GENETIC-POLYMORPHISM OF HUMAN-LIVER ALCOHOL AND ALDEHYDE DEHYDROGENASES, AND THEIR RELATIONSHIP TO ALCOHOL METABOLISM AND ALCOHOLISM
GENETIC-POLYMORPHISM OF HUMAN-LIVER ALCOHOL AND ALDEHYDE DEHYDROGENASES, AND THEIR RELATIONSHIP TO ALCOHOL METABOLISM AND ALCOHOLISM
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DOI：
10.1002/hep.1840060330
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发表时间：
1986-05-01
期刊：
影响因子：
13.5
通讯作者：
LI, TK
中科院分区：
文献类型：
--
作者：
BOSRON, WF;LI, TK
现在人们普遍认为，酒精消费的各种药理学和成瘾性后果与乙醇或其代谢产物的组织浓度有关。乙醇在肝脏中的氧化代谢主要由乙醇脱氢酶和乙醛脱氢酶催化。这两种酶都以多种分子形式存在，并且已经提出了遗传模型来解释同工酶的多样性。乙醇脱氢酶亚基编码在五个不同的基因位点，遗传多态性发生在两个乙醇脱氢酶位点。在两个多态性醇脱氢酶位点产生的变异同工酶解释了个体间观察到的酶电泳图谱的差异。这些变体同工酶中的一些表现出广泛不同的动力学特性，这可能解释了个体之间酒精消除率的2至3倍变化。由于几种醇脱氢酶亚基的蛋白质序列已被确定，几种醇脱氢酶基因已被克隆，一些结构变化引起的催化和电泳性能的差异是已知的。乙醛脱氢酶基因座也存在遗传多态性，该基因座编码线粒体乙醛脱氢酶同工酶的低Km。变体同工酶表现出很少或没有催化活性。具有这种“空”变体的个体具有高于正常血液乙醛水平的乙醛水平，并且表现出酒精潮红反应，这似乎是对大量饮酒和酒精中毒的威慑。由于流行病学调查表明，酒精滥用和酒精中毒的遗传易感性，这是合理的假设，无论是乙醇脱氢酶或乙醛脱氢酶的多态性可能是一个潜在的生物学因素，有助于酒精中毒的遗传性质。
It is now widely accepted that the various pharmacologic and addictive consequences of alcohol consumption are related to the tissue concentration of ethanol or its metabolic products. The oxidative metabolism of ethanol in liver is principally catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase. Both of these enzymes exist in multiple molecular forms, and genetic models have been proposed to account for the multiplicity of isoenzymes. Alcohol dehydrogenase subunits are encoded at five different gene loci, and genetic polymorphism occurs at two alcohol dehydrogenase loci. Variant isoenzymes produced at the two polymorphic alcohol dehydrogenase loci account for the differences in enzyme electrophoretic patterns observed among individuals. Some of these variant isoenzymes exhibit widely different kinetic properties, and this may account for the 2‐ to 3‐fold variation in alcohol elimination rate among individuals. Since the protein sequence of several of the alcohol dehydrogenase subunits has been determined and several of the alcohol dehydrogenase genes has been cloned, some of the structural changes which give rise to differences in catalytic and electrophoretic properties are now known. Genetic polymorphism also occurs at the aldehyde dehydrogenase gene locus which encodes the mitochondrial low Kmfor acetaldehyde aldehyde dehydrogenase isoenzyme. The variant isoenzyme exhibits little or no catalytic activity. Individuals with this “null” variant have higher than normal blood acetaldehyde levels and exhibit an alcohol‐flush reaction which appears to be a deterrent to heavy drinking and alcoholism. Since epidemiological surveys have demonstrated genetic predisposition to alcohol abuse and alcoholism, it is reasonable to suppose that the polymorphism of either alcohol dehydrogenase or aldehyde dehydrogenase might be one of the underlying biological factors contributing to the inherited nature of alcoholism.