Depression of liver drug metabolism and increase in plasma fibrinogen by interleukin 1 and tumor necrosis factor: a comparison with lymphotoxin and interferon.
Different recombinant cytokines were studied for their effects on mouse liver in vivo: interleukin 1-alpha and -beta, tumor necrosis factor, lymphotoxin, interferon-alpha A/D and gamma depressed liver cytochrome P450-dependent drug metabolism (measured by ethoxycoumarin deethylase activity) 24 h after treatment, at doses in the microgram range, while IL-2 had no effect on this enzymatic system. Interleukin 1 (both alpha and beta), tumor necrosis factor and lymphotoxin also increased plasma fibrinogen, a marker of liver acute phase inflammatory response. Interferon-gamma and tumor necrosis factor had an additive effect in depressing liver drug metabolism. When tested in vitro on isolated hepatocytes, only interleukin 1 depressed P450-dependent drug metabolism, while all the other cytokines were inactive, thus suggesting that their effect on the liver in vivo is not a direct effect but is mediated by other mediators.
Bertini
R
R
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Bianchi
M
M
Villa
P
P
Ghezzi
P
P
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016207:Cytokines; D005340:Fibrinogen / Q000378:metabolism*; D066298:In Vitro Techniques; D007372:Interferons / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D008297:Male; D051379:Mice; D010105:Oxygenases / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D001685:Biological Factors; D016207:Cytokines; D007375:Interleukin-1; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D007372:Interferons; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase