SPECIFIC MYOCARDIAL METABOLITES OF ETHANOL

在目前美国1000万慢性酗酒者中，1%至2%或 近20万人将患上酒精引起的心肌疾病 (AIHMD)，但这种疾病的发病机制仍不清楚。 此外，尽管已经记录了心肌细胞的变化 酒精暴露后的中间代谢，如三酰甘油酯 脂肪酸的积累和β-氧化减少，缺乏 心脏对乙醇代谢的演示损害了对 AIHMD的发病机制。我们实验室的最新结果记录在案 心脏匀浆和隔离灌流对乙醇的直接代谢 兔心。在这些研究中，一种特定的心肌乙醇产物 新陈代谢，脂肪酸乙酯(FAEE)被鉴定为第一个 时间到了。我们还在死亡的人类受试者的心脏中发现了FAEE 未染毒时(n=3)。这里提出的研究旨在进行 通过定量观察这些观察的病理生理学意义 这些已经确定的产物的形成和描述的机制 FAFE的形成和降解与亚细胞定位有关， 负责的酶，底物依赖，和器官特异性 涉及新陈代谢途径。其产品的生物学意义 乙醇代谢将通过评估它们之间的相互作用来表征 三酰甘油脂肪酶，因为初步数据表明它们可能 作为竞争底物，并通过评估它们对 脂肪酸的β-氧化。此外，蜂窝 我们将评估这些代谢产物的电生理效应。 因为FAEE可能导致通常与AIHMD相关的心律失常。 乙醇的心脏代谢也将在给药后进行评估 体内的乙醇。心肌标本将从可用的 慢性乙醇依赖大鼠群体对FAEE的测定 负责其生物合成的酶的浓度和活性 和降解，以确定是否发生诱导或抑制。这个 拟议研究的目标是对心肌产物进行表征 乙醇代谢及其可能贡献的评估 与AIHMD的发展相关的异常。

Among the current 10 million American chronic abusers of alcohol, 1 to 2% or nearly 200,000 people will develop alcohol-induced heart muscle disease (AIHMD), but the pathogenesis of this disorder remains obscure. Furthermore, although changes have been documented in myocardial intermediary metabolism after ethanol exposure, such as triacylglyceride accumulation and decreased beta-oxidation of fatty acids, lack of demonstration of ethanol metabolism by the heart has impaired elucidation of the pathogenesis of AIHMD. Recent results from our laboratory documented direct metabolism of ethanol by heart homogenates and isolated perfused rabbit hearts. In these studies a specific product of myocardial ethanol metabolism, fatty acid ethyl esters (FAEE), was identified for the first time. We have also identified FAEE in hearts from human subjects who died while inoxicated (n = 3). The studies proposed here are designed to pursue the pathopysiological implications of these observations by quantitating formation of these already identified products and delineating mechanisms of FAFE formation and degradation with respect to subcellular localization, responsible enzymes, substrate dependence, and organ specificity of the metabolic pathways involved. the biological significance of products of ethanol metabolism will be characterized by evaluation of their interactions with triacylglycerol lipase,since preliminary data indicate that they may act as competitive substrates, and by evaluation of their effects on beta-oxidation of fatty acids. In addition, the cellular electrophysiological effects of these metabolic products will be assesed since FAEE may contribute to dysrhythmias commonly associated with AIHMD. Cardiac metabolism of ethanol will be assessed also after administration of ethanol in vivo. Myocardial specimens will be obtained from an available colony of rats chronically depedent on ethanol for determination of FAEE concentrations and activities of enzymes responsible for their biosynthesis and degradation to determine whether induction or suppression occurs. The goal of the proposed studies is characterization of myocardial products of ethanol metabolism and assessment of their possible contributions to abnormalities associated with development of AIHMD.