In an attempt to clarify the genetic factors in alcohol-(ADH1, ADH2, and ADH3) have low Michaelis-Menten ism among the Japanese, polymorphism of alcohol dehyconstants (K m s) for ethanol (0.049 to 36 mmol/L), while drogenase (ADH) and aldehyde dehydrogenase (ALDH) ADH4 has a relatively high K m (34 mmol/L) and ADH5 genes has been investigated. Genetic polymorphism of shows very low affinity for ethanol. Thus, class I enzymes ADH2/ALDH2 in 66 cases of normal subjects, 90 cases of play an important role in the metabolism of ethanol. alcohol dependent, and 31 patients with alcoholic liver Among the class I enzymes, polymorphism occurs at two disease among Japanese has been analyzed using a polyloci, ADH2 and ADH3, which encode the b and g subunits, merase chain reaction assay followed by a direct serespectively. The ADH2 locus has three alleles encoding quencing method, because ethanol is mainly catabolized b1 (ADH2*1), b2 (ADH2*2), and b3 (ADH2*3) subunits, 4,5 by ADH and ALDH and less by cytochrome P450IIE1 and and their differences among ADH polymorphism are catalase. The incidence of both ADH2*1/*1 and ALDH2*1/ shown to be a single base substitution at codons 47 and *1 was significantly higher in patients with alcohol de-369 of the ADH2 gene (Table ). The homodimer isozyme pendence and in patients with alcoholic liver disease of b1 has a low K m (0.049 mmol/L) for ethanol and a low when compared with that in control subjects. In addition, the incidence of ALDH2*1/*2 and ALDH2*2/*2 was maximum velocity (V max ) (0.23 U/min), in contrast to a significantly reduced in alcoholics compared with conrelatively low K m (0.94 mmol/L) and high V max (8.6 U/min) trol subjects. Genetic polymorphism of ADH2/ALDH2 in in the homodimer isozyme of b2. On the other hand, the patients with alcoholic liver disease was not different homodimer isozyme of b3 has a high K m (36 mmol/L) for from that of alcohol dependents. According to these reethanol and high V max (7.9 U/min), indicating that sults, not only ALDH2 gene, often claimed to be responsi-ADH2*3 may contribute to the metabolism of ethanol at ble for alcohol dependence among Japanese, but also higher concentration. However, the gene frequency of ADH2 gene polymorphism, which modulates the metab-ADH2*3 is negligible among the Japanese population. In olism of ethanol, play important roles in habitual alcohol addition, ADH3*1 and ADH3*2 are known to encode the intake behavior in Japanese patients and in some pa-g1 and g2 subunit, respectively. These subunits differ by tients leads to alcoholic liver diseases. (HEPATOLOGY two amino acids and the difference between them is one 1996;23:234-239.) base substitution at codon 271 (from arginine to glutamine) and 349 (from isoleucine to valine). Because the Alcohol dehydrogenase (ADH; alcohol:NAD/oxidoredifference of the kinetic properties among ADH3 subunits ductase. EC 1.1.1.1.) and aldehyde dehydrogenase (ALDH; is relatively smaller than for ADH2, the polymorphism of aldehyde:NAD/oxidoreductase. EC 1.2.1.3.) are known to the latter could play an important role in alcohol metaboplay important roles during alcohol metabolism in the lism. liver. [2] ADH is a zinc metallo-enzyme with at least five On the other hand, acetaldehyde, a metabolite of ethclasses of multiple molecular forms. Class I enzymes anol by ADH, is quickly metabolized into acetate by ALDH. Although there are multiple forms of ALDH in the liver, 9,10 the mitochondrial enzyme encoded by the ALDH2 locus on the chromosome 12, has a very low Abbreviations: ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; Vmax, maximum velocity; Km, Michaelis-Menten constant; PCR, polymer-K m for acetaldehyde (3 mmol/L) and is responsible for ase chain reaction.