INTERFERON AND P-450 - DRUG METABOLIZING SYSTEM

干扰素（IF）最初被认为是一种抗病毒剂， 各种细胞对病毒感染的反应。 现在已知它 影响各种生物系统：IF在性质上是多重的， 不同的物种表现出不同的活动模式。 IFs 被认为是细胞过程的天然调节剂; 在许多情况下，它们通过抑制大分子的合成而起作用。 在 1976年我们观察到IF诱导剂（例如，多晶硅集成电路和 替洛酮）显着抑制肝细胞色素P-450相关药物 代谢系统 这些系统在很大程度上决定了 药物作用的持续时间，因为它们将大多数药物代谢为毒性较小的药物 和更容易排泄的产物。 由于接受IF的患者将 通常与其他药物同时治疗，重要的是 知道IF在多大程度上会抑制人体的药物代谢。最近， 已经表明，纯重组IF抑制这些系统。 我们实验室的研究使我们得出了一个工作假设， P-450的更快翻转物种是P-450最受抑制的物种， 如果. 这些P-450在被诱导时更沮丧。 现在 已知IF抑制多种蛋白质的合成， 该假设被扩展到包括P-450以外的酶， 特别是在产前、新生儿早期和哺乳期诱发的 所有这些都在荷尔蒙的控制下。 的 提出了以下主要项目：1）IF的影响， IF诱导剂对多种酶的作用，半衰期差异很大 将在体内和培养的原代小鼠肝细胞中进行研究; 2） IF对小鼠发育标志酶的影响 产前，新生儿早期和哺乳期将与效果进行比较 3）纯的重新合成的人IFs对组成型酶的作用; 将在恒河猴中研究药物代谢; 4）已经在 不纯人白细胞干扰素对茶碱作用的研究进展 癌症患者的代谢将继续进行;这些研究可能是 扩展至包括使用纯重组人IF的研究。 研究 在这个项目中描述的应该有助于理解 IF的监管功能，特别是应用于与P-450相关的 药物代谢系统和发育过程。

Interferon (IF) was first recognized as an antiviral agent formed in a variety of cells in response to viral infections. It is now known to affect a wide variety of biological systems: IF is multiple in nature, with individual species exhibiting different patterns of activities. IFs are becoming recognized as natural regulators of cellular processes; in many cases they function by inhibiting the synthesis of macromolecules. In 1976 we made the observation that IF inducing agents (e.g., poly IC and tilorone) markedly depress hepatic cytochrome P-450-linked drug metabolizing systems. These systems largely determine the intensity and duration of drug action because they metabolize most drugs to less toxic and more readily excreted products. Since patients who receive IF will often be treated simultaneously with other drugs, it will be important to know to what extent IF will depress drug metabolism in man. More recently, it has been shown that pure recombinent IF depresses these systems. Studies in our laboratory have led us to the working hypothesis that the more rapidly turning over species of P-450 are the P-450s most depressed by IF. This P-450s are more depressed while they are being induced. Now that it is known that IF depresses the synthesis of a wide variety of proteins, the hypothesis is extended to include enzymes other than the P-450s, particularly those induced during prenatal, early neonatal and suckling phases of development, all of which are under hormonal control. The following major projects are proposed: 1) the effects of IF and IF-inducing agents on a variety of enzymes with widely different half-lives will be studied both in vivo and in cultured primary mouse hepatocytes; 2) the effects of IF on the developmental marker enzymes of mice through prenatal, early neonatal and suckling periods will be compared with effects on constitutive enzymes; 3) the effects of pure reaconstituted human IFs on drug metabolism will be studied in the rhesus monkey; 4) studies already in progress on the effect of impure human leukocyte IF on theophylline metabolism in cancer patients will be continued; these studies may be extended to include studies with pure recombinant human IFs. The research described in this project should contribute to the understanding of the regulatory functions of IF, particularly as applied to the P-450-linked drug metabolizing systems and developmental processes.