The administration of cytokines has been associated with a variYety of effects on many organ systems. One consequence of administration of cytokines is the inhibition of hepatic drug metabolism. The mechanism for this effect remains unknown. We have administered IL2 and IFNa to mice. The coadministration of these two cytokines causes inhibition of cytochrome P-450 levels, decreased microsomal drug metabolizing enzymes and increased hexobarbital-induced sleep times. All of these effects are more pronounced when both agents are given together than with either cytokine alone at a similar dose. Similar effects have been observed when IL-1 or IFN-gamma has been administered. As with vaccine administration, we are isolating the livers of mice treated with cytokines and are using cDNA probes to meausre specific isozymes of cytochrome P-450. In addition, probes to IL2 and IL1 have been used to see if these cytokines are elevated in the livers of mice treated with DTP vaccine. These results will be compared to the effects of direct cytokine administration to elucidate the cytokines involved in the inhibition of drug metabolizing enzymes. Mice infected with murine AIDS show a number of alterations in hepatic drug metabolism. Studies are in progress to determine the extent of the alterations and the possible mechanism. Spleen cell cultures are being examined for cytokine induction to see if altered cytokine levels could account for some of the observed effects. In addition, studies at the level of the RNA are planned to see if there are increased cytokine mRNAs which might explain the changes.
