IMPACT OF ETHANOL ON OXIDATION OF METABOLITES

乙醇对代谢物氧化的影响

• 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
• 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

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 酒精滥用的许多负面健康结果中有两个是胎儿酒精综合征（FAS），以及肝脏和其他机火癌。广泛认为，饮酒和酒精中毒至少部分是通过抑制视黄醇（维生素A）的转录激活剂视黄酸（RA）合成的合成而导致癌症和FA的。更好地了解饮酒导致RA产量降低的机制对于预防和改善酒精相关疾病将是有价值的。众所周知，乙醇直接与内源性视黄醇竞争，以通过几种酒精脱氢酶的同工型（ADH，EC 1.1.1.1）氧化。有一个广泛但未经证实的理论，即乙醇诱导的纳德水平的变化也在ADH降低视黄醇的氧化中发挥了作用。很难设计实验来量化视黄醇氧化中各种抑制机制的作用，因为抑制是一种细胞系统特性，而不是可分配给单个酶的现象。我们已经开发了一种新型的视黄醇氧化计算模型，该模型可用于解决几种酶系统一起运行的抑制作用，以允许分析和操纵包括乙醇的重要反应及其与视黄醇代谢的相互作用。在实验室中，通过重组人酶和表达酒精和醛脱氢酶的人类细胞系评估了计算研究的发现。 我们假设乙醇诱导的NADH通过抑制醛和酒精脱氢酶的抑制作用增加了肝细胞中的RA合成。这代表了乙醇可以减少RA合成的新机制。易感组织的NADH氧化能力以及乙醇氧化的潜力（生产NADH）都是FASD/发育毒性的可测量风险因素，以及酒精可能影响RA信号传导的上呼吸道/GI癌。此外，由于氧化应激被视为有助于肝癌发展的危险因素，因此该假设提供了一种额外的机制，通过该机制，NADH水平升高有助于疾病状态的发展。