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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA005763-05
Application #
3109065
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1983-04-01
Project End
1989-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Hsu, L C; Chang, W C; Yoshida, A (1997) Human aldehyde dehydrogenase genes, ALDH7 and ALDH8: genomic organization and gene structure comparison. Gene 189:89-94
Lin, S W; Chen, J C; Hsu, L C et al. (1996) Human gamma-aminobutyraldehyde dehydrogenase (ALDH9): cDNA sequence, genomic organization, polymorphism, chromosomal localization, and tissue expression. Genomics 34:376-80
Hsu, L C; Chang, W C (1996) Sequencing and expression of the human ALDH8 encoding a new member of the aldehyde dehydrogenase family. Gene 174:319-22
Hsu, L C; Chang, W C; Lin, S W et al. (1995) Cloning and characterization of genes encoding four additional human aldehyde dehydrogenase isozymes. Adv Exp Med Biol 372:159-68
Yoshida, A (1994) Genetic polymorphisms of alcohol metabolizing enzymes related to alcohol sensitivity and alcoholic diseases. Alcohol Alcohol 29:693-6
Hsu, L C; Chang, W C; Hiraoka, L et al. (1994) Molecular cloning, genomic organization, and chromosomal localization of an additional human aldehyde dehydrogenase gene, ALDH6. Genomics 24:333-41
Sherman, D; Dave, V; Hsu, L C et al. (1993) Diverse polymorphism within a short coding region of the human aldehyde dehydrogenase-5 (ALDH5) gene. Hum Genet 92:477-80
Yoshida, A; Hsu, L C; Yanagawa, Y (1993) Biological role of human cytosolic aldehyde dehydrogenase 1: hormonal response, retinal oxidation and implication in testicular feminization. Adv Exp Med Biol 328:37-44
Hsu, L C; Chang, W C; Shibuya, A et al. (1992) Human stomach aldehyde dehydrogenase cDNA and genomic cloning, primary structure, and expression in Escherichia coli. J Biol Chem 267:3030-7
Yoshida, A; Hsu, L C; Dave, V (1992) Retinal oxidation activity and biological role of human cytosolic aldehyde dehydrogenase. Enzyme 46:239-44

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