Role of acetaldehyde in mediating the pharmacological and behavioral effects of alcohol

Alcohol Research & Health, Winter, 2006 by Etienne Quertemont, Vincent Didone

Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological properties). Recent studies have shown that the direct administration of acetaldehyde, especially into the brain, induces several effects that mimic those of alcohol. High doses of acetaldehyde induce sedative as well as movement- and memory-impairing effects, whereas lower doses produce behavioral effects (e.g., stimulation and reinforcement) that are characteristic of addictive drugs. When acetaldehyde accumulates outside the brain (i.e., in the periphery), adverse effects predominate and prevent further alcohol drinking. To investigate the role of acetaldehyde in mediating alcohol's effects, investigators have pharmacologically manipulated alcohol metabolism and the production of acetaldehyde within the body (i.e., endogenous acetaldehyde production). Studies manipulating the activity of the enzyme catalase, which promotes acetaldehyde production in the brain, suggest that acetaldehyde contributes to many behavioral effects of alcohol, especially its stimulant properties. However, it remains controversial whether acetaldehyde concentrations obtained under normal physiological conditions are sufficient to induce significant pharmacological effects. Current evidence suggests that the contribution of acetaldehyde to alcohol's effects is best explained by a process in which acetaldehyde modulates, rather than mediates, some of alcohol's effects. KEY WORDS: Ethanol metabolism; ethanol-to-acetaldehyde metabolism; acetaldehyde; aldehyde dehydrogenases (ALDHs); alcohol dehydrogenase (ADH); alcohol metabolite; catalase; brain; central nervous system; protective factors; alcohol flush reaction; pharmacology and toxicology

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Many chemical compounds, including many medications and drugs, are eliminated from the body through their metabolism, which leads to the production of breakdown products (i.e., metabolites) that are readily excreted. In general, these metabolites are biologically inactive; accordingly, metabolism of the original compound terminates its biological activity. Some metabolites, however, may exert potent effects on the body (i.e., have pharmacological properties) or have toxic properties; these are referred to as active metabolites. Finally, some medications or drugs actually are pharmacologically inactive compounds; these so-called prodrugs must be converted to biologically active metabolites in order to exert their pharmacological effects.

Acetaldehyde is the first product generated during the metabolism of alcohol (chemically known as ethanol). It is generated primarily in the liver by the enzyme alcohol dehydrogenase (ADH). The acetaldehyde then is converted rapidly to acetate by the enzyme aldehyde dehydrogenase (ALDH). (For more information on the pathways of ethanol metabolism, see the article by Zakhari in this issue.)

Acetaldehyde is an active metabolite that induces a range of toxic, pharmacological, and behavioral effects. However, the role of acetaldehyde in mediating alcohol's effects, especially its effects on the brain (i.e., its central effects), has been controversial for more than two decades (Deitrich 2004; Quertemont and Tambour 2004). Some investigators argue that acetaldehyde is a key mediator of ethanol's pharmacological and behavioral effects. According to the most radical version of this theory, ethanol would be a mere prodrug whose effects are fully mediated by its first metabolite, acetaldehyde. It even has been suggested that instead of "alcoholism," the term "acetaldehydism" would be more appropriate to describe alcohol abuse and addiction (Raskin 1975). Conversely, other scientists deny any significant role for acetaldehyde in ethanol's pharmacological effects. These investigators generally contend that following normal alcohol consumption, acetaldehyde concentrations in the blood and brain are far too low to induce any significant pharmacological or behavioral effects (see discussion in Deitrich 2004).

An intermediate, and probably more sustainable, position states that the pharmacological properties of acetaldehyde modulate (rather than mediate) some, but not all, of ethanol's effects. This modulatory action of acetaldehyde probably greatly depends on specific conditions. For example, acetaldehyde may contribute only to those alcohol effects that occur at high alcohol concentrations, which also result in high acetaldehyde levels. Moreover, the contribution of acetaldehyde to alcohol's effects likely varies across individuals, in part due to individual differences in alcohol-metabolizing enzymes (Quertemont 2004).

This article provides an overview of acetaldehyde's pharmacological and behavioral effects in the body and reviews some of the mechanisms that may underlie these effects. It then explores the issue of acetaldehyde concentrations in the brain and periphery before summarizing the results of studies in which ethanol metabolism was manipulated in order to more specifically delineate acetaldehyde's contribution to ethanol's effects.