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Toxicological Control Mechanisms of Human CYP1A2

人类CYP1A2的毒理学控制机制

基本信息

批准号：
6705059
负责人：
LINDA C QUATTROCHI
金额：
$ 33.1万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 2006-03-31
项目状态：
已结题

项目摘要

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，如药物和各种化学致癌物等外源性物质。A1 A，脊椎动物中由两个成员，CYP 1A 1和 CYP 1A 2催化多环芳烃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CYP 1A酶的表达，包括化学物质（例如，多环芳烃和卤代烃），膳食成分（如杂环胺，黄酮，吲哚）和遗传因素。在目前的研究建议中，我们将研究假设，参与人CYP 1A 2调节的分子机制包括反式作用因子在多重和冗余的调节元件，以及天然存在的膳食类黄酮改变 A2和A1 A1的表达。我们的目标是即将到来的赠款阶段的重点是定义CYP 1A 2基础的基本机制事件和细胞类型特异性表达，并定义自然的作用，膳食黄酮类化合物对CYP 1A基因表达的调节作用这些试剂与转录因子（例如芳基烃）的相互作用受体、其他碱性螺旋-环-螺旋蛋白）可能介导人类 CYP 1A基因表达。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人CYP 1A基因表达的体内调节中。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系含有表达人CYP 1A 1的细菌人工染色体， CYP1A2。长期目标是了解细胞和分子阐明CYP 1A 2的表达调控机制，影响CYP 1A 1和CYP 1A 2的化学保护作用天然存在的黄酮类化合物的性质。此外，了解与CYP 1A基因表达改变相关的分子事件，这些“天然”药物如类黄酮和其他植物衍生产品应导致对可能的不利影响的认识。