DRUG-AND XENOBIOYIC-METABOLIZING ENZYME SYSTEMS

尽管对毒品进行了数千次调查， 代谢本身，对参与药物代谢的酶 （活化以及解毒），以及对药物诱导的影响 生物转化和药物代谢酶，我们仍然知之甚少， 关于药物和其他外源性物质的实际位置， 在组织内代谢。 此外，对这一点知之甚少。 复杂哺乳动物体内特定区域或细胞类型的能力 组织来代谢药物和其他异生物质。 长期目标 在本申请中描述的研究的目的是提供这种重要的， 基本信息。 为此，本研究的目标是 项目是确定药物代谢及其诱导发生在 在肝脏、皮肤和肺内原位，其中三个主要器官， 药物和其他异生物质被代谢。 本文中描述的研究 因此，应用程序被设计为评估相对能力 肝小叶的三个区域内的肝细胞代谢 外源性物质，以确定如何以及在肝小叶内 药物代谢酶和单加氧酶活性可以改变， 酶诱导的结果，以确定进行性改变， 肝药物代谢酶和单加氧酶活性 2-乙酰氨基芴诱导的肝细胞癌发生，最后， 以确定药物和其他外源性物质可以在体内代谢的位置， 皮肤和肺，以及药物在这些组织中的代谢方式和位置 可以诱导。 为了实现这些目标，将采用以下方法 采用：定性和半定量免疫组织化学和 免疫细胞化学技术，使调查的 细胞色素P-450同工酶的定位和分布， NADPH-细胞色素P-450还原酶、环氧化物水解酶和谷胱甘肽 在组织内的光镜水平和在细胞内的S-转移酶 细胞内的电子显微镜水平;组织化学技术， 许可证调查的定位和分布 异生物质单加氧酶活性（例如，苯并（a）芘和苯胺 羟化酶和7-去乙氧基试卤灵O-脱乙基酶活性） 组织内的微观水平;以及放射自显影技术， 允许测定组织内和细胞内位点， 其在体内形成的外源性物质的代谢物共价结合。 的 因此，这些调查的结果将非常 极大地推进了我们对药理学-形态学 参与药物代谢的关系。

Despite the thousands of investigations that have been conducted on drug metabolism per se, on enzymes that participate in drug metabolism (activation as well as detoxication), and on the induction of drug biotransformations and drug-metabolizing enzymes, we still know very little regarding the actual sites at which drugs and other xenobiotics are metabolized within tissues. Moreover, little is known regarding the capabilities of specific regions or cell types within complex mammalian tissues to metabolize drugs and other xenobiotics. The long-term objective of the research described in this application is to provide this important, fundamental information. To this end, the goal of the present research project is to determine where drug metabolism and its induction occur in situ within the liver, skin, and lung, three of the major organs in which drugs and other xenobiotics are metabolized. The studies described in this application have, thus, been designed to assess the relative capabilities of hepatocytes within the three regions of the liver lobule to metabolize xenobiotics, to determine how and where within the liver lobule drug-metabolizing enzymes and monooxygenase activities can be altered as a consequence of enzyme induction, to determine progressive alterations in hepatic drug-metabolizing enzymes and monooxygenase activities during 2-acetylaminofluorene-induced hepatocellular carcinogenesis, and, finally, to determine where drugs and other xenobiotics can be metabolized within the skin and lung and how and where within these tissues drug metabolism can be induced. To achieve these aims, the following methods will be employed: qualitative and semiquantitative immunohistochemical and immunocytochemical techniques which allow for investigations on the localizations and distributions of cytochrome P-450 isozymes, NADPH-cytochrome P-450 reductase, epoxide hydrolase, and glutathione S-transferases at the light microscopic level within tissues and at the electron microscopic level within cells; histochemical techniques which permit for investigations on the localizations and distributions of xenobiotic monooxygenase activities (e.g., benzo(a)pyrene and aniline hydroxylase and 7-dethoxyresorufin O-deethylase activities) at the light microscopic level within tissues; and autoradiographic techniques which allow for determinations of the intratissue and intracellular sites at which metabolites of xenobiotics formed in vivo bind covalently. The results to be forth-coming from these investigations will, therefore, very greatly advance our knowledge of the pharmacological-morphological relationship involved in drug metabolism.