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Description
The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes occur in several forms that are encoded by different genes; moreover, there are variants (i.e., alleles) of some of these genes that encode enzymes with different characteristics and which have different ethnic distributions. Which ADH or ALDH alleles a person carries influence his or her level of alcohol consumption and risk of alcoholism. Researchers to date primarily have studied coding variants in the ADH1B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes. For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism. A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect. It is becoming clear that noncoding variants in both ADH and ALDH genes also may influence alcohol metabolism and, consequently, alcoholism risk; the specific nature and effects of these variants still need further study. KEY WORDS: Alcohol and other drug (AOD) use (AODU), abuse and dependence; alcoholism; genetics and heredity; genetic theory of AODU; ethnic group; protective factors; ethanol metabolism; liver; alcohol dehydrogenase (ADH); aldehyde dehydrogenase (ALDH); risk factors; protective factors; alcohol flush reaction
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The effects of ingested beverage alcohol (i.e., ethanol) on different organs, including the brain, depend on the ethanol concentration achieved and the duration of exposure. Both of these variables, in turn, are affected by the absorption of ethanol into the blood stream and tissues as well as by ethanol metabolism (Hurley et al. 2002). The main site of ethanol metabolism is the liver, although some metabolism also occurs in other tissues and can cause local damage there. The main pathway of ethanol metabolism involves its conversion (i.e., oxidation) to acetaldehyde, a reaction that is mediated (i.e., catalyzed) by enzymes known as alcohol dehydrogenases (ADHs). In a second reaction catalyzed by aldehyde dehydrogenase (ALDH) enzymes, acetaldehyde is oxidized to acetate. Other enzymes, such as cytochrome P450 (e.g., CYP2E1), metabolize a small fraction of the ingested ethanol.
There are multiple ADH and ALDH enzymes that are encoded by different genes (Tables 1 and 3). Some of these genes occur in several variants (i.e., alleles (1)), and the enzymes encoded by these alleles can differ in the rate at which they metabolize ethanol (Table 2) or acetaldehyde or in the levels at which they are produced. These variants have been shown to influence a person's drinking levels and, consequently, the risk of developing alcohol abuse or dependence (Hurley et al. 2002). Studies have shown that people carrying certain ADH and ALDH alleles are at significantly reduced risk of becoming alcohol dependent. In fact, these associations are the strongest and most widely reproduced associations of any gene with the risk of alcoholism. As will be discussed later in this article, the alleles encoding the different ADH and ALDH variants are unevenly distributed among ethnic groups.
The mechanism through which ADH and ALDH variants influence alcoholism risk is thought to involve at least local elevation of acetaldehyde levels, resulting either from a more rapid ethanol oxidation (in cases of more active ADH variants) or from slower acetaldehyde oxidation (in cases of less active ALDH variants). Acetaldehyde is a toxic substance whose accumulation leads to a highly aversive reaction that includes facial flushing, nausea, and rapid heart beat (i.e., tachycardia). This reaction is similar to that experienced by alcoholics who consume alcohol after taking disulfiram (Antabuse[R]), a medication that discourages further drinking.
Most of the numerous variants of the ADH and ALDH genes involve changes of single DNA building blocks (i.e., nucleotides) and therefore are known as single-nucleotide polymorphisms (SNPs). (For sources of data on SNPs, see the Textbox.) Some SNPs occur in those parts of a gene that actually encode the corresponding protein. These SNPs are called coding variations and in many cases result in the generation of enzymes with altered activity. Other SNPs, however, occur outside the coding regions of a gene (i.e., are noncoding variations). Several noncoding variations have been demonstrated to affect the expression of the genes (e.g., Chen et al. 2005; Edenberg et al. 1999), and it is likely that others have the same effect. (For more information on the typical structure of genes and gene expression in higher organisms, see the Sidebar.) Comprehensive analyses of the ADH genes recently demonstrated that both coding and noncoding variations in those genes are associated with the risk for alcoholism in European-American families (Edenberg et al. 2006). Therefore, earlier studies of ADH and ALDH genes and the associated risk of alcoholism should be reexamined in light of the many coding and noncoding variations that have since been identified.
This article summarizes current knowledge regarding coding and noncoding variations in the various ADH and ALDH genes and the possible association of these variations with risk for alcoholism. The article also briefly touches on the differential ethnic distribution of some of these variants. (For more detailed information, readers are referred to the following articles by Ehlers, Scott and Taylor, Moore and colleagues, and Eng and colleagues, which focus on specific ethnic groups.)
ADH GENES AND THEIR POLYMORPHISMS
Humans have seven different genes, called ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, and ADH7, that encode medium-chain ADHs (see Table 1). (2) These genes all are aligned along a small region of chromosome 4 (Figure 1). The ADH enzymes they encode function as dimers--that is, the active forms are composed of two subunits. Based on similarities in their amino acid sequences and kinetic properties (e.g., the rate at which ethanol is oxidized), the seven ADH types have been divided into five classes (see Table 1). The three class I genes, ADH1A, ADH1B, and ADH1C, are very closely related; they encode the [alpha], [beta], and [gamma] subunits, which can form homodimers or heterodimers (3) that account for most of the ethanol-oxidizing capacity in the liver (Hurley et al. 2002; Lee et al. 2006). ADH4 encodes... |
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