Ethanol & Farnesol: Metabolic Interactions

乙醇

• 批准号: 6621943
• 负责人: Jean-Baptiste O Roullet
• 金额: $ 15.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621943
• 关键词: alcohol oxidoreductases; alcoholic beverage consumption; alcoholism /alcohol abuse; alcohols; brain; cytoplasm; enzyme activity; ethanol; farnesyl compound; fatty acid biosynthesis; genetic strain; intermolecular interaction; laboratory mouse; liver; male; metabolism; mevalonate; mitochondria; protein localization; radiotracer; tissue /cell preparation; toxicology

DESCRIPTION (provided by applicant): Ethanol (alcohol) is converted into acetyl CoA by mammalian cells and serves as metabolic precursor to the synthesis of mevalonate and mevalonate-derived endogenous farnesol, a 15-carbon long isoprenol. In the liver, the enzymes which oxidize ethanol also control the oxidation of farnesol into farnesal and farnesoic acid. Several studies including studies by our group indicate that farnesol is implicated in cell growth, apoptosis, nuclear receptor activation, voltage-gated Ca2+ channel activity and free radical production. Because ethanol also affects these processes, and because both alcohols share common metabolic pathways, it is possible that the adverse effects of ethanol and alcoholism in general, are in part, secondary to the metabolic interaction of ethanol with the farnesol pathway. To support this hypothesis, we propose to collect preliminary data providing evidence that indeed ethanol modifies farnesol metabolism. Our objectives are: 1. To determine if ethanol affects the in vivo metabolism of radioactive MVA into hepatic farnesoids, 2. To determine if ethanol administration affects hepatic farnesol concentrations, and To characterize the effect of acute and chronic ethanol on farnesol metabolism by subcellular fractions. Experiments will be performed in the C57BL/6J mouse strain. The data will be used as a foundation to future projects addressing the issues of ethanol/farnesol metabolic interactions in other tissues and evaluating the contribution of farnesol to ethanol toxicity in target tissues. Finally, the data will serve as a rationale to characterize farnesol metabolism in alcohol-sensitive individuals or animals or to examine new pharmacological strategies for the treatment of alcohol toxicity based on modulation of the farnesol pathway.

描述（由申请人提供）： 乙醇（酒精）被哺乳动物细胞转化为乙酰辅酶A并发挥作用 作为甲羟戊酸和甲羟戊酸衍生物合成的代谢前体 内源性金合欢醇，一种 15 个碳长的异戊二烯醇。在肝脏中，酶 氧化乙醇的同时也控制法呢醇氧化成法呢醛和 法尼酸。包括我们小组的研究在内的多项研究表明 金合欢醇参与细胞生长、细胞凋亡、核受体激活、 电压门控 Ca2+ 通道活性和自由基产生。因为 乙醇也会影响这些过程，并且因为这两种醇有共同点 代谢途径，乙醇和的不利影响可能是 一般来说，酒精中毒在一定程度上是继发于代谢相互作用的 乙醇与法呢醇途径。为了支持这一假设，我们建议 收集初步数据，提供乙醇确实改变的证据 法尼醇代谢。我们的目标是： 1. 确定乙醇是否会影响 放射性MVA在体内代谢为肝法尼醇，2. 确定乙醇给药是否影响肝脏法尼醇浓度， 表征急性和慢性乙醇对金合欢醇的影响 亚细胞部分的代谢。实验将在 C57BL/6J 小鼠品系。这些数据将作为未来的基础 解决乙醇/金合欢醇代谢相互作用问题的项目 其他组织并评估金合欢醇对乙醇毒性的影响 在靶组织中。最后，数据将作为描述特征的基本原理 对酒精敏感的个体或动物的金合欢醇代谢或检查 治疗酒精中毒的新药理学策略 法尼醇途径的调节。