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Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Variants
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
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...