The Class I alcohol dehydrogenases (ADH) and the cytosolic and mitochondrial aldehyde dehydrogenases (ALDHl and ALDH2) play major roles in ethanol and acetaldehyde oxidation. The genetic variations of these enzymes would affect the clearance of the toxic chemicals and alcohol intoxication, and indirectly affect the development of alcohol-related diseases. The racial differences in the incidence of alcohol sensitivity and alcoholism may be, in Part, attributed to the genetic background. The overall objectives of the Project are: to elucidate the genomic structures and gene expressions of ADH and ALDH; to examine their genetic variations and identify their mutation sites, and to elucidate the correlations of these genetic variations to alcoholic-related problems. The following projects will be undertaken: 1) Determination of the genomic structure of ADH cluster locus, which includes three genes, i.e. ADH, (for alpha-subunit), ADH1 (for beta-subunit), and ADH1 (for gamma-subunit), their 3'- and 5'- regions, and possibly pseudogene(s); 2) Study of developmental regulation of expression of the cytosolic ALDH1 and the mitochondrial ALDH2 loci, by analyzing translation products and quantity and quality of primary transcripts and mRNAs in fetal and adult livers; 3) Determination of the genotypes of ADH2 and ALDH2 loci in subjects with alcoholic diseases and control subjects in Caucasians, Orientals (Japanese and Koreans) and American Indians, and examination of restriction fragment length polymorphism of the loci in these populations; and 4) Exploration and characterization of the cytosolic ALDHl variants related to alcohol sensitivity and other alcoholic problems.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA005763-08
Application #
3109067
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1983-04-01
Project End
1994-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
8
Fiscal Year
1990
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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