GENETIC AND METABOLIC STUDIES OF HUMAN ALCOHOLICS

人类酗酒者的遗传和代谢研究

• 批准号: 3808627
• 负责人: R L VEECH
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3808627
• 关键词: acetaldehyde; acetone; alcoholic beverage consumption; alcoholic fatty liver; alcoholic liver cirrhosis; alcoholism /alcohol abuse; biomarker; blood; blood chemistry; brain metabolism; butanols; diol; disease /disorder model; drug interactions; enzyme complex; enzyme mechanism; enzyme substrate; fasting; fatty acid metabolism; gas chromatography; genetic markers; human subject; human tissue; inborn metabolism disorder; interview; laboratory rat; liver metabolism; pyruvate dehydrogenase; stereoisomer

In three separate studies involving three different sets of collaborators, elevated levels of 2,3- butanediol have been found in the blood of 80% of chronic alcoholics, but not social drinkers consuming distilled spirits. Two separate methods of gas chromatographic analysis of diols have been developed. One method involving formation of the bromophenylboronate derivative can accurately measure to D-L, or meso-2,3-butanediol to 5uM. In the rat, two pathways of butanediol formation have been demonstrated. The first (Veech RL, et al. Curr Top Cell Regul 1981;18:151-179) involves elevated blood acetaldehyde entering the brain with an active pyruvate dehydrogenase multi-enzyme complex where it condenses with hydroxyethyl thiamine pyrophosphate to form acetoin. The acetoin is subsequently converted in liver to 2,3-butanediol. In a second animal model, 2,3- butanediol in the rat is produced by acetone feeding. Prolonged fasting in man, however, produces only 1,2- propanediol. Whether D/L-2,3-butanediol production is due to expression of an aberrant gene product or is due to some other metabolic change caused by chronic ethanol consumption is not known, but the presence of this compound in approximately 40% of all alcoholics prior to the onset of alcoholic liver disease during periods of ethanol ingestion, and in approximately 25% of all alcoholics with alcoholic cirrhosis in the absence of recent ingestion of ethanol make this compound a useful indicator of alcoholic liver disease.

在涉及三组不同合作者的三项独立研究中， 80% 的人血液中发现 2,3-丁二醇水平升高 长期酗酒者，但不包括饮用蒸馏酒的社交饮酒者。 两种独立的二醇气相色谱分析方法 发达。一种涉及形成溴苯硼酸酯的方法 衍生物可以精确测量至 D-L，或内消旋 2,3-丁二醇至 5uM。 在大鼠中，已证实丁二醇形成的两种途径。 第一个（Veech RL 等人 Curr Top Cell Regul 1981；18：151-179）涉及 升高的血液乙醛随着活性丙酮酸盐进入大脑 脱氢酶多酶复合物，与羟乙基缩合 焦磷酸硫胺素形成乙偶姻。随后将乙偶姻 在肝脏中转化为2,3-丁二醇。在第二种动物模型中，2,3- 大鼠体内的丁二醇是通过丙酮喂养产生的。长期禁食 然而，人类只能产生1,2-丙二醇。是否为D/L-2,3-丁二醇 产生是由于异常基因产物的表达或由于 慢性乙醇消耗引起的其他一些代谢变化并不是 已知，但大约 40% 的物质中存在这种化合物 酒精性肝病发病前的酗酒者 乙醇摄入，大约 25% 的酗酒者 最近没有摄入乙醇的酒精性肝硬化使得 化合物是酒精性肝病的有用指标。