HUMAN ALCOHOL DEHYDROGENASE AND ALDEHYDE DEHYDROGENASE

人类乙醇脱氢酶和乙醛脱氢酶

• 批准号: 3109065
• 负责人: AKIRA Y YOSHIDA
• 金额: $ 21.77万
• 依托单位: BECKMAN RES INST OF THE CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3109065
• 关键词: Asians; Native Americans; acetaldehyde; alcohol dehydrogenase; alcoholic beverage consumption; alcoholism /alcohol abuse; aldehyde dehydrogenases; alleles; biological polymorphism; complementary DNA; drug tolerance; genetic library; genetic manipulation; genetic mapping; genome; genotype; human population genetics; human tissue; isozymes; molecular cloning; structural genes; ultracentrifugation

Remarkable genetic differences in the alcohol-metabolizing enzymes, i.e., alcohol dehydrogenase and aldehyde dehydrogenase, have been recognized between Caucasians and Orientals. It has been suggested that the very high incidence of alcohol sensitivity in Orientals could be due to the rapid acetaldehyde formation by the Oriental-type alcohol dehydrogenase variant (ADH-2-2) with high catalytic activity, or due to the accumulation of acetaldehyde caused by the absence of one of the major aldehyde dehydrogenase isoenzymes (ALDH2, mitochondrial isozyme) in the majority of Orientals. A lower incidence of alcoholism in Orientals than in Caucasians could be due to most alcohol-sensitive subjects being discouraged from drinking heavily. Utilizing the cDNA clones for human ADHs and ALDHs, which were obtained under the present grant, the following projects will be undertaken: 1) Study of the genomic organization of three major ADH (i.e., ADH-1, ADH-2, ADH-3) loci; 2) Study of the genomic structures of ALDH-1 (for cytosolic isozyme) and ALDH-2 (for mitochondrial isozyme) loci; 3) Study of restriction-site polymorphism related to these gene loci; and 4) Determination of genotype distributions of these loci in Caucasians, Orientals, and American Indians, and in alcohol-sensitive and alcoholic subjects. These studies will extend our knowledge of the genomic structures of the human ADH gene cluster and the ALDH-1 and ALDH-2 loci, and shed light on the process of evolutional divergence of these isozymes. The possible correlation between the genetic background (i.e., genotypes of these genes and restriction-site polymorphism associated with these loci) and the predisposition of alcohol sensitivity and/or alcoholism will be clarified.

酒精代谢酶的显着遗传差异，即 酒精脱氢酶和醛脱氢酶已被识别 在高加索人和东方人之间。 有人建议很高 东方酒精敏感性的发生率可能是由于迅速 东方型酒精脱氢酶变体形成乙醛 （ADH-2-2）具有高催化活性，或者由于积累 乙醛是由缺乏主要醛之一引起的 大多数脱氢酶同工酶（ALDH2，线粒体同工酶） 东方。 与高加索人相比，东方酒精中毒的发病率较低 可能是由于大多数对酒精敏感的受试者都不鼓励 大量喝酒。 利用获得的cDNA克隆来获得人类ADH和ALDHS 根据目前的赠款，将进行以下项目：1） 三个主要ADH的基因组组织研究（即ADH-1，ADH-2， ADH-3）基因座； 2）研究ALDH-1的基因组结构（用于胞质 同工酶）和ALDH-2（用于线粒体同工酶）基因座； 3）研究 与这些基因基因座有关的限制位点多态性；和4） 确定这些基因座在高加索人中的基因型分布， 东方人，美国印第安人，以及对酒精敏感和酒精的 主题。 这些研究将扩展我们对这些基因组结构的了解 人ADH基因簇以及ALDH-1和ALDH-2基因座，并阐明 这些同工酶进化差异的过程。 可能 遗传背景之间的相关性（即这些基因的基因型 与这些基因座相关的限制位点多态性）和 酒精敏感性和/或酒精中毒的易感性将被阐明。