IMPACT OF ETHANOL ON OXIDATION OF METABOLITES

乙醇对代谢物氧化的影响

基本信息

批准号：
7959935
负责人：
Jennifer R Chase
金额：
$ 7.06万
依托单位：
UNIVERSITY OF IDAHO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7959935
关键词：
Address Affect Alcohol abuse Alcohol consumption Alcohol dehydrogenase Alcoholism Alcohols Aldehydes All-Trans-Retinol Cells Computer Retrieval of Information on Scientific Projects Database Computer Simulation Development Disease Enzymes Ethanol Fetal Alcohol Syndrome Funding Grant Health Hepatocyte Human Human Cell Line Idaho Institution Lead Liver Malignant Neoplasms Malignant neoplasm of liver Measurable NADH Operating System Oxidative Stress Play Prevention Production Property Protein Isoforms Reaction Recombinants Research Research Personnel Resources Retinol Metabolism Pathway Risk Factors Role Signal Transduction Source System Tissues Toxic effect Transcription Coactivator Tretinoin United States National Institutes of Health Vitamin A aldehyde dehydrogenases computer studies design novel oxidation programs research study theories

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Two of the many negative health results of alcohol abuse are fetal alcohol syndrome (FAS), and liver and other aerodigestive cancers. It is broadly believed that alcohol consumption and alcoholism lead to cancer and FAS, at least in part, via inhibition of synthesis of the transcription activator retinoic acid (RA) synthesis from retinol (vitamin A). A better understanding of the mechanism by which alcohol consumption leads to decreased RA production would be valuable for both prevention and amelioration of alcohol-associated disease. It is well established that ethanol directly competes with endogenous retinol for oxidation by several isoforms of alcohol dehydrogenase (ADH, EC 1.1.1.1). There is a widely-held, but unproven, theory that the ethanol-induced shifts in the levels of NADH also play a role in decreased oxidation of retinol by ADH. It has been difficult to design experiments to quantify the roles of the various inhibition mechanisms in retinol oxidation because inhibition is a cell system property rather than a phenomenon assignable to a single enzyme. We have developed a novel computational model of retinol oxidation that can be used to address inhibition in the context of several enzyme systems operating together to allow analysis and manipulation of the significant reactions encompassing ethanol and its interaction with retinol metabolism. The findings from computational studies are evaluated in the lab with recombinant human enzymes and human cell lines expressing alcohol and aldehyde dehydrogenases. We hypothesize that the ethanol-induced NADH increase inhibits RA synthesis in liver cells by inhibition of aldehyde and alcohol dehydrogenases. This represents the novel mechanism by which ethanol may decrease RA synthesis. The NADH-oxidative capacity of susceptible tissue and the potential for ethanol oxidation (producing NADH) are both measurable risk factors for FASD/developmental toxicity and upper airway/GI cancers where alcohol may affect RA signaling. Furthermore, since oxidative stress is implicated as a risk factor contributing to the development of liver cancer, this hypothesis provides an additional mechanism by which elevated NADH levels contribute to the development of the disease state.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是中心，不一定是研究者的机构。酗酒对健康造成的诸多负面影响中，有两种是胎儿酒精综合症 (FAS) 以及肝癌和其他呼吸消化系统癌症。人们普遍认为，饮酒和酗酒至少部分是通过抑制视黄醇（维生素 A）合成转录激活剂视黄酸（RA）而导致癌症和 FAS。更好地了解饮酒导致 RA 产生减少的机制对于预防和改善酒精相关疾病非常有价值。众所周知，乙醇直接与内源性视黄醇竞争，通过乙醇脱氢酶的几种亚型（ADH、EC 1.1.1.1）进行氧化。有一个广泛接受但未经证实的理论，即乙醇引起的 NADH 水平变化也在减少 ADH 对视黄醇的氧化方面发挥着作用。设计实验来量化视黄醇氧化中各种抑制机制的作用是很困难的，因为抑制是细胞系统的特性，而不是单一酶的现象。我们开发了一种新颖的视黄醇氧化计算模型，可用于解决多个酶系统一起运行的情况下的抑制问题，从而分析和操作包括乙醇及其与视黄醇代谢相互作用的重要反应。计算研究的结果在实验室中使用重组人类酶和表达乙醇和乙醛脱氢酶的人类细胞系进行评估。我们假设乙醇诱导的 NADH 增加通过抑制乙醛和乙醇脱氢酶来抑制肝细胞中 RA 的合成。这代表了乙醇可能减少 RA 合成的新机制。易感组织的 NADH 氧化能力和乙醇氧化（产生 NADH）的潜力都是 FASD/发育毒性和上呼吸道/胃肠道癌症的可测量危险因素，其中酒精可能影响 RA 信号传导。此外，由于氧化应激被认为是导致肝癌发展的危险因素，因此该假设提供了另一种机制，即NADH水平升高有助于疾病状态的发展。