Toxicological Control Mechanisms of Human CYP1A2

人类CYP1A2的毒理学控制机制

• 批准号: 6655486
• 负责人: LINDA C QUATTROCHI
• 金额: $ 2.55万
• 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/6655486
• 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：(改编自申请者摘要)：细胞色素P450(CYP) 酶在内源化合物的新陈代谢中起着重要作用 如药物和各种化学致癌物等外源底物。CYP 1 A， 脊椎动物中的一个CyP亚家族，由两个成员组成：CyP1A1和CyP1A1 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 似乎调节了包括化学物质(例如， 多环芳香烃和卤代烃)，膳食 成分(如杂环胺、黄酮类、吲哚类)和遗传因素。 在目前的研究方案中，我们将检验以下假设 参与调节人类细胞色素P1A2的分子机制包括 多个和冗余的反式作用因子的复杂相互作用 调节元素，以及自然产生的饮食类黄酮改变 CYP 1 A2和CYP IA 1的表达。我们即将到来的拨款的目标 期间将重点关注定义CYP1A2基础的基本机械事件 和细胞类型特定的表达，并自然地定义作用 膳食中的类黄酮类物质通过调节细胞色素P1a基因的表达 这些试剂与转录因子(如芳烃)的相互作用 受体，其他碱性螺旋-环-螺旋蛋白)，潜在地介导人类 细胞色素P1a基因的表达。为此，我们将使用各种细胞系进行体外培养 研究，我们将开发模型来研究所涉及的分子机制 在体内调节人细胞色素P1a基因的表达。体内研究将 利用基因组整合报告基因构建和转基因小鼠系 含有表达人类细胞色素P1A1的细菌人工染色体和 细胞色素P450 1A2。长期目标是在细胞和分子水平上理解 调控细胞色素P1A2表达的机制及其作用机制 影响细胞色素P1A1和细胞色素P1A2的化学保护作用 天然黄酮类化合物的性质。此外，了解 与CYP1A基因表达改变相关的分子事件 黄酮类等“天然”药物的相互作用 植物衍生产品应使人们意识到可能的不良影响。