Toxicological Significance of Alkylbenzene Metabolism

烷基苯代谢的毒理学意义

• 批准号: 7845292
• 负责人: WAYNE L BACKES
• 金额: $ 1.87万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-01-15 至 2010-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845292
• 关键词: Abbreviations; Address; Affect; Age; Aging; Aromatic Hydrocarbons; Behavior; Binding; CYP1A2 gene; CYP2B4 gene; CYP2E1 gene; Catalysis; Cell Respiration; Cells; Charge; Chemicals; Complex; Coupling; Crowding; Cytochrome P450; Cytochromes; Effectiveness; Electron Transport; Electrons; Electrostatics; Endoplasmic Reticulum; Enzyme Interaction; Enzymes; Flavoproteins; Gasoline; Generations; Goals; Grant; Heme; Heterogeneity; Hydrocarbons; Hydroxylation; Individual; Investigation; Laboratories; Lead; Lipids; Location; Malignant Neoplasms; Mediating; Membrane; Metabolism; Mixed Function Oxygenases; Molecular Models; NADP; NADPH-Ferrihemoprotein Reductase; Oxidoreductase; Oxygen; Oxygenases; Phospholipids; Process; Protein Subunits; Proteins; Reaction; Research; Research Design; Reticulum; Role; Sea; Site-Directed Mutagenesis; Structure; Surface; System; Testing; Time; Toluene; Toxic effect; Xenobiotic Metabolism; Xenobiotics; base; consumer product; design; enzyme substrate; molecular modeling; protein distribution; public health relevance; research study

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to better understand how the proteins of the P450 monooxygenase system are organized in the endoplasmic reticulum, the role of P450-P450 interactions on the function of these enzymes, and how these interactions may make individuals susceptible to alkylbenzene-induced toxicity by alterations in P450-mediated hydrocarbon metabolism. Alkylbenzenes are produced in extensive quantities throughout the world, with simple aromatic hydrocarbons being major components of gasoline and used in a wide variety of consumer products. The P450 system is responsible for both aliphatic and aromatic hydroxylation of the aromatic hydrocarbons, with several forms, CYP1A2, CYP2B4, and CYP2E1, being implicated in hydrocarbon metabolism. This process requires a functional interaction between P450 and the flavoprotein NADPH-cytochrome P450 reductase. However, total P450 levels exceed those of reductase by a ratio of 20:1. These conditions raise basic questions as to how the enzymes of this microsomal electron transport chain are organized. During the previous grant period we demonstrated that P450s interact through the formation of heteromeric P450 complexes. We have identified complexes between CYP2B4-CYP1A2 as well as CYP1A2-CYP2E1. These interactions were shown to have a profound effect on xenobiotic metabolism, largely due to an alteration in the manner in which NADPH-cytochrome P450 reductase transfers electrons to P450s in the heteromeric complex. Interestingly, we did not observe an effect on P450 function from CYP2B4-CYP2E1 complexes. The proposed studies are designed to extend our investigation and address questions related to the organization of reductase and P450, their interactions within the endoplasmic reticulum, and how these interactions affect xenobiotic metabolism, including the metabolism of alkylbenzenes. We plan to continue our characterization of these interactions, examining (1) the functional consequences of P450-P450 interactions, (2) the structural basis for these interactions by identifying the region(s) responsible for P450-P450 complex formation, and (3) the organizational consequences to P450-P450 complex formation (i.e. how do such interactions affect their regional distribution in the endoplasmic reticulum). These studies will increase our understanding of how the P450 electron transport chain is organized, and will provide new important information on the role of the P450 system in the bioactivation of aromatic hydrocarbons and the generation of reactive oxygen - a process that can have a significant influence on chemical toxicity. PUBLIC HEALTH RELEVANCE: The purpose of this proposal is to examine the organization of the enzymes of the P450 system in membranes within the cell. How the P450s are organized will govern not only their effectiveness in removing foreign compounds from the body, but also their ability to form reactive compounds that can lead to toxicity, cancer, and aging.

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to better understand how the proteins of the P450 monooxygenase system are organized in the endoplasmic reticulum, the role of P450-P450 interactions on the function of these enzymes, and how these interactions may make individuals susceptible to alkylbenzene-induced toxicity by alterations in P450-mediated hydrocarbon metabolism.烷基苯烯在全球范围内广泛生产，简单的芳香烃是汽油的主要组成部分，并用于多种消费产品。 P450系统负责芳香烃的脂肪族和芳族羟基化，具有几种形式的CYP1A2，CYP2B4和CYP2E1，与碳氢化合物代谢有关。这个过程需要P450和黄蛋白NADPH-CYTOCHROME P450还原酶之间的功能相互作用。但是，总P450水平超过还原于20：1的比率。这些条件提出了有关如何组织微粒电子传输链的酶的基本问题。在上一个赠款期间，我们证明了P450通过杂体P450复合物的形成相互作用。我们已经确定了CYP2B4-CYP1A2和CYP1A2-CYP2E1之间的复合物。这些相互作用被证明对异种生物的代谢具有深远的影响，这在很大程度上是由于NADPH-CYTOCHROME P450还原酶在异源络合物中转移到P450的方式改变了。有趣的是，我们没有观察到对CYP2B4-CYP2E1复合物的P450功能的影响。拟议的研究旨在扩大我们的研究并解决与还原酶和P450的组织，它们在内质网中的相互作用以及这些相互作用如何影响异生物代谢的问题，包括烷基苯甲酸的代谢。 We plan to continue our characterization of these interactions, examining (1) the functional consequences of P450-P450 interactions, (2) the structural basis for these interactions by identifying the region(s) responsible for P450-P450 complex formation, and (3) the organizational consequences to P450-P450 complex formation (i.e. how do such interactions affect their regional distribution in the endoplasmic reticulum).这些研究将提高我们对P450电子传输链的组织方式的理解，并将提供有关P450系统在芳族碳氢化合物生物活化和活性氧的生成中的作用的新重要信息 - 这一过程可以对化学毒性产生重大影响。公共卫生相关性：该提案的目的是检查细胞内膜中P450系统酶的组织。 P450的组织方式不仅会控制它们从体内去除外国化合物的有效性，而且还将控制形成可导致毒性，癌症和衰老的反应性化合物的能力。