DRUG AND STEROID GLUCURONYLTRANSFERASE ACTIVITIES

大多数药物的新陈代谢涉及几个阶段，在这个阶段，异源生物 底物通常通过以下过程变得更易溶于水 氧化，然后是共轭。大量的工作已经允许 我们对异种生物加工第一阶段的认识 通过肝微粒体细胞色素P-450依赖系统。我们的 实验室在某些秒的鉴定中发挥了重要作用 相反应、UDP-葡萄糖醛酸基转移酶活性。这些酶 催化药物与葡萄糖醛酸的共价键。问题是 是否存在一个或多个UDP-葡萄糖醛酸基转移酶活性可以 现在可以回答了，有很多种。此外，我们发现， 大鼠肝脏内质网中存在同工酶，它们可以 催化单一底物的葡萄糖醛酸化反应。海流 应用程序将解决与分离和 大鼠肝脏和肝脏UDP-葡萄糖醛酸基转移酶活性的研究 关注可用于催化葡萄糖醛酸化的同工酶的数量 毒品和类固醇。已经开发出新的技术，允许 雌激素相关异构体的分离与鉴定 底物，雄激素底物，药物和相关底物。一定的 在长期服用阿司匹林后，特定的异构体被诱导 3-甲基胆蒽。其他诱导剂将被研究。特定的 抗体将被提高到这些酶的各种形式。 抗体可用于生化和免疫组织化学研究， 各种UDP-葡萄糖醛酸基转移酶的免疫组织化学定位 活性将证明给定的酶在给定的 组织。初步研究已经取得了成功。这 调查将促进我们对药理学和毒理学的了解 药物代谢的第二阶段，即处理结合 动物有机体可用的机制。

The metabolism of most drugs involves several phases whereby the xenobiotic substrate is usually rendered more water-soluble through a process of oxidation followed by conjugation. A great deal of work has allowed for our understanding of the first phase in the processing of xenobiotic through hepatic microsomal cytochrome P-450-dependent systems. Our laboratory has played a major role in the identification of certain second phase reactions, UDP-glucuronyltransferase activities. These enzymes catalyze the covalent linkage of drugs with glucuronic acid. The question of whether there are one or many UDP-glucuronlyltransferase activities can now be answered; there are many. Furthermore, we have discovered that there are isozymes present in rat liver endoplasmic reticulum which can catalyze the glucuronidation of a single substrate. The current application will address questions dealing with the separation and characterization of UDP-glucuronyltransferase activities in rat liver and focus on the number of isozymes available to catalyze the glucuronidation of drugs and steroids. New techniques have been developed which allow for the separation and characterization of isoforms dealing with estrogenic substrates, androgenic substrates, drugs and related substrates. Certain specific isoforms are induced following the chronic administration of 3-methylcholanthrene. Other inducing agents will be studied. Specific antibodies will be raised to the various forms of these enzymes. Antibodies may be used in both biochemical and immunohistochemical studies, and immunohistochemical localization of various UDP-glucuronyltransferase activities will demonstrate the locality of a given enzyme in a given tissue. Preliminary studies have already been successful. This investigation will advance our knowledge of the pharmacology and toxicology of the second phase of drug metabolism, that dealing with conjugation mechanisms available to the animal organism.