Tumor necrosis factor‐induced lethal hepatitis: pharmacological intervention with verapamil, tannic acid, picotamide and K76COOH

FEBS Letters

Libert, Claude¹  Brouckaert, Peter¹  Vanden Berghe, Joke¹  Van Molle, Wim¹ 

[1] Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Gent, K.L. Ledeganckstraat 35, B-9000 Gent, Belgium

关键词: Complement;    Calcium channel;    Thromboxane;    Platelet;    Apoptosis;   

DOI  :  10.1016/S0014-5793(00)01152-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Tumor necrosis factor (TNF) induces hepatitis when injected in human beings or in rodents. The molecular mechanism by which TNF induces hepatic distress remains largely unknown, although induction of apoptosis of hepatocytes appears to be an essential step. In order to increase the therapeutic value of TNF, we have studied the protective activity of several molecules and found that four chemically totally different substances confer significant protection in the model of TNF-induced lethal hepatitis in mice sensitized with D-(+)-galactosamine (GalN), but not in mice sensitized with actinomycin-D (ActD) or against anti-Fas-induced lethal hepatitis. Verapamil, a calcium-channel blocker, tannic acid, picotamide, a thromboxane A₂ receptor antagonist, and K76COOH, an inhibitor, amongst others, of complement, protected significantly against induction of lethality, release of the liver-specific enzyme alanine aminotransferase (ALT) and induction of apoptosis in the liver after TNF/GalN, except for K76COOH, which paradoxically increased ALT values after challenge, and which also protected against TNF/GalN in complement-deficient mice. The data suggest that activation of platelets and neutrophils, as well as induction of inflammation occur in the TNF/GalN model, but not in the TNF/ActD or anti-Fas models, in which direct induction of apoptosis of hepatocytes may be more relevant. The protective activity of the drugs may lead to an increase in therapeutic value of TNF.

【 授权许可】

Unknown