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 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.
Nakama
T
T
Department of Internal Medicine II, Miyazaki Medical College, Miyazaki, Japan.
Hirono
S
S
Moriuchi
A
A
Hasuike
S
S
Nagata
K
K
Hori
T
T
Ido
A
A
Hayashi
K
K
Tsubouchi
H
H
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D003574:Cytochrome c Group / Q000037:antagonists & inhibitors; D003593:Cytoplasm / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology*; D005688:Galactosamine; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017093:Liver Failure / Q000139:chemically induced / Q000401:mortality* / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051020:bcl-X Protein
D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; C494812:Bcl2l1 protein, mouse; D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D005047:Etoposide; D005688:Galactosamine; C505409:Casp3 protein, mouse; D053148:Caspase 3