Participation of Cytochrome b5 in Anesthetic Metabolism

细胞色素 b5 参与麻醉代谢

基本信息

批准号：
7214130
负责人：
LUCY A WASKELL
金额：
$ 29.44万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-07-01 至 2009-09-29
项目状态：
已结题

项目摘要

The cytochromes P450 (cyts P450) are a ubiquitous superfamily of 8,000 oxygenases whose activity is influenced by a second protein, cytochrome b5 (cyt b5). The long-term goal of this project is to understand the structural and mechanistic basis of the modification of human cyt P450-mediated metabolism by cyt b5 in order to develop and employ strategies to modify the activity of these essential isozymes for human benefit. Accomplishing this goal will require that we also simultaneously acquire a better understanding of the reaction mechanism of cyt P450. Moreover, to understand the molecular mechanism by which cyt b5 influences oxidation by cyt P450 in vivo, one must understand the details of how cyt b5 interacts with cyt P450 and how it modifies the catalytic cycle of cyt P450 relative to cyt P450 reductase. Humans possess 56 different cyts P450, many of which are essential for early development and life itself. Other human cyts P450 determine the toxicity, duration of action, and elimination of the vast majority of therapeutic agents, carcinogens, and environmental agents to which humans are exposed. Xenobiotic metabolizing cyts P450 are also responsible for the majority of drug-drug interactions and adverse drug reactions. A third group of cyts P450 are responsible for the biosynthesis or metabolism of essential endogenous compounds. This includes virtually all steroids (cholesterol, bile acids, estrogens, testosterone, cortisol, and vitamin D) and many lipids and eicosanoids. Cyts P450 exist in virtually every organ and tissue of humans. A second protein, cyt b5, modulates the biochemical mechanism and activity of selected cyts P450. In fact, cyt b5 is essential for testosterone biosynthesis by a cyt P450 that is currently a therapeutic target for the treatment of prostate cancer. The knowledge gained from the proposed experiments will serve as the foundation for understanding the in vivo regulation of the catalytic mechanism of cyt P450. The findings of the planned biochemical and structural experiments will also significantly enhance our ability to predict and eventually modify the routes of metabolism of a large number of environmental contaminants and a vast number of drugs, including chemotherapeutic agents, psychoactive compounds, and cardiovascular therapies. Knowledge of the molecular mechanism by which the activity of human cyts P450 can be modulated will also prove to be an asset in developing drugs and procedures to alter the large number of critical physiologic processes in which the 56 human cyts P450 participate. The results of the proposed studies will be extremely valuable in designing less toxic and more specific therapeutic agents and prodrugs, especially chemotherapeutic agents and environmental contaminants.

细胞色素 P450 (cyts P450) 是一个由 8,000 种加氧酶组成的普遍存在的超家族其活性受到第二种蛋白质细胞色素 b5 (cyt b5) 的影响。长期来看该项目的目标是了解通过 cyt b5 修饰人类 cyt P450 介导的代谢，以开发和采用策略来改变这些必需同工酶的活性，以造福于人类。实现这一目标需要我们同时获得更好的了解cyt P450的反应机制。此外，要了解细胞色素b5在体内影响细胞色素P450氧化的分子机制，必须了解 cyt b5 如何与 cyt P450 相互作用以及它如何修改 cyt P450 相对于 cyt P450 还原酶的催化循环。人类拥有56种不同的 cyts P450，其中许多对于早期发育和生命本身至关重要。其他人类细胞色素 P450 决定毒性、作用持续时间以及大量物质的消除人类接触的大多数治疗剂、致癌物和环境因素被暴露。异生物质代谢细胞 P450 也负责大部分药物间相互作用和药物不良反应。第三组细胞色素 P450 是负责必需内源化合物的生物合成或代谢。这几乎包括所有类固醇（胆固醇、胆汁酸、雌激素、睾酮、皮质醇和维生素 D）以及许多脂质和类二十烷酸。 Cyts P450 几乎存在于人类的每一个器官和组织。第二种蛋白质，细胞色素b5，调节生化所选细胞色素 P450 的机制和活性。事实上，细胞色素b5对于睾丸激素至关重要细胞色素 P450 的生物合成目前是治疗以下疾病的治疗靶点前列腺癌。从所提出的实验中获得的知识将作为为了解细胞色素催化机制的体内调控奠定基础 P450。计划中的生化和结构实验的结果也将显着增强我们预测并最终修改路线的能力大量环境污染物和大量物质的代谢药物，包括化疗药物、精神活性化合物和心血管药物疗法。了解人类细胞细胞活性的分子机制可以调节的 P450 也将被证明是开发药物和药物的资产改变大量关键生理过程的程序，其中 56 人类细胞色素 P450 参与。拟议研究的结果将非常在设计毒性更小、特异性更强的治疗剂和前药方面具有价值，特别是化疗药物和环境污染物。