SPECIFIC MYOCARDIAL METABOLITES OF ETHANOL

在目前1000万美国慢性酒精滥用者中， 近20万人将患上酒精诱发的心肌疾病 （AIHMD），但这种疾病的发病机制仍不清楚。 此外，虽然已经记录了心肌细胞的变化， 乙醇暴露后的中间代谢，如甘油三酯 积累和减少脂肪酸的β-氧化，缺乏 心脏乙醇代谢的证明损害了 AIHMD的发病机制。 我们实验室的最新结果记录了 心脏匀浆和离体灌流乙醇的直接代谢 兔子心 在这些研究中，心肌乙醇的特定产物 代谢，脂肪酸乙酯（FAEE），被确定为第一个 时间 我们还在死亡的人类受试者的心脏中发现了FAEE 而氧化组（n = 3）。 这里提出的研究旨在追求 这些观察结果的病理生理学意义，通过定量 这些已经确定的产品的形成和描绘的机制， FAFE形成和降解的亚细胞定位， 负责任的酶，底物依赖性和器官特异性， 参与代谢途径。 产品的生物学意义 乙醇代谢将通过评价它们之间的相互作用来表征 与甘油三酯脂肪酶，因为初步数据表明，他们可能 作为竞争性底物，并通过评估其对 脂肪酸的β-氧化。 此外，蜂窝 这些代谢产物的电生理效应将被评估 因为FAEE可能导致通常与AIHMD相关的心律失常。 还将在给予以下物质后评估乙醇的心脏代谢： 体内乙醇。 心肌标本将从可用的 用于测定FAEE的长期依赖于乙醇的大鼠群体 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。 的 拟议研究的目标是表征心肌产物， 乙醇代谢和评估其可能的贡献， 与AIHMD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.