Pretranslational suppression of cytochrome P-450h (IIC11) gene expression in rat liver after administration of interferon inducers.

Administration of the interferon inducer polyriboinosinic acid.polyribocytidylic acid (poly rl.poly rC) (10 mg/kg, ip) to male rats suppressed the constitutive hepatic expression of the male-specific cytochrome P-450 [AH, reduced-flavoprotein/oxygen oxidoreductase (RH hydroxylating), EC 1.14.14.1] isozyme P450IIC11 (P-450h) to 21% of control levels within 24 hr. The mRNA for P-450h was more rapidly suppressed by the drug, being significantly suppressed to 56% of control values within 6 hr of administration. P-450h mRNA levels were further lowered to 10% of control by 24 hr. The kinetics of suppression of P-450h apoprotein and mRNA by poly rl.poly rC indicate that the primary mechanism(s) is (are) at a pretranslational level. Tilorone analog R11-877DA (TA) (50 mg/kg, ip), also an interferon inducer, produced qualitatively similar effects to those of poly rl.poly rC, although the TA produced lesser (51% and 59%) decreases in P-450h protein and mRNA, respectively, 24 hr after injection. Again, the results indicate a pretranslational mechanism of P-450h suppression. Although both interferon inducers suppressed hepatic P-450h expression, the magnitudes of these effects were not notably greater than those on total hepatic P-450, indicating that suppression of rat liver P-450 isozymes by interferon inducers is not confined to P-450h.