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

Abstract

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.

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  • Authors+Show Affiliations

    ,

    Department of Internal Medicine II, Miyazaki Medical College, Miyazaki, Japan.

    , , , , , , ,

    Source

    Hepatology (Baltimore, Md.) 33:6 2001 Jun pg 1441-50

    MeSH

    Animals
    Antigens, CD
    Antineoplastic Agents, Phytogenic
    Apoptosis
    Caspase 3
    Caspase Inhibitors
    Cytochrome c Group
    Cytoplasm
    Etoposide
    Galactosamine
    Hepatocytes
    Lipopolysaccharides
    Liver
    Liver Failure
    Male
    Mice
    Mice, Inbred BALB C
    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

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    11391533

    Citation

    Nakama, T, et al. "Etoposide Prevents Apoptosis in Mouse Liver With D-galactosamine/lipopolysaccharide-induced Fulminant Hepatic Failure Resulting in Reduction of Lethality." Hepatology (Baltimore, Md.), vol. 33, no. 6, 2001, pp. 1441-50.
    Nakama T, Hirono S, Moriuchi A, et al. Etoposide prevents apoptosis in mouse liver with D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure resulting in reduction of lethality. Hepatology. 2001;33(6):1441-50.
    Nakama, T., Hirono, S., Moriuchi, A., Hasuike, S., Nagata, K., Hori, T., ... Tsubouchi, H. (2001). Etoposide prevents apoptosis in mouse liver with D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure resulting in reduction of lethality. Hepatology (Baltimore, Md.), 33(6), pp. 1441-50.
    Nakama T, et al. Etoposide Prevents Apoptosis in Mouse Liver With D-galactosamine/lipopolysaccharide-induced Fulminant Hepatic Failure Resulting in Reduction of Lethality. Hepatology. 2001;33(6):1441-50. PubMed PMID: 11391533.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Etoposide prevents apoptosis in mouse liver with D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure resulting in reduction of lethality. AU - Nakama,T, AU - Hirono,S, AU - Moriuchi,A, AU - Hasuike,S, AU - Nagata,K, AU - Hori,T, AU - Ido,A, AU - Hayashi,K, AU - Tsubouchi,H, PY - 2001/6/8/pubmed PY - 2001/6/29/medline PY - 2001/6/8/entrez SP - 1441 EP - 50 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 33 IS - 6 N2 - 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. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/11391533/Etoposide_prevents_apoptosis_in_mouse_liver_with_D_galactosamine/lipopolysaccharide_induced_fulminant_hepatic_failure_resulting_in_reduction_of_lethality_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270-9139(01)00020-9 DB - PRIME DP - Unbound Medicine ER -