Molecular genetics of human aldehyde dehydrogenase.

Four non-allelic genes, which encode four different aldehyde dehydrogenase (ALDH) isozymes, have been cloned and characterized at the present time. The coding nucleotide sequences, and organization of introns and exons of these genes have been elucidated. The ALDH1 gene encodes the major cytosolic ALDH1 existing in the liver and other tissues. The genetic deficiency of this isozyme was found at a low frequency (<< 10%) in both Caucasians and Orientals. The deficiency and alcohol sensitivity character are inherited together in one large Caucasian family examined. The ALDH1 gene contains two hormone response elements in its upstream 5' region. The ALDH2 gene encodes the major liver mitochondrial ALDH2 which has a very low Km for acetaldehyde. The atypical ALDH2(2) allele is common (about 30%) in Orientals; and subjects with ALDH2(2) allele, both homozygous and heterozygous status, lack ALDH activity. These individuals are alcohol sensitive and have a markedly reduced risk in developing alcoholism and alcoholic liver diseases. The ALDH3 gene produces a cytosolic ALDH3 isozyme existing in the stomach and liver carcinoma but hardly in normal liver. The ALDH3 locus is polymorphic in Orientals and presumably other populations. The ALDH5 gene, which is expressed in testes and liver, is highly polymorphic in both Caucasians and Orientals. The variation of these two loci may affect the development of alcohol-related problems.