Bosron W F, Lumeng L, Li T K
Indiana University School of Medicine, Indianapolis.
Mol Aspects Med. 1988;10(2):147-58. doi: 10.1016/0098-2997(88)90019-2.
Differences in the pharmacokinetics of alcohol absorption and elimination are, in part, genetically determined. There are polymorphic variants of the two main enzymes responsible for ethanol oxidation in liver, alcohol dehydrogenase and aldehyde dehydrogenase. The frequency of occurrence of these variants, which have been shown to display strikingly different catalytic properties, differs among different racial populations. Since the activity of alcohol dehydrogenase in liver is a rate-limiting factor for ethanol metabolism in experimental animals, it is likely that the type and content of the polymorphic isoenzyme subunit encoded at ADH2, beta-subunit, and at ADH3, the gamma-subunit, are contributing factors to the genetic variability in ethanol elimination rate. The recent development of methods for genotyping individuals at these loci using white cell DNA will allow us to test this hypothesis as well as any relationship between ADH genotype and the susceptibility to alcoholism or alcohol-related pathology. A polymorphic variant of human liver mitochondrial aldehyde dehydrogenase, ADLH2, which has little or no acetaldehyde oxidizing activity has been identified. Individuals with the deficient ALDH2 phenotype do not have altered ethanol elimination rates but they do exhibit high blood acetaldehyde levels and dysphoric symptoms such as facial flushing, nausea and tachycardia, after drinking alcohol. Because acetaldehyde is so reactive, it binds to free amino groups of proteins including a 37 kilodalton hepatic protein-acetaldehyde adduct and may elicit an antibody response. We would predict that individuals who have low ALDH2 activity because of liver disease or because they have the inactive ALDH2 variant isoenzyme might form more protein-acetaldehyde adducts and elicit a greater immune response. These adducts may represent good biological markers of alcohol abuse and may also play a role in liver injury due to chronic alcohol consumption.
酒精吸收和消除的药代动力学差异部分由基因决定。肝脏中负责乙醇氧化的两种主要酶——乙醇脱氢酶和乙醛脱氢酶存在多态性变体。这些变体的催化特性显著不同，其出现频率在不同种族人群中也有所差异。由于在实验动物中，肝脏乙醇脱氢酶的活性是乙醇代谢的限速因素，因此很可能由ADH2编码的β亚基和由ADH3编码的γ亚基的多态同工酶亚基的类型和含量是乙醇消除率遗传变异性的影响因素。最近利用白细胞DNA对这些位点进行个体基因分型的方法的发展，将使我们能够检验这一假设以及ADH基因型与酒精中毒或酒精相关病理易感性之间的任何关系。已鉴定出人类肝脏线粒体乙醛脱氢酶ADLH2的一种多态变体，其乙醛氧化活性很低或没有。具有ALDH2缺陷表型的个体乙醇消除率并未改变，但饮酒后他们确实表现出高血乙醛水平和诸如面部潮红、恶心和心动过速等烦躁症状。由于乙醛具有很强的反应性，它会与包括一种37千道尔顿肝脏蛋白 - 乙醛加合物在内的蛋白质的游离氨基结合，并可能引发抗体反应。我们预计，由于肝脏疾病或具有无活性的ALDH2变异同工酶而导致ALDH2活性低的个体可能会形成更多的蛋白 - 乙醛加合物并引发更强的免疫反应。这些加合物可能是酒精滥用的良好生物学标志物，也可能在慢性酒精摄入导致的肝损伤中起作用。
