INHIBITION OF MONOOXYGENASE ACTIVITIES IN HUMAN HEPATOCYTES BY INTERFERONS

Thee effects of human recombinant interferons alpha and gamma on monoo xygenase activities in cultured human hepatocytes have been investigat ed. Dose-response and time course studies showed that interferons redu ced 7-ethoxyresorufin O-deethylase activity of human hepatocytes after a 12-hr incubation with 300 U/ml interferons alpha and gamma (52% and 38% decrease, respectively). A reduction in 7-ethoxyresorufin O-deeth ylase activity was also observed in HepG2 cells, although in these cel ls maximal inhibition was observed after 24 hr of treatment with 1000 U/ml (a 41% and 28% decrease with interferon alpha and gamma, respecti vely). A decrease in activity was also observed in 7-pentoxyresorufin O-depentylase, 7-ethoxycoumarin O-deethylase and testosterone 2alpha- and 6beta-hydroxylase. It is noteworthy that the marked increase in 7- ethoxyresorufin O-deethylase activity detected in human hepatocytes af ter incubation with 2 muM-3-methylcholanthrene (10-fold over non-treat ed cells) was reduced by 40% in the presence of interferons (300 U/ml) , thus indicating that the inducibility of monooxygenases could be alt ered by interferon treatment. The inhibitory effect of interferons on 7-ethoxyresorufin O-deethylase was transient and HepG2 cells recovered their normal activity 24 hr after interferon removal from culture med ium. This study provides the first direct evidence that interferons do wn-regulate the level of monooxygenases in human hepatic cells and pre vent, in part, their induction by xenobiotics.