Cytochrome P4501A1 and cytochrome P4501A2 are downregulated at both transcriptional and post-transcriptional levels by conditions resulting in interferon-alpha/beta induction

Life Sci. 1997;60(10):787-96. doi: 10.1016/s0024-3205(97)00006-4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Northern
  • Cytochrome P-450 CYP1A1 / genetics*
  • Cytochrome P-450 CYP1A2 / genetics*
  • Dactinomycin / pharmacology
  • Down-Regulation
  • Interferon Inducers / pharmacology
  • Interferon-alpha / biosynthesis*
  • Interferon-beta / biosynthesis*
  • Male
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Poly I-C / pharmacology
  • Protein Biosynthesis* / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Transcription, Genetic* / drug effects
  • beta-Naphthoflavone / pharmacology

Substances

  • Interferon Inducers
  • Interferon-alpha
  • Nucleic Acid Synthesis Inhibitors
  • RNA, Messenger
  • Dactinomycin
  • beta-Naphthoflavone
  • Interferon-beta
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1A2
  • Poly I-C