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-16 alpha-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.
Delaporte
E
E
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Cribb
A E
AE
Renton
K W
KW
D000818:Animals; D001059:Apoproteins / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D007369:Interferon Inducers / Q000494:pharmacology*; D007372:Interferons / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D011070:Poly I-C / Q000494:pharmacology*; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014217:Troleandomycin / Q000494:pharmacology
D001059:Apoproteins; D007369:Interferon Inducers; D007527:Isoenzymes; D012333:RNA, Messenger; D011285:Pregnenolone Carbonitrile; D007372:Interferons; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D011070:Poly I-C