Ethanol & Farnesol: Metabolic Interactions

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，并提供 甲氧丙戊酸及其衍生物合成的代谢前体 内源性法尼醇，一种15碳长的异丙肾上醇。在肝脏中，酶 它能氧化乙醇，也能控制法尼醇氧化成法尼醇和 金合欢酸。包括我们小组的研究在内的几项研究表明 法尼醇与细胞生长、细胞凋亡、核受体激活、 电压门控性钙通道活性和自由基的产生。因为 乙醇也会影响这些过程，因为这两种醇都有共同的 代谢途径，有可能乙醇的不利影响和 一般来说，酒精中毒在一定程度上是次要的 乙醇与法尼醇途径。为了支持这一假设，我们建议 收集提供证据的初步数据，证明乙醇确实可以 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在体内代谢为肝法呢类化合物，2。 确定酒精给药是否会影响肝脏法尼醇浓度， 研究急性和慢性乙醇对金合欢醇的影响。 亚细胞部分的新陈代谢。实验将在 C57BL/6J小鼠品系。这些数据将作为未来的基础 年解决乙醇/法尼醇代谢相互作用问题的项目 其他组织和评价法尼醇对乙醇毒性的贡献 在目标组织中。最后，这些数据将作为描述特征的依据 酒精敏感型个体或动物的法尼醇代谢或检查 治疗酒精中毒的新药理策略 法尼醇途径的调控。

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.