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Novel Mechanisms of Quinone Toxicity

醌毒性的新机制

基本信息

批准号：
8081829
负责人：
DAVID ROSS
金额：
$ 33.79万
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/8081829
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）：已发现苯醌和萘醌均干扰多种细胞系统中的蛋白质处理和降解。蛋白质处理和降解不限于蛋白酶体，还涉及蛋白伴侣、未折叠蛋白反应（UPR）/内质网（ER）应激反应、侵袭体的形成和溶酶体自噬。已发现醌类影响这些系统中的每一个，并且改变的蛋白质处理正在成为醌类诱导毒性的潜在关键机制。我们的研究将集中在模型1，4-苯醌和萘醌以及多巴胺衍生的1，2-醌，氨基色素，这些都已被证明可以诱导蛋白质处理的变化。在目标1中，我们将描述由模型苯并-和萘醌以及氨基色素诱导的所有主要蛋白质处理系统的变化。这些实验将表征由于用反应性醌处理细胞而改变的蛋白质处理机制以及这种变化与细胞系统中毒性的相关性。在目标2中，我们将定义芳基化和醌诱导的氧化应激在抑制蛋白质处理中的各自作用，使用醌只能进行氧化还原循环或同时进行氧化还原循环和芳基化。我们还将研究醌诱导的蛋白质处理的变化，在细胞中稳定转染的一个电子还原酶细胞色素P450还原酶或细胞色素b5还原酶，导致增加醌一个电子的氧化还原循环和增加活性氧的产生。主要的哺乳动物醌还原酶NQO 1和NQO 2是高度多态性的，具有导致显著表型变化的变异等位基因的高流行率。因此，这些酶活性的缺乏或变化可能代表醌诱导毒性的易感性因素。在目标3中，我们将研究NQO 1和NQO 2在调节醌诱导的蛋白质处理变化和毒性中的作用。这些实验将在专门设计用于探索NQO 1和NQO 2在相同遗传背景中的作用的同基因胰腺、乳腺和神经细胞系统中进行。总的来说，这些实验将表征在蛋白质处理水平上醌诱导毒性的新机制，定义内部-关系和蛋白质处理毒性变化的各自作用，并将NQO 1和NQO 2的作用定义为这些变化的易感因素。变化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：本申请的重点是在蛋白质处理水平上阐明外源性和内源性醌类的毒性的新机制。芳基化和氧化应激在醌诱导的蛋白质处理和毒性改变中的作用将被定义。醌还原酶的药物遗传学已被表征，它们具有高度多态性，可能代表醌诱导毒性的易感因素。这些研究将广泛适用于各种器官系统。