Toxicological Control Mechanisms of Human CYP1A2

人类CYP1A2的毒理学控制机制

• 批准号: 6327321
• 负责人: LINDA C QUATTROCHI
• 金额: $ 28.76万
• 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/6327321
• 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起重要作用 药物和各种化学致癌物等外源底物。 CYP 1 A， 脊椎动物中的CYP亚家族之一，由两个成员组成，CYP1A1和 CYP1A2，催化诸如多环境等环境化学物质的代谢 芳族烃和芳基胺以及众多药物。几个因素 似乎调节包括化学物质在内的CYP1A酶的表达（例如 多环芳烃和卤代烃），饮食 成分（例如杂环胺，黄酮，吲哚）和遗传因素。 在本研究建议中，我们将研究以下假设 与人CYP1A2调节有关的分子机制涉及 在多种和冗余的跨性别因子的复杂相互作用 调节元素，并且天然饮食类黄酮改变了 CYP 1 A2和CYP IA 1的表达。我们即将到来的赠款的目标 时期将重点放在定义CYP1A2基础的基本机械事件上 和细胞类型特异性表达，并定义自然的作用 发生饮食类黄酮在调节CYP1A基因表达中 这些药物与转录因子的相互作用（例如芳基水合碳 受体，其他基本的螺旋环螺旋蛋白），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涉及的分子机制 在人类CYP1A基因表达的体内调节中。体内研究将 利用基因组集成的报告基因构建体和转基因小鼠系 包含表达人CYP1A1和的细菌人造染色体 CYP1A2。长期目标是在细胞和分子上了解 将控制CYP1A2表达和机制的机制升级 这会影响CYP1A1和CYP1A2相对于化学保护 天然存在的类黄酮的特性。另外，了解 与CYP1A基因表达改变有关的分子事件 类黄酮和其他类黄酮和其他的“天然”药物的相互作用 植物来源的产品应导致对可能不利影响的认识。