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 ( and ). Some of these genes occur in several variants (i.e., alleles1
), and the enzymes encoded by these alleles can differ in the rate at which they metabolize ethanol () 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
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.
Alcohol Dehydrogenase (ADH) Genes and Proteins
Aldehyde Dehydrogenase (ALDH) Genes and Proteins
Kinetic Properties of Alcohol Dehydrogenase (ADH) Proteins
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®), a medication that discourages further drinking.
Most of the numerous variants of the ADH
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
genes and the associated risk of alcoholism should be reexamined in light of the many coding and noncoding variations that have since been identified.
Sources of Data on Genetic Variations
There are several excellent sources of data on single-nucleotide polymorphisms (SNPs) and other genetic variations in different populations, including the following:
Gene Structure and Gene Expression in Higher Organisms
In higher organisms, including humans, the genes encoding the various components of the body are not just simple stretches of DNA that serve as a template from which proteins are generated. Instead, they have a complex structure involving, in some cases, dozens of pieces of coding sequences interspersed with noncoding sequences. The coding sequences, which are those parts of the gene that actually serve as templates for protein production, are called exons. The intervening noncoding sequences are known as introns (see ). In addition to the exons and introns, genes contain regulatory sequences that determine in which cell, at what time, and in what amount the gene is actively converted into the corresponding protein (i.e., is expressed). Most of these regulatory sequences are located in front of (i.e., upstream from) the start of the coding sequences; however, other regulatory elements may be located in introns or even behind (i.e., downstream from) the coding sequences. The promoter is a set of regulatory elements located closely near the start of the gene that also specify the exact start site where conversion of the DNA template into intermediary molecules begins. However, other regulatory elements may be located quite a distance away upstream of the gene.
Converting the genetic information contained in a gene on the DNA into a finished protein product is a complex process involving several steps. The first step is known as transcription. During transcription, certain enzymes “read” the DNA (beginning at a specific start signal and continuing to a specific stop signal) and produce a copy of this DNA segment, which consists of similar building blocks as the DNA and is known as messenger RNA, or mRNA. The mRNA that is produced this way still contains copies of both exons and introns. Next, the introns are removed in a process known as splicing. The spliced mRNA then serves as a template that tells other cell components which protein building blocks (i.e., amino acids) they must link together to form a protein, in a process known as translation. The protein that is generated still does not correspond to the final desired protein but has to undergo posttranslational modifications. For example, all translation products begin with the same amino acid that, in most cases, must be removed from the amino acid chain to obtain the final protein product. Furthermore, many proteins require additional modifications (e.g., the addition of sugar molecules or other chemical groups) in order to become fully functional. The entire process of transcription, splicing, translation, and posttranslational modification is collectively referred to as gene expression. Each step in this process is subject to various regulatory processes.
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.)