Toxicological Control Mechanisms of Human CYP1A2

人类CYP1A2的毒理学控制机制

• 批准号: 6519758
• 负责人: LINDA C QUATTROCHI
• 金额: $ 28.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6519758
• 关键词: artificial chromosomes; carbopolycyclic compound; cytochrome P450; cytotoxicity; environmental toxicology; flavonoids; gene expression; genetic enhancer element; genetic promoter element; genetic regulation; genetic regulatory element; genetically modified animals; human genetic material tag; laboratory mouse; molecular dynamics; protein structure function; reporter genes; tissue /cell culture; toxicant interaction; toxin metabolism; transcription factor; yeast two hybrid system

DESCRIPTION: (Adapted from the Applicant's Abstract): Cytochrome P450 (CYP) enzymes play an important role in the metabolism of endogenous compounds and such exogenous substrates as drugs and various chemical carcinogens. CYP 1 A, one of the CYP subfamilies in vertebrates consisting of two members, CYP1A1 and CYP1A2, catalyzes the metabolism of such environmental chemicals as polycyclic aromatic hydrocarbons and arylamines as well as numerous drugs. Several factors appear to modulate the expression of CYP1A enzymes including chemicals (e.g. polycyclic aromatic hydrocarbons and halogenated hydrocarbons), dietary constituents (e.g. heterocyclic amines, flavones, indoles) and genetic factors. In the present research proposal, we will examine the hypothesis that the molecular mechanisms involved in the regulation of human CYP1A2 involves complex interactions of trans-acting factors at multiple and redundant regulatory elements, and that naturally-occurring dietary flavonoids alter the expression of both CYP 1 A2 and CYP IA 1. Our goals for the forthcoming grant period are to focus on the fundamental mechanistic events defining CYP1A2 basal and cell type-specific expression, and to define the role of naturally occurring dietary flavonoids in modulating CYP1A gene expression through the interactions of these agents with transcription factors (e.g. arylhydrocarbon receptor, other basic helix-loop-helix proteins) that potentially mediate human CYP1A gene expression. To this end, we will use various cell lines for in vitro studies, and we will develop models to study the molecular mechanisms involved in the in vivo regulation of human CYP1A gene expression. In vivo studies will utilize genome-integrated reporter gene constructs and a transgenic mouse line containing a bacterial artificial chromosome expressing the human CYP1A1 and CYP1A2. The long-term goals are to understand at the cellular and molecular level the mechanisms controlling the expression of CYP1A2 and the mechanisms that affect both CYP1A1 and CYP1A2 in relation to the chemoprotective properties of naturally occurring flavonoids. Additionally, understanding the molecular events associated with altered CYP1A gene expression due to interactions of such "natural" pharmaceuticals as flavonoids and other plant-derived products should lead to an awareness of possible adverse effects.

描述：（改编自申请人的摘要）：细胞色素 P450 (CYP) 酶在内源性化合物的代谢中发挥着重要作用 药物和各种化学致癌物质等外源性底物。 CYP1A， 脊椎动物中的 CYP 亚科之一，由两个成员组成：CYP1A1 和 CYP1A2，催化多环等环境化学物质的代谢 芳香烃和芳胺以及许多药物。几个因素 似乎可以调节 CYP1A 酶的表达，包括化学物质（例如 多环芳烃和卤代烃），膳食 成分（例如杂环胺、黄酮、吲哚）和遗传因素。 在本研究计划中，我们将检验以下假设： 参与人类 CYP1A2 调节的分子机制包括 多个且冗余的反式作用因子的复杂相互作用 调节元件，以及天然存在的膳食黄酮类化合物改变 CYP 1 A2 和 CYP IA 1 的表达。我们即将资助的目标 周期的重点是定义 CYP1A2 基础的基本机制事件 和细胞类型特异性表达，并自然地定义其作用 膳食黄酮类化合物通过调节 CYP1A 基因表达 这些试剂与转录因子（例如芳基烃）的相互作用 受体，其他基本螺旋-环-螺旋蛋白），可能介导人类 CYP1A 基因表达。为此，我们将使用各种细胞系进行体外 研究，我们将开发模型来研究所涉及的分子机制 人 CYP1A 基因表达的体内调节。体内研究将 利用基因组整合的报告基因构建体和转基因小鼠品系 含有表达人类 CYP1A1 的细菌人工染色体和 CYP1A2。长期目标是了解细胞和分子 水平控制CYP1A2表达的机制及其机制 影响与化学保护相关的 CYP1A1 和 CYP1A2 天然黄酮类化合物的特性。此外，了解 与 CYP1A 基因表达改变相关的分子事件 黄酮类化合物和其他“天然”药物的相互作用 植物衍生产品应引起人们对可能的不利影响的认识。