Cytochrome P4501A1 and cytochrome P4501A2 are downregulated at both transcriptional and post-transcriptional levels by conditions resulting in interferon-alpha/beta induction.
The interferon mediated downregulation of constitutive and inducible cytochrome P450 enzymes occurs through a pretranslational mechanism which depresses the mRNA encoding cytochrome P450s. We measured the transcription rates of CYP1A genes and the turnover of CYP1A mRNA in rats treated with the interferon-alpha/beta inducer polyinosinic acid-polycytidylic acid. The rate of transcription of CYP1A1 and CYP1A2 genes was significantly decreased in hepatic nuclei isolated from male rats treated with polyinosinic acid-polycytidylic acid (10 mg/kg). In addition the rate of degradation of hepatic CYP1A1 and CYP1A2 mRNA was examined following the inhibition of de novo transcription by actinomycin D (1 mg/kg). Messenger RNA levels were analysed by Northern and slot blotting with a 1.2 kb murine CYP1A1 cDNA probe. Interferon significantly augmented the rate of loss of CYP1A1 and CYP1A2 mRNAs suggesting that post-transcriptional degradation of mRNA contributes to the pre-translational events that cause cytochrome P450 downregulation. These results support the involvement of both transcriptional and post-transcriptional mechanisms in the loss of cytochrome P450s mediated by interferon inducers.
Delaporte
E
E
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Renton
K W
KW
D000818:Animals; D015152:Blotting, Northern; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation; D007369:Interferon Inducers / Q000494:pharmacology; D016898:Interferon-alpha / Q000096:biosynthesis*; D016899:Interferon-beta / Q000096:biosynthesis*; D008297:Male; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects; D019324:beta-Naphthoflavone / Q000494:pharmacology
D007369:Interferon Inducers; D016898:Interferon-alpha; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D003609:Dactinomycin; D019324:beta-Naphthoflavone; D016899:Interferon-beta; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D011070:Poly I-C