SPECIFIC MYOCARDIAL METABOLITES OF ETHANOL

在目前的1000万美国慢性酒精滥用者中，有1%到2%的人

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.