Alcohol and the liver: metabolism of alcohol and its role in hepatic and extrahepatic diseases.
Alcohol and the liver: metabolism of alcohol and its role in hepatic and extrahepatic diseases.
复制标题
DOI：
--
复制
发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Lieber Cs
中科院分区：
文献类型：
--
作者：
Lieber Cs
查尔斯·利伯 (Charles S. Lieber) 博士进行了四十多年的临床和实验研究（其中三次在西奈山和布朗克斯退伍军人医疗中心），重点研究肝脏、营养和胃肠道病理生理学。他的主要贡献包括通过证明酒精的毒性作用和描述相关的代谢紊乱来阐明酒精性肝病的发病机制。这是通过明智的临床研究和新开发的啮齿动物和灵长类动物模型以及在流质饮食中添加乙醇而实现的。阐明了乙醇各种病理和代谢效应的机制，包括高脂血症（伴随HDL升高）、高尿酸血症、乙醛毒性的作用和酒精诱导的氧化应激。后者，包括谷胱甘肽的消耗，可以通过给酒精喂养的狒狒注射S-腺苷-1-蛋氨酸来纠正。该化合物现已在欧洲成功用于治疗酒精性肝病患者。酒精性肝硬化首次在非人类灵长类动物中产生，并被证明可以通过多烯磷脂酰胆碱完全预防，目前正在多中心临床试验中进行测试。 Lieber 还发现了一种新的乙醇代谢（微粒体）途径，该途径导致对乙醇的耐受性以及与其他药物（例如对乙酰氨基酚）、麻醉剂、工业溶剂、致癌物以及视黄醇和 β-胡萝卜素的几种临床上重要的毒性相互作用，并缩小了它们的治疗窗口。他的工作定义了胃在乙醇代谢中的作用，描述了相应的性别差异，克隆了（首次）西格玛ADH（一种新识别的胃醇脱氢酶同工酶）基因及其染色体定位，并发现了常用药物（例如H2阻滞剂和阿司匹林）对该酶活性和社交饮酒者血液酒精水平的影响。利伯是最早使用抗生素消除人类胃细菌脲酶及其氨产生的人之一，从而减轻慢性胃炎和胃酸过少，并减轻肝硬化患者的肝性脑病。他通过定义肝硬化前病变和饮酒标志，提倡在酗酒者的社会或医疗崩溃之前及早发现和治疗他们。结论 Lieber 博士和他的团队的研究使人们更好地了解了常见的肝脏、胃和营养疾病的发病机制，阐明和预防了严重的有毒酒精-药物相互作用，并开发了早期识别方法和更有效的方法来预防和治疗肝脏和胃肠道疾病。
UNLABELLED Dr. Charles S. Lieber conducted clinical and experimental studies for more than four decades (three at Mount Sinai and the Bronx VA Medical Centers) with emphasis on liver, nutrition and GI pathophysiology. His major contributions include elucidation of the pathogenesis of alcoholic liver disease, by demonstrating the toxic role of alcohol and describing associated metabolic disorders. This was achieved through judicious clinical studies and newly-developed rodent and primate models with the administration of ethanol in liquid diets. The mechanisms of various pathological and metabolic effects of ethanol were clarified, including hyperlipemia (with the rise in HDL), hyperuricemia, the role of acetaldehyde toxicity and alcohol-induced oxidative stress. The latter, including glutathione depletion, was corrected by S-adenosyl-1-methionine given to alcohol-fed baboons; the compound is now being used successfully for the treatment of patients with alcoholic liver disease in Europe. Alcoholic cirrhosis was produced for the first time in nonhuman primates and shown to be fully prevented by polyenylphosphatidylcholine, which is now being tested in a multicenter clinical trial. Lieber also discovered a new (microsomal) pathway of ethanol metabolism, responsible for the tolerance to ethanol and for several clinically important toxic interactions with other drugs (e.g., acetaminophen), anesthetics, industrial solvents, carcinogens, as well as retinol and b-carotene, with narrowing of their therapeutic window. His work defined the role of the stomach in ethanol metabolism, description of corresponding gender differences, cloning (for the first time) of the gene for sigma ADH (a newly-recognized gastric alcohol dehydrogenase isozyme) with its chromosomal localization, and the discovery of the effects of commonly used medications (e.g., H2 blockers and aspirin) on the activities of the enzyme and on blood alcohol levels in social drinkers. Lieber was among the first to use antibiotics for the elimination of gastric bacterial urease and its ammonia production in man, thereby alleviating chronic gastritis and hypoacidity, with attenuation of hepatic encephalopathy in cirrhotics. He promoted early detection and treatment of heavy drinkers before their social or medical disintegration, by defining precirrhotic lesions and markers of alcohol consumption. CONCLUSIONS The research of Dr. Lieber and his group yielded a better understanding of the pathogenesis of common hepatic, gastric and nutritional disorders, with elucidation and prevention of serious toxic alcohol-drug interactions and the development of methods for early recognition and more effective approaches to prevent and treat liver and gastrointestinal diseases.