W. Van Molle et al., Tumor necrosis factor-induced lethal hepatitis: pharmacological intervention with verapamil, tannic acid, picotamide and K76COOH, FEBS LETTER, 467(2-3), 2000, pp. 201-205
Tumor necrosis factor (TNF) induces hepatitis when injected in human beings
or in rodents. The molecular mechanism by which TNF induces hepatic distre
ss 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 f
ound that four chemically totally different substances confer significant p
rotection in the model of TNF-induced lethal hepatitis in mice sensitized w
ith D-(+)-galactosamine (GalN), but not in mice sensitized with actinomycin
-D (ActD) or against anti-Fas-induced lethal hepatitis. Verapamil, a calciu
m-channel blocker, tannic acid, picotamide, a thromboxane A(2) receptor ant
agonist, and K76COOH, an inhibitor, amongst others, of complement, protecte
d significantly against induction of lethality, release of the liver-specif
ic 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 compl
ement-deficient mice. The data suggest that activation of platelets and neu
trophils, 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 a
poptosis of hepatocytes may be more relevant. The protective activity of th
e drugs may lead to an increase in therapeutic value of TNF. (C) 2000 Feder
ation of European Biochemical Societies.