Academic journal article Alcohol Research: Current Reviews

Genes Encoding Enzymes Involved in Ethanol Metabolism

Academic journal article Alcohol Research: Current Reviews

Genes Encoding Enzymes Involved in Ethanol Metabolism

Article excerpt

The duration and extent of the body's exposure to beverage alcohol (i.e., ethanol) is the primary determinant of ethanol's pleiotropic effects on human health (Edenberg 2007). The time course of its concentration and the concentration of its byproducts in the tissues and the circulation, and, consequently, its effects, are determined mainly by the rate of ethanol's 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 intermediary 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 disease if high amounts of alcohol are ingested over time.

Both ADH and ALDH exist in different variants with different levels of activity, therefore resulting in different rates of ethanol metabolism. This article discusses how these differences influence a person's sensitivity to ethanol's 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 genes (1) produce closely related proteins that function as homo- and heterodimers (Hurley et al. 2002); their kinetic properties, tissue 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.

* The product of the ubiquitously expressed ADH5 gene is the glutathione-dependent formaldehyde dehydrogenase (also known as nitrosoglutathione reductase [GSNOR]). The physiological substrates for ADH5 ([alpha]-ADH) are compounds (i.e., adducts) formed during the reaction between glutathione and formaldehyde and between glutathione and nitric oxide (Que et al. 2005; Sanghani et al. 2000). The main functions of this enzyme are to oxidize formaldehyde to formic acid and to terminate nitric oxide signaling. The human ADH5 enzyme is nonsaturable with ethanol as a substrate, unless medium-chain fatty acids are present in the assay (Engeland et al. 1993), and was originally thought to contribute little to ethanol oxidation. However, its relatively high maximal velocity, coupled with its ubiquitous expression pattern and the high concentrations of ethanol found in gastric tissues, has led some researchers to suggest that it plays a significant role in first-pass metabolism (Lee et al. 2003).

* Although the ADH6 gene has been identified, there are as yet no physiological data on the functions of the ADH6 enzyme.

* The ADH7 gene has a limited expression pattern and mainly is found in endothelial cells, such as those lining the esophageal and stomach tissues, as well as during embryonic development when it may contribute to the metabolism of retinol, a form of vitamin A (Hurley et al. 2002). In adults, ADH7 has been implicated in the first-pass metabolism of ethanol taking place in the gastroesophageal tissues, before the ethanol is delivered to the liver via the portal vein (Hurley et al. …

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