Calabrese V, Scapagnini G, Latteri S, Colombrita C, Ravagna A, Catalano C, Pennisi G, Calvani M, Butterfield D A
Biochemistry and Molecular Biology Section, Department of Chemistry, Faculty of Medicine, University of Catania, Catania, Italy.
Int J Tissue React. 2002;24(3):97-104.
Chronic alcoholism is a major public health problem and causes multiorgan diseases and toxicity. Although the majority of ethanol ingested is metabolized by the liver, it has intoxicating effects in the brain. Evidence is accumulating that intermediates of oxygen reduction may be associated with the development of alcoholic disease. Several studies have shown the capacity of carnitine and its derivatives to influence ethanol metabolism. We have previously demonstrated that preadministration of L-carnitine to rats receiving ethanol significantly reduced fatty acid ethyl esters in different organs and that the carnitine/acylcarnitine system is crucial for maintaining a functional acetyl-CoA/CoA ratio under conditions in which cellular homeostasis is exposed to the deleterious effects of accumulating organic acids. Ethanol, administered to rats for 20 months, induced significant changes in the status of glutathione, primarily in the brain regions of hippocampus and cerebellum, followed by cortex and striatum, where a decrease in reduced glutathione (GSH) and the GSH/oxidized glutathione ratio was found. The same brain regions showed a significant increase in free radical-induced luminescence and hydroxynonenal (HNE), which were associated with decreased GSH reductase activity. Long-term supplementation with acetyl carnitine significantly reduced GSH depletion, particularly in the brain regions of hippocampus, an effect associated with decreased luminescence and HNE formation. In addition, acetyl carnitine treatment increased GSH reductase and arginase activities. Our results indicate that decreased GSH reductase activities associated with thiol depletion are important factors sustaining a pathogenic role in alcohol-related pathologies. Administration of acetyl carnitine greatly reduces these metabolic abnormalities. This evidence supports the pharmacological potential of acetyl carnitine in the management of alcoholic disturbances.
慢性酒精中毒是一个主要的公共卫生问题，会导致多器官疾病和毒性。尽管摄入的大部分乙醇由肝脏代谢，但它对大脑具有致醉作用。越来越多的证据表明，氧还原中间体可能与酒精性疾病的发展有关。多项研究表明肉碱及其衍生物有影响乙醇代谢的能力。我们之前已经证明，对接受乙醇的大鼠预先给予L-肉碱可显著降低不同器官中的脂肪酸乙酯，并且在细胞稳态受到积累的有机酸有害影响的条件下，肉碱/酰基肉碱系统对于维持功能性乙酰辅酶A/辅酶A比率至关重要。给大鼠喂食乙醇20个月后，谷胱甘肽状态发生了显著变化，主要是在海马体和小脑的脑区，其次是皮质和纹状体，在这些区域发现还原型谷胱甘肽（GSH）和GSH/氧化型谷胱甘肽比率降低。相同的脑区显示自由基诱导的发光和羟基壬烯醛（HNE）显著增加，这与GSH还原酶活性降低有关。长期补充乙酰肉碱可显著减少GSH耗竭，尤其是在海马体的脑区，这种作用与发光和HNE形成减少有关。此外，乙酰肉碱治疗可提高GSH还原酶和精氨酸酶的活性。我们的结果表明，与硫醇耗竭相关的GSH还原酶活性降低是在酒精相关病理中发挥致病作用的重要因素。给予乙酰肉碱可大大减少这些代谢异常。这一证据支持了乙酰肉碱在治疗酒精性障碍方面的药理潜力。
