The Genetics of Alcohol Metabolism Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Variants Howard J. Edenberg, Ph.D. 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 (ADHs). In a second reaction catalyzed duced. These variants have been he effects of ingested beverage by aldehyde dehydrogenase (ALDH) shown to influence a person’s drink- alcohol (i.e., ethanol) on differ- enzymes, acetaldehyde is oxidized ing levels and, consequently, the risk ent organs, including the brain, T to acetate. Other enzymes, such as of developing alcohol abuse or depen­ depend on the ethanol concentration cytochrome P450 (e.g., CYP2E1), dence (Hurley et al. 2002). Studies achieved and the duration of exposure. metabolize a small fraction of the have shown that people carrying cer- Both of these variables, in turn, are ingested ethanol. tain ADH and ALDH alleles are at affected by the absorption of ethanol There are multiple ADH and significantly reduced risk of becom­ into the blood stream and tissues as ALDH enzymes that are encoded by ing alcohol dependent. In fact, these well as by ethanol metabolism (Hurley different genes (Tables 1 and 3). Some associations are the strongest and most et al. 2002). The main site of ethanol of these genes occur in several vari- widely reproduced associations of any metabolism is the liver, although some ants (i.e., alleles1), and the enzymes gene with the risk of alcoholism. As metabolism also occurs in other tissues encoded by these alleles can differ and can cause local damage there. The in the rate at which they metabolize main pathway of ethanol metabolism HOWARD J. EDENBERG, PH.D., is a ethanol (Table 2) or acetaldehyde or involves its conversion (i.e., oxidation) chancellor’s professor in the Department in the levels at which they are pro- to acetaldehyde, a reaction that is of Biochemistry and Molecular Biology, mediated (i.e., catalyzed) by enzymes 1For a definition of this and other technical terms, see the Indiana University School of Medicine, known as alcohol dehydrogenases glossary, p. 32. Indianapolis, Indiana. Vol. 30, No. 1, 2007 5 will be discussed later in this article, the alleles encoding the different ADH Table 1 Alcohol Dehydrogenase (ADH) Genes and Proteins and ALDH variants are unevenly dis­ tributed among ethnic groups. Official Gene Old Name† Nonstandard Sequence§ Protein Class¶ The mechanism through which Name* Name‡ ADH and ALDH variants influence ADH1A ADH1 ADH1A NM_000667 α I alcoholism risk is thought to involve ADH1B ADH2 ADH1B NM_000668 β I at least local elevation of acetaldehyde ADH1C ADH3 ADH1C NM_000669 γ I levels, resulting either from a more ADH4 ADH4 ADH2 NM_000670 π II rapid ethanol oxidation (in cases of ADH5 ADH5 ADH3 NM_000671 χ III more active ADH variants) or from ADH6 ADH6 ADH5 NM_000672 ADH6 V ADH7 ADH7 ADH4 NM_000673 σ IV slower acetaldehyde oxidation (in cases of less active ALDH variants). *Gene symbol approved by the Human Genome Organization (HUGO) Gene Nomenclature Committee Acetaldehyde is a toxic substance (www.gene.ucl.ac.uk/nomenclature/), as used by the National Center for Biotechnology Information (NCBI). †Original nomenclature. ‡A set of nonstandard gene names proposed by Duester and colleagues (1999). whose accumulation leads to a highly §Reference sequence number as listed in the NCBI RefSeq database (www.ncbi.nlm.nih.gov/RefSeq/). aversive reaction that includes facial ¶ADH proteins have been divided into five classes based on sequence and structural similarities. flushing, nausea, and rapid heart beat SOURCE: Modified from Hurley et al. 2002. (i.e., tachycardia). This reaction is similar to that experienced by alco­ holics who consume alcohol after tak­ ing disulfiram (Antabuse®), a medica­ tion that discourages further drinking. Sources of Data on Genetic Variations Most of the numerous variants of There are several excellent sources of data on single-nucleotide polymor­ the ADH and ALDH genes involve phisms (SNPs) and other genetic variations in different populations, changes of single DNA building including the following: blocks (i.e., nucleotides) and therefore are known as single-nucleotide poly­ • dbSNP (www.ncbi.nlm.nih.gov/SNP) morphisms (SNPs). (For sources of • HapMap (www.hapmap.org) data on SNPs, see the Textbox.) Some SNPs occur in those parts of a gene • ALFRED (alfred.med.yale.edu/Alfred) that actually encode the correspond­ ing protein. These SNPs are called coding variations and in many cases result in the generation of enzymes with altered activity. Other SNPs, Table 2 Kinetic Properties of Alcohol Dehydrogenase (ADH) Proteins however, occur outside the coding Amino Acid regions of a gene (i.e., are noncoding Official Differences Protein Km(ethanol) Turnover variations). Several noncoding varia­ Gene Name* Between Alleles Name mM (min-1) tions have been demonstrated to affect ADH1A α 4.0 30 the expression of the genes (e.g., Chen ADH1B*1 Arg48, Arg370 β 0.05 4 et al. 2005; Edenberg et al. 1999), and 1 ADH1B*2 His48, Arg370 β2 0.9 350 it is likely that others have the same ADH1B*3 Arg48, Cys370 β3 40 300 effect. (For more information on the ADH1C*1 Arg272, Ile350 γ1 1.0 90 typical structure of genes and gene ADH1C*2 Gln272, Val350 γ2 0.6 40 expression in higher organisms, see the ADH1C*352Thr Thr 352† — — — Sidebar.) Comprehensive analyses of ADH4 π 30 20 the ADH genes recently demonstrated ADH5 χ >1,000 100 that both coding and noncoding vari­ ADH6 ADH6 ? ? ADH7 σ 30 1800 ations in those genes are associated with the risk for alcoholism in European- *The *1, *2, etc., designations represent particular alleles of the genes indicated. †ADH1C*352Thr has been American families (Edenberg et al. found in Native Americans as an additional variation on chromosomes with the Val350 characteristic of 2006). Therefore, earlier studies of ADH1C*2 (Osier et al. 2002a); the protein has not been isolated for study. ADH and ALDH genes and the asso­ NOTE: Km(ethanol) indicates the concentration of ethanol at which the enzyme works at 50 percent capacity. Turnover indicates how many molecules of ethanol the enzyme will convert to acetaldehyde in 1 minute at ciated risk of alcoholism should be saturating ethanol concentrations. reexamined in light of the many coding and noncoding variations that have SOURCE: Modified from Hurley et al. 2002. since been identified. 6 Alcohol Research & Health ADH and ALDH Variants in Alcohol Metabolism This article summarizes current oxidizing capacity in the liver (Hurley dinucleotide (NAD+), which is required knowledge regarding coding and et al. 2002; Lee et al. 2006). ADH4 for ethanol oxidation (Hurley et al. noncoding variations in the various encodes π-ADH, which contributes 2002). In both cases, the substitu­ ADH and ALDH genes and the pos­ significantly to ethanol oxidation at tions result in enzymes that have a sible association of these variations higher concentrations (Table 2). 70- to 80-fold higher turnover rate with risk for alcoholism. The article ADH5 encodes χ-ADH, a ubiqui­ than the β1 subunit because the also briefly touches on the differential tously expressed formaldehyde dehy­ coenzyme is released more rapidly ethnic distribution of some of these drogenase with very low affinity for at the end of the reaction. variants. (For more detailed informa­ ethanol. ADH6 mRNA is present in There also are three alleles of the tion, readers are referred to the fol­ fetal and adult liver, but the enzyme ADH1C gene (Table 2). ADH1C*1 lowing articles by Ehlers, Scott and has not been isolated from tissue and encodes the γ1 subunit that has Arg Taylor, Moore and colleagues, and little is known about it. ADH7 at position 272 and isoleucine (Ile) at Eng and colleagues, which focus on encodes σ-ADH, which contributes position 350. ADH1C*2 encodes the specific ethnic groups.) to both ethanol and retinol oxidation. γ2 subunit that shows two differences Researchers have identified SNPs compared with ADH1C*1—it codes in the ADH1B and ADH1C genes for a glutamine (Gln) at position 272 ADH Genes and Their that result in the production of and a valine (Val) at position 350. In Polymorphisms enzymes with different kinetic prop­ almost all cases, these two SNPs occur erties. These SNPs and their effects together (i.e., are in very high linkage Humans have seven different genes, have been widely studied in different disequilibrium [LD]). ADH consisting called ADH1A, ADH1B, ADH1C, populations (see other articles in this of two γ1 subunits (i.e., the γ1γ1 ADH4, ADH5, ADH6, and ADH7, issue).