DRUG-AND XENOBIOTIC-METABOLIZING ENZYME SYSTEMS

尽管对毒品进行了数以千计的调查 代谢本身，依赖于参与药物代谢的酶 (激活和解毒)，以及关于药物诱导 生物转化和药物代谢酶，我们仍然知之甚少 关于药物和其他外来生物物质的实际位置 在组织内代谢。此外，人们对此知之甚少 复杂哺乳动物体内特定区域或细胞类型的能力 代谢药物和其他外源物质的组织。长期目标 在本申请中描述的研究的目的是提供这一重要的、 基本信息。为此，本研究的目标是 项目是确定药物新陈代谢及其诱导在哪里发生 位于肝、皮肤和肺内，其中三个主要器官 药物和其他外来生物物质是代谢的。在这篇文章中描述的研究 因此，应用程序被设计为评估相对能力 肝小叶三个区域内的肝细胞进行代谢 外源生物，以确定如何以及在肝小叶中的位置 药物代谢酶和单加氧酶活性可以改变为 酶诱导的结果，以确定进行性变化 肝脏药物代谢酶和单加氧酶活性 2-乙酰氨基荧致肝细胞癌，最后， 以确定药物和其他外源物质可以在哪里代谢 皮肤和肺以及这些组织中药物代谢的方式和位置 可以被诱导。为了实现这些目标，将采取以下方法 应用：定性和半定量免疫组织化学和 免疫细胞化学技术，允许研究 细胞色素P-450同工酶的定位与分布， NADPH-细胞色素P-450还原酶、环氧化物水解酶和谷胱甘肽 S-转移酶在组织内和组织内的光镜水平 细胞内的电子显微镜水平；组织化学技术 关于本地化和分布的调查许可证 异源生物单加氧酶活性(如苯并(A)芘和苯胺 羟基酶和7-脱氧基间苯二酚O-脱乙基酶活性)。 组织内的微观水平；以及放射自显影技术 允许在以下位置确定细胞内和细胞内位置 在体内形成的外源物质的代谢产物是共价结合的。这个 因此，从这些调查中得出的结果将非常 极大地提高了我们对药理形态学的认识 与药物代谢有关的关系。

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.