MODULATION OF RAT HEPATIC CYP3A1 INDUCTION BY THE INTERFERON INDUCER POLYINOSINIC ACID-POLYCYTIDYLIC ACID (POLYIC)

Interferon and interferon inducers are well known to depress hepatic cytochrome P-450 (P-450). Previous reports have suggested that all constitutive members of the P-450 family of proteins are affected in this manner, whereas inducible P-450s-including cytochrome P-4503A1 (CYP3A1)-are resistant to the effects of interferons. We examined the effect of interferon [produced in response to polyinosinic acid-polycytidylic acid (polyIC; 10 mg/kg) administration] on the induction of CYP3A1 in the female rat by the macrolide antibiotic troleandomycin (TAO; 200 mg/kg), and the antiglucocorticoid pregnenolone-16alpha-carbonitrile (PCN; 300 mg/kg). The induction of CYP3A1 was characterized by erythromycin N-demethylation, Western blotting, and mRNA quantitation with a specific oligonucleotide cDNA probe. PCN-mediated induction of erythromycin metabolism was depressed by 85% following polyIC administration. PolyIC depressed the induction of CYP3A1 apoprotein by TAO (84%) and PCN (73%). The depression of enzyme activity and protein were accompanied by a corresponding decrease in hepatic CYP3A1 mRNA. It is concluded that CYP3A1 is sensitive to the depressant effects of interferon, and that interferon appears to act at a pretranslation step that is independent of the induction process per se.