Novel Mechanisms of Quinone Toxicity

醌毒性的新机制

基本信息

批准号：
8242837
负责人：
DAVID ROSS
金额：
$ 33.78万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-04 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242837
关键词：
Adverse effects Affect Affinity Chromatography Aftercare Alleles Autophagocytosis Benzoquinones Biological Models Breast Cells Chemicals Data Disease Dopamine Electrons Enzymes Event Frequencies General Population Generations Genetic Genetic Polymorphism High Prevalence Hydroquinones Individual Knock-in Mouse Modeling Molecular Chaperones NADPH-Ferrihemoprotein Reductase NQO1 gene NRH - quinone oxidoreductase2 Naphthoquinones Nature Neurons Oxidation-Reduction Oxidative Stress Oxidoreductase Oxygen Pancreas Pharmacogenetics Predisposition Process Production Proteins Quinone Reductases Quinones Reaction Reactive Oxygen Species Role System Toxic effect Variant Xenobiotics adduct aminochrome 1 biological adaptation to stress body system cell type cytochrome b5 reductase design endoplasmic reticulum stress enzyme activity hydroquinone liquid chromatography mass spectrometry multicatalytic endopeptidase complex novel p-Benzoquinones protein protein interaction public health relevance relating to nervous system research study response suicide inhibitor

项目摘要

DESCRIPTION (provided by applicant): Both benzoquinones and naphthoquinones have been found to perturb protein handling and degradation in a variety of cellular systems. Protein handling and degradation is not restricted to the proteasome and also involves protein chaperones, the unfolded protein response (UPR)/endoplasmic reticulum (ER) stress response, formation of aggresomes and lysosomal autophagy. Quinones have been found to affect each of these systems and altered protein handling is emerging as a potentially key mechanism of quinone induced toxicity. Our studies will focus on model 1,4-benzo- and naphtho-quinones as well as the dopamine derived 1,2-quinone, aminochrome which have all been shown to induce changes in protein handling. In aim 1, we will characterize changes in all major protein handling systems induced by model benzo- and naphtho- quinones and by aminochrome. These experiments will characterize altered mechanisms of protein handling as a result of treatment of cells with reactive quinones and the relevance of such changes for toxicity in cellular systems. In aim 2, we will define the respective roles of arylation and quinone-induced oxidative stress in inhibited protein handling using quinones capable only of either redox cycling or of both redox cycling and arylation . We will also examine quinone induced changes in protein handling in cells stably transfected with the one electron reductases cytochrome P450 reductase or cytochrome b5 reductase which cause increased quinone one electron redox cycling and increased reactive oxygen generation. The major mammalian quinone reductases NQO1 and NQO2 are highly polymorphic with a high prevalence of variant alleles resulting in marked phenotypic changes. A lack or variation in activity of these enzymes may therefore represent susceptibility factors for quinone induced toxicity. In aim 3, we will examine the role of NQO1 and NQO2 in modulating quinone induced protein handling changes and toxicity. These experiments will be performed in isogenic pancreatic, breast and neural cellular systems specifically designed to explore the roles of NQO1 and NQO2 in the same genetic background Overall, these experiments will characterize novel mechanisms of quinone-induced toxicity at the level of protein handling, define the inter-relationships and the respective roles of protein handling changes in toxicity and define the role of NQO1 and NQO2 as susceptibility factors for these changes. The studies will have broad mechanistic applicability to a variety of organ systems. PUBLIC HEALTH RELEVANCE: The focus of this application is to elucidate novel mechanisms of toxicity of xenobiotic and endogenous quinones at the level of protein handling. The role of both arylation and oxidative stress in quinone-induced alterations in protein handling and toxicity will be defined. The pharmacogenetics of quinone reductases has been characterized and they are highly polymorphic and may represent susceptibility factors for quinone induced toxicity. The studies will have broad applicability to a variety of organ systems.

描述（由申请人提供）：在多种细胞系统中都发现了苯喹酮和萘喹酮可扰动蛋白质处理和降解。蛋白质处理和降解不限于蛋白酶体，还涉及蛋白质伴侣，未折叠的蛋白质反应（UPR）/内质网（ER）应激反应，脂肪组的形成和溶酶体自噬。已经发现奎因酮会影响这些系统中的每一个，并且蛋白质处理的改变正在成为喹酮诱导毒性的潜在关键机制。我们的研究将重点放在1,4-苯并和萘型的型号上，以及多巴胺衍生的1,2-喹酮氨基染料，这些氨基酸剂均显示出诱导蛋白质处理的变化。在AIM 1中，我们将表征由模型苯甲和萘酮诱导的所有主要蛋白质处理系统的变化以及氨基色素。这些实验将表征由于用反应性奎因酮治疗细胞的结果以及这种变化对细胞系统中毒性的相关性而改变了蛋白质处理的机制。在AIM 2中，我们将使用仅能够仅能氧化还原循环或氧化还原循环和芳基化的奎因酮来定义芳基化和喹酮诱导的氧化应激的各自作用。我们还将检查喹酮诱导的蛋白质处理变化，该细胞中稳定转染的细胞中，用一个电子还原酶细胞色素p450还原酶或细胞色素B5还原酶，这会导致奎因酮一个电子氧化还原循环增加并增加活性氧的产生。主要的哺乳动物喹酮还原酶NQO1和NQO2是高度多态性的，具有较高的变异等位基因，导致表型变化显着。因此，这些酶的活性缺乏或差异可能代表喹酮诱导毒性的易感因素。在AIM 3中，我们将研究NQO1和NQO2在调节喹酮诱导蛋白质处理的变化和毒性中的作用。这些实验将在同基因性胰腺，乳腺和神经细胞系统中进行，专门设计用于探索NQO1和NQO2在总体上相同遗传背景中的作用，这些实验将表征奎因酮诱导的毒性在蛋白质处理水平上的新型机制，并定义了蛋白质间的作用，并定义了蛋白质中的质量和蛋白质的作用，并定义了蛋白质的作用，并定义了蛋白质的作用，并在蛋白质处理水平上进行了质量和固定的作用。 NQO2作为这些变化的易感因素。这些研究将对各种器官系统具有广泛的机械适用性。公共卫生相关性：该应用的重点是阐明在蛋白质处理水平上在异生元和内源性喹酮毒性的新机制。芳基化和氧化应激在喹酮诱导的蛋白质处理和毒性改变中的作用将被定义。喹酮还原酶的药物遗传学已经表征，它们具有高度多态性，并且可能代表了喹酮诱导毒性的易感因子。这些研究将对各种器官系统具有广泛的适用性。