Cribb A E, Delaporte E, Kim S G, Novak R F, Renton K W
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
J Pharmacol Exp Ther. 1994 Jan;268(1):487-94.
The down regulation of constitutive hepatic microsomal cytochromes P-450 (P450) by interferons has been well described in experimental animals and humans, however the down regulation of induced forms of P450 has not been documented clearly. Differential down regulation of constitutive and induced P450 could alter the proportions of P450 enzymes and, hence, the relative bioactivation/detoxification of xenobiotics. We investigated the effects of polyinosinic acid-polycytidylic acid, a potent stimulator of interferon alpha/beta production on CYP1A and CYP2E induction in the rat. Polyinosinic acid-polycytidylic acid down regulated the constitutive and pyridine-induced expression of CYP2E1 and the pyridine- and beta-naphthoflavone-induced expression of CYP1A1 as demonstrated by metabolic activity and immunoblot analyses. Depression of CYP2E1 and CYP1A1 protein expression by polyinosinic acid-polycytidylic acid was accompanied by a corresponding decrease in mRNA encoding these proteins. Induction of CYP1A2 mRNA also was depressed. Therefore, interferon alpha/beta down regulated induction of members of the CYP1A and CYP2E subfamilies at a pretranslational level independent of the mechanism of induction. Induction of the CYP1A and CYP2E subfamilies did not confer resistance to down regulation by interferon, although the magnitude of down regulation by interferon appeared to be influenced by the magnitude of P450 induction. The potential significance of down regulation of induced P450 in the clearance of certain therapeutic agents and in xenobiotic bioactivation and detoxification is discussed.
干扰素对组成型肝微粒体细胞色素P-450（P450）的下调作用在实验动物和人类中已有充分描述，然而，P450诱导型的下调作用尚未得到明确记录。组成型和诱导型P450的差异下调可能会改变P450酶的比例，从而改变外源性物质的相对生物活化/解毒作用。我们研究了聚肌苷酸-聚胞苷酸（一种有效的α/β干扰素产生刺激剂）对大鼠CYP1A和CYP2E诱导的影响。代谢活性和免疫印迹分析表明，聚肌苷酸-聚胞苷酸下调了CYP2E1的组成型和吡啶诱导型表达以及CYP1A1的吡啶和β-萘黄酮诱导型表达。聚肌苷酸-聚胞苷酸对CYP2E1和CYP1A1蛋白表达的抑制伴随着编码这些蛋白的mRNA相应减少。CYP1A2 mRNA的诱导也受到抑制。因此，α/β干扰素在翻译前水平下调CYP1A和CYP2E亚家族成员的诱导作用，且与诱导机制无关。CYP1A和CYP2E亚家族的诱导并未赋予对干扰素下调的抗性，尽管干扰素下调的程度似乎受P450诱导程度的影响。本文讨论了诱导型P450下调在某些治疗药物清除以及外源性物质生物活化和解毒中的潜在意义。
