Functional Relevance of Human ADH Polymorphism

Abstract

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 (6) ADH genotypes and alcohol use in Europeans, by John B. Whitfield.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 oxidized 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 alcohol oxidation is the crucial factor that determines the metabolic consequences during alcohol intoxication. The hepatic NADH reoxidation together with the functional ADH and ALDH activities regulate the steady-state alcohol oxidation 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 inheritance and high penetrance of the phenotype, which involves 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 individual from high consumption and alcoholism. Virtually no case of alcoholism has been reported in those individuals (about 5% to 10% of the entire Asian population) 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 flushing. Within these individuals, the average alcohol consumption 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 chromosome 4 in humans, relevant polymorphism has been found only for ADH2 and ADH3 (Smith, 1986). The kinetic differences 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 (encoded by ADH2*1) homodimers, whereas the V max of ␥ 1

Contribution of the alcohol dehydrogenase‐1B genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men

“…The high and prolonged exposure to ethanol may partly explain the finding that individuals with ADH1B*1/*1 are at high risk of developing alcoholism, 7,8 and that alcoholics with ADH1B*1/*1 are prone to binge drinking and the withdrawal syndrome earlier in life than those with other genotypes. 39 Contrary to expectation, the ALDH2 genotype did not affect the ethanol or acetaldehyde levels of the subjects in the morning after drinking the day before. These findings also contrast with the results of alcohol challenge tests, which clearly showed very high peak acetaldehyde concentrations in the blood 9 and saliva 22 of inactive ALDH2 heterozygotes after light drinking.…”

Disposition and Metabolism of GSK2251052 in Humans: A Novel Boron-Containing Antibiotic

“…Both ADH and ALDH are polymorphic enzymes and critical players in ethanol metabolism; ADH1B catalyzes the oxidation of ethanol to acetaldehyde, and ALDH2 catalyzes the oxidation of acetaldehyde to acetate. Functional polymorphisms in the ADH1B and ALDH2 genes (Agarwal, 2001) have a significant influence on the activities of both enzymes, and are stratified by race, with the ADH1B*2 (increased catalytic activity) and ALDH2*2 (reduced catalytic activity) alleles being common in East Asians and virtually absent in Caucasians (Eriksson et al, 2001). Theoretically, subjects with increased or rapid ADH activity may quickly metabolize GSK2251052, leading to lower parent concentrations, which in turn may impact efficacy.…”

Alcohol dehydrogenase 1B (ADH1B) genotype, alcohol consumption and breast cancer risk by age 50 years in a German case–control study

“…The alcohol dehydrogenase 1B (ADH1B) gene (formerly called ADH2) exhibits genetic polymorphisms resulting in altered functional and catalytic properties in vitro (Agarwal, 2001). A strongly increased oxidation capability has been associated with the *2 allele (Bosron et al, 1983;Eriksson et al, 2001), an Arg47His substitution with reported allele frequencies ranging between 0 and 6.8% in Europeans (Brennan et al, 2004).…”