Functional Relevance of Human ADH Polymorphism C. J. Peter Eriksson, Tatsushige Fukunaga, Taisto Sarkola, Wei J. Chen, C. C. Chen, J. M. Ju, Andrew T. A. Cheng, Hidetaka Yamamoto, Kathrin Kohlenberg-Müller, Mitsuru Kimura, Masanobu Murayama, Sachio Matsushita, Haruo Kashima, Susumu Higuchi, Lucinda Carr, D. Viljoen, L. Brooke, T. Stewart, T. Foroud, J. Su, Ting-Kai Li, and John B. Whitfield This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were C. J. Peter Eriksson and Tatsushige Fukunaga. The presentations were (1) 4-Methylpyrazole as a tool in the investigation of the role of ADH in the actions of alcohol in humans, by Taisto Sarkola and C. J. Peter Eriksson; (2) ADH2 polymorphism and flushing in Asian populations, by Wei J. Chen, C. C. Chen, J. M. Ju, and Andrew T. A. Cheng; (3) Role of ADH3 genotypes in the acute effects of alcohol in a Finnish population, by Hidetaka Yamamoto, Kathrin Kohlenberg-Müller, and C. J. Peter Eriksson; (4) Clinical characteristics and disease course of alcoholics with different ADH2 genotypes, by Mitsuru Kimura, Masanobu Murayama, Sachio Matsushita, Haruo Kashima, and Susumu Higuchi; (5) ADH2 polymorphism, alcohol drinking, and birth defects, by Lucinda Carr, D. Viljoen, L. Brooke, T. Stewart, T. Foroud, J. Su, and Ting-Kai Li; and (6) ADH genotypes and alcohol use in Europeans, by John B. Whitfield. Key Words: ADH2, ADH3, Polymorphism, Alcohol Drinking, Flushing, Birth Defects. T HE BULK OF human alcohol metabolism takes place in the liver, where alcohol is first oxidized by alcohol dehydrogenase (ADH) to acetaldehyde, which is then oxi- dized by aldehyde dehydrogenase (ALDH) to acetate. All alcohol effects primarily can be derived from alcohol per se and/or its metabolism, including redox changes and the production of acetaldehyde and acetate. The rate of alco- hol oxidation is the crucial factor that determines the met- abolic consequences during alcohol intoxication. The he- patic NADH reoxidation together with the functional ADH and ALDH activities regulate the steady-state alcohol oxi- dation rate. Thus, any genetic polymorphism that affects functional ADH and ALDH activities may be relevant for the biological actions of alcohol. The first gene shown to affect the biological actions of alcohol was ALDH2. Deficiency of the ALDH2 enzyme, common in Asian populations, follows the pattern of a classical inborn error of metabolism, with dominant inher- itance and high penetrance of the phenotype, which in- volves facial flushing due to blood vessel vasodilation, tachycardia, nausea, and headache in response to alcohol intake. These reactions, caused by inhibited acetaldehyde metabolism and subsequently elevated acetaldehyde levels, make alcohol drinking less pleasant and protect the indi- vidual from high consumption and alcoholism. Virtually no case of alcoholism has been reported in those indi- viduals (about 5% to 10% of the entire Asian popula- tion) who are homozygous for the genotype (ALDH2*2/ *2). The heterozygous individuals with one *2-allele (30% to 40% of the entire Asian population) can drink but develop a number of side effects that include flush- ing. Within these individuals, the average alcohol con- sumption is less than in the *1/*1 population, but still alcoholism may develop. The relevance of the ADH system for the actions of alcohol is less well known than is the case with ALDH. Although seven ADH genes have been mapped to chromo- some 4 in humans, relevant polymorphism has been found only for ADH2 and ADH3 (Smith, 1986). The kinetic dif- ferences among ADH2 isozymes are much more striking than those among the ADH3 isozymes. For example, the maximum rate of reaction (V max ) of  2 (encoded by ADH2*2) homodimers is around 40 times that of  1 (en- coded by ADH2*1) homodimers, whereas the V max of  1 From the Department of Mental Health and Alcohol Research (CJPE, T. Sarkola), National Public Health Institute, Helsinki Finland; the Department of Forensic Medicine and Sciences (T. Fukunaga, HY), Mie University School of Medicine, Tsu, Mie, Japan; the Institute of Epidemiology (WJC), College of Public Health, National Taiwan University, Taipei, Taiwan; the Department of Adult Psychiatry (CCC, JMJ), Taipei City Psychiatric Center, Taipei, Taiwan; the Division of Epidemiology and Public Health (ATAC), Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; the University of Applied Science Fulda (KK-M), Fulda, Germany; the Division of Clinical Research (MK, SM, SH), National Institute on Alcoholism, Kurihama National Hospital, Yokosuka, Kanagawa, Japan; Akagi Kougen Hospital (MM), Gunma, Japan; the Department of Neuropsychiatry (HK), Keio University School of Medicine, Tokyo, Japan; the Department of Med- icine (LC, T. Stewart, T. Foroud, JS, T-KL), Indiana University School of Medicine, Indianapolis, Indiana; the Foundation for Alcohol Related Re- search (DV, LB), Cape Town, South Africa; and the Department of Clinical Biochemistry (JBW), Royal Prince Alfred Hospital, Camperdown, Australia. Received for publication January 11, 2001; accepted January 11, 2001 Reprint requests: C. J. Peter Eriksson, PhD, Department of Mental Health and Alcohol Research, National Public Health Institute, POB 719, 00101 Helsinki, Finland; Fax: 358-9-1332781; E-mail: peter.eriksson@ktl.fi Copyright © 2001 by the Research Society on Alcoholism. 0145-6008/01/2505-0157$03.00/0 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 25, No. 5 May Supplement 2001 Alcohol Clin Exp Res, Vol 25, No 5, 2001: pp 157S–163S 157S