The administration of cytokines has been associated with a variety 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. Studies are in progress with other cytokines, IL1, IFNg and TNF to determine their effects on hepatic drug metabolism. As with vaccine administration, we are isolating the livers of mice treated with cytokines and are using cDNA probes to measure 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.
