Crabb David W, Matsumoto Michinaga, Chang David, You Min
Indiana University School of Medicine and Roudebush VA Medical Center, Emerson Hall Room 317, 545 Barnhill Drive, Indianapolis, IN 46202, USA.
Proc Nutr Soc. 2004 Feb;63(1):49-63. doi: 10.1079/pns2003327.
Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH beta2, encoded by the ADH22 gene, and the inactive ALDH22 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene-environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.
乙醇脱氢酶（ADH）和线粒体乙醛脱氢酶（ALDH2）负责代谢饮食中摄入的大部分乙醇，它们的活性有助于乙醇从血液中清除的速率。它们在肝脏中表达水平最高，但在许多组织中表达水平较低。这条途径可能是作为对环境酒精的解毒机制进化而来的。然而，随着大量乙醇的摄入，乙醇的氧化可成为主要能量来源，尤其是在肝脏中，会干扰其他营养物质的代谢。这些酶的基因多态性变体编码具有改变动力学特性的酶。这些变体的病理生理效应可能由乙醛积累介导；高活性ADH变体预计会增加乙醛生成速率，而低活性ALDH2变体与无法代谢该化合物有关。乙醛的影响可能在产生它的细胞中表现出来，或者通过血液甚至唾液将乙醛输送到各种组织中表现出来。由ADH22基因编码的高活性ADHβ2和无活性ALDH22基因产物的遗传已被确凿地证明与酒精中毒风险降低有关。这种关联受到基因-环境相互作用的影响，如宗教和国籍。这些变体也被研究与酒精性肝病、癌症、胎儿酒精综合征、心血管疾病、痛风、哮喘和外源性物质清除的关联。迄今为止发现的最强相关性是ALDH2*2等位基因与口咽癌和食管癌之间的相关性。重复这些变体与其他癌症和心脏病之间的其他有趣关联，并确定这些关联背后的生化机制将很重要。
