561.


D-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor alpha (TNF-alpha) 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 microg/g body weight)/LPS (100 ng/g body weight) with and without intraperitoneal etoposide (10 microg/g body weight) treatment. Liver injury was assessed biochemically and histologically. TNF-alpha 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-alpha 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 microg/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-alpha-induced fulminant hepatic failure. Etoposide treatment reduced CPP32/caspase-3 activity in the liver, although it did not alter the serum TNF-alpha 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-alpha-mediated liver diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspase Inhibitors
  • Cytochrome c Group / antagonists & inhibitors
  • Cytoplasm / metabolism
  • Etoposide / pharmacology*
  • Galactosamine
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Lipopolysaccharides
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver / physiopathology*
  • Liver Failure / chemically induced
  • Liver Failure / mortality*
  • Liver Failure / physiopathology*
  • Liver Failure / prevention & control
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Messenger / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha / metabolism
  • bcl-X Protein


  • Antigens, CD
  • Antineoplastic Agents, Phytogenic
  • Bcl2l1 protein, mouse
  • Caspase Inhibitors
  • Cytochrome c Group
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • bcl-X Protein
  • Etoposide
  • Galactosamine
  • Casp3 protein, mouse
  • Caspase 3