Involvement of acetaldehyde for full protection against alcoholism by homozygosity of the variant allele of mitochondrial aldehyde dehydrogenase genein Asians

There is a functional polymorphism of the mitochondrial aldehyde dehydrogen ase (ALDH2) gene with the variant allele (ALDH2*2) encoding a protein subun it that confers low activity to the tetrameric enzyme. Genetic epidemiologi c studies have strongly suggested that homozygosity for the allele ALDH2*2 is sufficient in completely inhibiting the development of alcoholism in Asi ans. To study the pathophysiology of this unique pharmacogenetic effect, we recruited a total of eighteen adult Han Chinese men, matched by age, body- mass index, nutritional state and homozygosity at the alcohol dehydrogenase gene loci from a population base of 273 men. Six individuals were chosen f or each of the three ALDH2 allelotypes: homozygous ALDH2*2/*2, heterozygous ALDH2*1/*2, and homozygous ALDH2*1/*1. Following a low dose of ethanol (0. 2 g/kg body weight), blood ethanol/acetaldehyde concentrations, cardiac and extracranial/intracranial arterial hemodynamic parameters, as well as self -rated subjective sensations, were measured for 130 min. Homozygous ALDH2*2 individuals were found to be strikingly responsive to the small amount of alcohol, as evidenced by the pronounced cardiovascular hemodynamic effects as web as subjective perception of general discomfort for as long as 2 h fo llowing ingestion. This loci-dose alcohol hypersensitivity, accompanied by a prolonged and large accumulation of acetaldehyde in blood, provides an ex planation for the strong protection against heavy drinking and alcoholism i n individuals homozygous for the ALDH2*2 gene allele, Pharmacogenetics 9:46 3-476 (C) 1999 Lippincott Williams & Wilkins.