Genetics of Alcohol and Aldehyde Dehydrogenases

Abstract

Abstract: This paper reviews the genetic status of the two key enzymes of alcohol metabolism in humans, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Human ADH is encoded by at least five genes, giving rise to three classes of enzyme. The Class I genes are located on chromosome 4 and encode three homologous polypeptides α, β and γ‐ADH, generating six isozymes in homozygous individuals. The ADH2 (β subunit) gene coding sequence is interrupted by eight introns and spans approximately 15 kilobases. Polymorphisms at the ADH2 and ADH3 (γ subunit) loci generate allelic isozymes in human populations of which two have widely divergent kinetic properties. Class II (π‐ADH) and Class III (khgr;‐ADH) ADH genes encode subunits that are more divergent in sequence, reflecting earlier evolutionary origins, as compared with the three human Class I genes. The Class III gene (ADH5) is localized on human chromosome 4, near the Class I genes. Human ALDHs are encoded by at least three genes giving rise to two major liver isozymes, ALDH1 and ALDH2, differentially localized in cytosol and mitochondria respectively, and ALDH3, exhibiting high activity in human stomach. cDNA nucleotide and subunit amino acid sequences for the ALDH1 and ALDH2 isozymes reflect 68% structural identity. A high frequency polymorphism exists for ALDH2 in Mongoloid populations, which has been associated with alcohol sensitivity. Human ALDH genes have been mapped to three separate chromosomes: ALDH1 (chromosome 9); ALDH2 (chromosome 12); and ALDH3 (chromosome 17).