Genes Encoding Enzymes Involved in Ethanol Metabolism

By Hurley, Thomas D.; Edenberg, Howard J. | Alcohol Research, October 1, 2012 | Go to article overview

Genes Encoding Enzymes Involved in Ethanol Metabolism


Hurley, Thomas D., Edenberg, Howard J., Alcohol Research


The effects of beverage alcohol (ethanol) on the body are determined largely by the rate at which it and its main breakdown product, acetaldehyde, are metabolized after consumption. The main metabolic pathway for ethanol involves the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Seven different ADHs and three different ALDHs that metabolize ethanol have been identified. The genes encoding these enzymes exist in different variants (i.e., alleles), many of which differ by a single DNA building block (i.e., single nucleotide polymorphisms [SNPs]). Some of these SNPs result in enzymes with altered kinetic properties. For example, certain ADH1B and ADH1C variants that are commonly found in East Asian populations lead to more rapid ethanol breakdown and acetaldehyde accumulation in the body. Because acetaldehyde has harmful effects on the body, people carrying these alleles are less likely to drink and have a lower risk of alcohol dependence. Likewise, an ALDH2 variant with reduced activity results n acetaldehyde buildup and also has a protective effect against alcoholism. In addition to affecting drinking behaviors and risk for alcoholism, ADH and ALDH alleles impact the risk for esophageal cancer. Key words: Alcohol consumption; alcohol dependence; alcoholism; ethanol metabolism; genetic factors; protective factors; risk factors; DNA; genetics; genetic variance; enzymes; acetaldehyde; alcohol dehydrogenase (ADH); aldehyde dehydrogenase (ALDH); single nucleotide polymorphisms (SNPs); esophageal cancer

The duration and extent of the body's exposure to bever- age alcohol (i.e., ethanol) is the primary determinant of ethanols pleiotropic effects on human health (Edenberg 2007). The time course of its concentration and the concen- tration of its byproducts in the tissues and the circulation, and, consequently, its effects, are determined mainly by the rate of ethanols processing (i.e., metabolism) in the body. Ethanol can be metabolized in several reactions, but this review focuses on the primary pathway through which it is eliminated from the systemic circulation. In humans, this primary pathway of ethanol metabolism involves oxidation to acetaldehyde by the enzyme alcohol dehydrogenase (ADH). The acetaldehyde then is further oxidized by the enzyme aldehyde dehydrogenase (ALDH) to acetate, which is either excreted in the urine or reincorporated into inter- mediary metabolism as acetyl-CoA. The hydrogen atoms that are released during these reactions are used to generate a compound called reduced nicotinamide dinucleotide (NADH), with two NADH molecules produced per molecule of acetate generated. The resulting NADH and acetate are thought to provide both the excess reducing equivalents and excess acetyl-CoA that are needed as starting material for fatty acid synthesis, which results in the development of fatty liver dis- ease if high amounts of alcohol are ingested over time.

Both ADH and ALDH exist in different variants with dif- ferent levels of activity, therefore resulting in different rates of ethanol metabolism. This article discusses how these dif- ferences influence a persons sensitivity to ethanols effects and his or her risk of alcohol dependence.

ADH Variants

Humans have seven ADHs that can carry out the first step in alcohol metabolism. The genes encoding these enzymes all are localized on chromosome 4 in a head-to-tail array about 370 kb long. The enzymes produced from these genes all differ slightly in their activities (see table 1):

* The ADH1A, ADH1B, and ADH1C genes1 produce closely related proteins that function as homo- and het- erodimers (Hurley et al. 2002); their kinetic properties, tis- sue localization, and developmental expression all support major roles in oxidative ethanol metabolism in the liver.

* The ADH4 gene is expressed almost exclusively in the liver (Hurley et al. 2002), where it contributes significantly to ethanol oxidation at higher levels of consumption. …

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