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.