HUMAN ALCOHOL DEHYDROGENASE AND ALDEHYDE DEHYDROGENASE

人类乙醇脱氢酶和乙醛脱氢酶

• 批准号: 3109061
• 负责人: AKIRA Y YOSHIDA
• 金额: $ 24.16万
• 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/3109061
• 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 乙醇脱氢酶和乙醛脱氢酶已被公认 白人和东方人之间。 有人建议，非常高 东方人酒精敏感性的发生率可能是由于快速 东方型乙醇脱氢酶变体形成乙醛 (ADH-2-2)具有高催化活性，或由于积累 由于缺少一种主要醛而引起的乙醛 大多数脱氢酶同工酶（ALDH2，线粒体同工酶） 东方人。 东方人酗酒的发生率低于白人 可能是由于大多数对酒精敏感的受试者不被鼓励 大量饮酒。 利用获得的人 ADH 和 ALDH 的 cDNA 克隆 根据目前的赠款，将开展以下项目：1) 研究三种主要 ADH（即 ADH-1、ADH-2、 ADH-3) 基因座； 2) ALDH-1基因组结构研究（胞质 同工酶）和 ALDH-2（线粒体同工酶）基因座； 3）研究 与这些基因位点相关的限制性位点多态性；和 4) 确定白种人中这些位点的基因型分布， 东方人、美洲印第安人以及对酒精敏感和酗酒的人 科目。 这些研究将扩展我们对基因组结构的了解 人类 ADH 基因簇以及 ALDH-1 和 ALDH-2 位点，并阐明 这些同工酶的进化分化过程。 可能的 遗传背景（即这些基因的基因型）之间的相关性 和与这些位点相关的限制性位点多态性）和 将明确酒精敏感性和/或酒精中毒的倾向。