Polymorphism of alcohol-metabolizing genes affects drinking behavior and alcoholic liver disease in Japanese men.
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.
Tanaka
F
F
Department of Internal Medicine (II), Faculty of Medicine, University of Tokyo, Japan.
Shiratori
Y
Y
Yokosuka
O
O
Imazeki
F
F
Tsukada
Y
Y
Omata
M
M
D000328:Adult; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000428:Alcohol Drinking / Q000235:genetics* / Q000503:physiopathology; D000437:Alcoholism / Q000235:genetics* / Q000523:psychology; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000483:Alleles; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D000431:Ethanol / Q000493:pharmacokinetics*; D005006:Ethnicity / Q000235:genetics* / Q000523:psychology; D005483:Flushing / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007564:Japan; D008108:Liver Diseases, Alcoholic / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*
D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial