ALR

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Introduction

Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing most of the ethanol consumed as part of the diet, and they contribute to the rapid elimination of ethanol from the blood. Both enzymes are expressed at low levels in many tissues but at high levels in the liver. This pathway may evolve as a detoxification mechanism for environmental alcohol. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source, especially in the liver, interfering with the metabolism of other nutrients.

Table 1. Properties of alcohol dehydrogenases in man (Crabb, D.W.; et al. 2004)

Polymorphic variants of these enzyme genes encode enzymes with altered kinetic properties, and the pathophysiological effects of these variants may be mediated by the accumulation of acetaldehyde. High-activity ADH variants are expected to lead to an increase in acetaldehyde generation, whereas low-activity ALDH2 variants are associated with an inability to metabolize acetaldehyde. Acetaldehyde can play a role in the cells that generate it as well as being transported to various tissues through blood or even saliva. Inheritance of the high-activity ADH β2 encoded by the ALDH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is strongly influenced by gene-environment interactions, such as religion and ethnic origin. The association of these variants with alcoholic liver disease, cancer, cardiovascular disease, fetal alcohol syndrome, gout, asthma, and other diseases has also been extensively studied. The strongest association found to date is between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. The most important thing now is to find the associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms behind these associations. 

Table 2. Properties of polymorphic forms of human alcohol dehydrogenase (Crabb, D.W.; et al. 2004)

Correlation between genetic variants and risk of alcoholism and organ-specific injury

The genetic predisposition to alcoholism has been well documented by numerous classical genetic studies. Despite the use of unbiased methods such as genome-wide screening, the strongest genetic associations identified to date are with the ADH and ALDH2 genes. Specifically, individuals with genes encoding highly active ADH (β2 ADH encoded by ADH2*2) or the dominant negative allele for ALDH2 (ALDH2*2) had a reduced risk of alcoholism, whereas individuals with ALDH2*2 have a much higher risk of alcoholism. Most current studies have focused on the imbalance between acetaldehyde production and disposal rates as a possible explanation for the association between ADH and ALDH2 polymorphisms and various pathologies. It is important to note that other mechanisms by which the inheritance of different isozymes alters risk for disease need to be considered, such as the effect of ethanol on redox state and metabolism of compounds (e.g., steroid hormones).

Effects of alcohol dehydrogenase on the risk of alcoholism

Although the effect of ADH genotype on alcohol elimination rate was small, ADH genotype, especially the presence of the ADH2*2 allele, was strongly associated with differences in drinking behavior. In a study of Chinese living in Taiwan, the ADH2*2 allele was found to be more common in the non-alcoholic group than in alcoholics, and similar findings were found in other parts of the world. A recent study showed that ADH2*1 is more common in heavy drinkers than in moderate drinkers. In addition, the ADH3*1 allele is also more prevalent in Asian non-alcoholics than in alcoholics, but the ADH3 locus has no apparent effect on the rate of alcoholism in Caucasians, and the mechanism of this protective effect is currently uncertain.

Effect of alcohol dehydrogenase on the risk of liver disease

The available evidence for genetic risk factors for alcoholic liver disease is not as strong as for alcoholism. In one study, monozygotic twins were shown to be more concordant for cirrhosis than dizygotic twins, suggesting a genetic component for the risk. A reanalysis of the database supported this conclusion, but found that most genetic liability for cirrhosis is the result of a shared risk of alcoholism. Specific candidate genes that confer risk and protection against alcoholic liver disease have not been identified, but findings suggest that ADH polymorphisms may play some role. The effect of ADH variants on the risk of alcoholic liver disease can be complex, with high activity ADH variants reducing the risk of alcoholism, but high levels of acetaldehyde in the liver may lead to liver damage if people with these isoenzymes persist in drinking.