Alcohol is known to be mainly metabolized in the liver by alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2), and cytochrome P-450IIEI. The purpose of this study was to clarify the role of polymorphism of these ethanol-metabolizing enzymes in drinking behavior and the progression of alcoholic liver disease among Japanese men. Polymorphism of the ADH2, ALDH2, and P-45IIEI genes were determined by polymerase chain reaction, followed by restriction fragment-length polymorphism analysis in 189 normal Japanese men and 26 male patients with alcoholic liver disease. Drinking behavior was estimated by self-assessment according to DSM-III-R criteria. Facial flushing was reported in 91 subjects heterozygous for ALDH2*1/*2 and in two subjects homozygous for ALDH2*2/*2, but was not found in 96 subjects homozygous for ALDH2*1/*1. In contrast, polymorphism of ADH2 and P-450IIEI did not differ between flushers and nonflushers. Although the flushers only drank a small amount of alcohol (< 20 g of ethanol/day), the nonflushers were divided into a group of moderate drinkers (20 to 80 g/day; n = 54) and a group of heavy drinkers (> 80 g/day; n = 42). A high preponderance of heterozygosity for the ADH2*1/*2 genes (20/42; 60%) and a high frequency of the ADH2*1 allele were found in heavy drinkers, compared with moderate drinkers. However, cytochrome P-45IIEI gene polymorphism was similar among the moderate and heavy drinkers. Not only a high frequency of the ALDH2*1 and ADH2*1 alleles, but also a high frequency of the P-450IIEI c2 allele was found in the patients with alcoholic liver disease. From these results, the drinking behavior of Japanese men is strongly influenced by the ALDH2*1 allele, and the level of alcohol intake is affected by the ADH2*1 allele, but not by cytochrome P-45IIEI. However, progression to alcoholic liver disease among heavy drinkers may be affected by the cytochrome P-450IIEI c2 allele.

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 dehy-constants (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 poly-loci, ADH2 and ADH3, which encode the b and g subunits, merase chain reaction assay followed by a direct se-respectively. 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 1). 6 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 con-relatively 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 re-ethanol 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. 7 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 pag1 and g2 subunit, respectively. These subunits differ by base substitution at codon 271 (from arginine to glutamine) and 349 (from isoleucine to valine). 8 Because the Alcohol dehydrogenase (ADH; alcohol:NAD/oxidore-difference 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.1-3...

In an attempt to clarify the genetic factors in alcoholism among the Japanese, polymorphism of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes has been investigated. Genetic polymorphism of ADH2/ALDH2 in 66 cases of normal subjects, 90 cases of alcohol dependent, and 31 patients with alcoholic liver disease among Japanese has been analyzed using a polymerase chain reaction assay followed by a direct sequencing method, because ethanol is mainly catabolized by ADH and ALDH and less by cytochrome P450IIE1 and catalase. The incidence of both ADH2*1/*1 and ALDH2*1/*1 was significantly higher in patients with alcohol dependence and in patients with alcoholic liver disease when compared with that in control subjects. In addition, the incidence of ALDH2*1/*2 and ALDH2*2/*2 was significantly reduced in alcoholics compared with control subjects. Genetic polymorphism of ADH2/ALDH2 in patients with alcoholic liver disease was not different from that of alcohol dependents. According to these results, not only ALDH2 gene, often claimed to be responsible for alcohol dependence among Japanese, but also ADH2 gene polymorphism, which modulates the metabolism of ethanol, play important roles in habitual alcohol intake behavior in Japanese patients and in some patients leads to alcoholic liver diseases.

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