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DRUG-AND XENOBIOTIC-METABOLIZING ENZYME SYSTEMS

药物和异生物代谢酶系统

基本信息

批准号：
3282715
负责人：
JEFFREY BARON
金额：
$ 16.97万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-04-01 至 1990-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3282715
关键词：
acetylaminofluorene carcinogenesis cell type drug metabolism electron microscopy enzyme induction /repression enzyme mechanism glutathione transferase histochemistry /cytochemistry immunochemistry laboratory mouse laboratory rat lung neoplasms skin neoplasms toxin metabolism

项目摘要

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.

尽管对毒品进行了数千次调查代谢本身，参与药物代谢的酶（激活和解毒），以及药物的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异生物质的实际场所在组织内代谢。此外，关于复杂哺乳动物中特定区域或细胞类型的能力组织代谢药物和其他外源物质。长期目标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，本研究的目标项目的目的是确定药物代谢及其诱导发生在哪里位于肝脏、皮肤和肺这三个主要器官内药物和其他外源物质被代谢。本文中描述的研究因此，应用程序被设计为评估相关能力肝小叶三个区域内的肝细胞进行代谢异生素，以确定肝小叶内的方式和位置药物代谢酶和单加氧酶活性可以改变酶诱导的结果，以确定逐步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变，最后，确定药物和其他异生物质可以在体内代谢的位置皮肤和肺以及这些组织内药物代谢的方式和地点可以被诱导。为实现上述目标，将采取以下方法采用：定性和半定量免疫组织化学和免疫细胞化学技术可用于研究细胞色素 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组织内光学显微镜水平上的 S-转移酶细胞内电子显微镜水平；组织化学技术允许对本地化和分布进行调查外源单加氧酶活性（例如苯并（a）芘和苯胺羟化酶和 7-脱氧试卤灵 O-脱乙基酶活性）在光照下组织内的微观水平；和放射自显影技术允许确定组织内和细胞内位点体内形成的异生物质的代谢物共价结合。这因此，这些调查得出的结果将非常重要极大地提高了我们对药理学形态学的认识与药物代谢的关系。