Genetic polymorphism of alcohol and aldehyde dehydrogenase and the effects on alcohol metabolism.

Influence of genetic polymorphism at the alcohol dehydrogenase2 (ADH2) and aldehyde dehydrogenase2 (ALDH2) loci on ethanol elimination and blood acetaldehyde level was studied in healthy subjects. Polymorphic regions of the ADH2 and ALDH2 genes were amplified for genomic DNA by using the technique of polymerase chain reaction. The ADH2 genotype was determined by digestion with the restriction enzyme MaeIII and the ALDH2 genotype was defined by hybridization with sequence specific oligonucleotide probes. Both loci were typed for unrelated 58 individuals by using the above methods. The gene frequencies of each locus were estimated as follows; 0.31 and 0.69 for ADH21 and ADH22, respectively, and 0.73 and 0.27 for ALDH21 and ALDH22, respectively. These values were consistent with the Hardy-Weinberg equilibrium. Pedigree analysis of 6 families with 46 subjects on both loci confirmed Mendelian inheritance. In order to investigate differences in ethanol elimination among ADH2 and ALDH2 genotype groups, 0.4 g/kg body weight of ethanol was administered to 93 subjects whose genotypes of both loci were determined by the above methods and blood ethanol and acetaldehyde levels were measured. None of the subjects homozygous for the ALDH21 allele showed facial flushing and any increase in blood acetaldehyde level. All the homozygotes and heterozygotes with the ALDH22 allele exhibited facial flushing, and the former showed a marked increase in blood acetaldehyde level and the latter did a mild increase. On the other hand, the influence of the ADH2 genotype on blood acetaldehyde level was not significant. The values of Widmark's beta 60 (mg/ml/hr) and ethanol elimination rate (mg/kg/hr) showed significant differences among the three groups of the ALDH2 genotypes in each group of the three ADH2 genotypes, and in decreasing order of both the values were ALDH 2*1/1, ALDH21/2, ALDH2/*2, However, there were no significant differences in the values among the ADH2 genotypes.