Delaporte E, Renton K W
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Life Sci. 1997;60(10):787-96. doi: 10.1016/s0024-3205(97)00006-4.
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.
干扰素介导的组成型和诱导型细胞色素P450酶的下调是通过一种转录前机制发生的，该机制会抑制编码细胞色素P450的mRNA。我们测量了用干扰素α/β诱导剂聚肌苷酸-聚胞苷酸处理的大鼠中CYP1A基因的转录速率和CYP1A mRNA的周转率。在用聚肌苷酸-聚胞苷酸（10mg/kg）处理的雄性大鼠分离的肝细胞核中，CYP1A1和CYP1A2基因的转录速率显著降低。此外，在用放线菌素D（1mg/kg）抑制从头转录后，检测了肝脏CYP1A1和CYP1A2 mRNA的降解速率。用1.2kb小鼠CYP1A1 cDNA探针通过Northern印迹和狭缝印迹分析mRNA水平。干扰素显著提高了CYP1A1和CYP1A2 mRNA的丢失速率，表明mRNA的转录后降解促成了导致细胞色素P450下调的转录前事件。这些结果支持转录和转录后机制均参与干扰素诱导剂介导的细胞色素P450的丢失。
