Role of Acetaldehyde in Mediating the Pharmacological and Behavioral Effects of Alcohol Etienne Quertemont, Ph.D., and 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 any chemical compounds, Acetaldehyde is the first product mediator of ethanol’s pharmacological including many medications generated during the metabolism of and behavioral effects. According to the Mand drugs, are eliminated alcohol (chemically known as ethanol). most radical version of this theory, ethanol from the body through their metabolism, It is generated primarily in the liver by would be a mere prodrug whose effects which leads to the production of break­ the enzyme alcohol dehydrogenase are fully mediated by its first metabolite, down products (i.e., metabolites) that (ADH). The acetaldehyde then is con- acetaldehyde. It even has been suggested are readily excreted. In general, these verted rapidly to acetate by the enzyme that instead of “alcoholism,” the term aldehyde dehydrogenase (ALDH). (For “acetaldehydism” would be more metabolites are biologically inactive; more information on the pathways of appropriate to describe alcohol abuse accordingly, metabolism of the original ethanol metabolism, see the article by and addiction (Raskin 1975). Conversely, compound terminates its biological Zakhari in this issue.) other scientists deny any significant activity. Some metabolites, however, Acetaldehyde is an active metabolite role for acetaldehyde in ethanol’s phar­ may exert potent effects on the body that induces a range of toxic, pharma- macological effects. These investigators (i.e., have pharmacological properties) cological, and behavioral effects. However, generally contend that following nor- or have toxic properties; these are referred the role of acetaldehyde in mediating to as active metabolites. Finally, some alcohol’s effects, especially its effects on ETIENNE QUERTEMONT, PH.D., is medications or drugs actually are pharma- the brain (i.e., its central effects), has an associate professor and VINCENT cologically inactive compounds; these been controversial for more than two DIDONE is a research assistant in the so-called prodrugs must be converted decades (Deitrich 2004; Quertemont Centre de Neurosciences Cognitives et to biologically active metabolites in order and Tambour 2004). Some investiga- Comportementales, Université de Liège, to exert their pharmacological effects. tors argue that acetaldehyde is a key Liège, Belgium. 258 Alcohol Research & Health Role of Acetaldehyde in Mediating Alcohol’s Effects mal alcohol consumption, acetaldehyde the ALDH enzyme known as ALDH2*2. including the following (for a review, concentrations in the blood and brain This allele results in the production of see Eriksson 2001): are far too low to induce any significant an inactive ALDH enzyme. If people pharmacological or behavioral effects carrying the deficient ALDH2*2 gene • Acetaldehyde stimulates the release (see discussion in Deitrich 2004). consume alcohol, their bodies cannot of signaling molecules called An intermediate, and probably more metabolize acetaldehyde, which there­ epinephrine and norepinephrine sustainable, position states that the fore accumulates to high concentra­ from certain nerve cells (i.e., sympa­ pharmacological properties of acetalde­ tions. Additional information comes thetic nerve cells) and from a gland hyde modulate (rather than mediate) from observations of alcoholics who located atop the kidneys (i.e., the some, but not all, of ethanol’s effects. This were treated with ALDH inhibitors adrenal gland). These signaling modulatory action of acetaldehyde (e.g., the medication disulfiram) to molecules lead to the cardiovascular probably greatly depends on specific deter further alcohol consumption but symptoms of the alcohol sensitivity conditions. For example, acetaldehyde who nevertheless drank alcohol and may contribute only to those alcohol therefore also accumulated acetaldehyde. reaction. effects that occur at high alcohol con­ The major problem associated with centrations, which also result in high these observations in humans is the • Acetaldehyde also induces the acetaldehyde levels. Moreover, the con­ lack of control over acetaldehyde con­ enhanced release of signaling tribution of acetaldehyde to alcohol’s centrations. Because the bulk of any molecules called histamine and effects likely varies across individuals, ingested ethanol is metabolized to bradykinin, which cause vasodila­ in part due to individual differences acetaldehyde in the liver, genetically or tion and facial flushing. in alcohol-metabolizing enzymes pharmacologically induced deficiencies (Quertemont 2004). in ALDH activity lead to high peripheral • Although intermediate acetaldehyde This article provides an overview concentrations of acetaldehyde, allow­ concentrations induce rapid heart of acetaldehyde’s pharmacological and ing no precise determination of the beat (i.e., tachycardia) and elevated behavioral effects in the body and reviews dose-response pattern of acetaldehyde blood pressure (i.e., hypertension), some of the mechanisms that may effects. Furthermore, the peripheral further increases in acetaldehyde levels underlie these effects. It then explores effects of these high acetaldehyde levels the issue of acetaldehyde concentra­ lead to abnormally low heart rate may mask the compound’s more spe­ tions in the brain and periphery before and blood pressure, probably because cific actions in the nervous system (i.e., summarizing the results of studies in of acetaldehyde’s direct effects on which ethanol metabolism was manip­ neuropharmacological properties). the muscles making up the inner ulated in order to more specifically Therefore, such studies in humans are organs (i.e., smooth muscles). delineate acetaldehyde’s contribution to not well suited for studying the effects ethanol’s effects. of acetaldehyde in the central nervous In people with deficient ALDH system (CNS), particularly the brain. activity, these peripheral effects together generally lead to an adverse reaction Acetaldehyde’s Physiological Effects in the Periphery Pharmacological and to alcohol and prevent further drink­ Behavioral Effects Acetaldehyde accumulation in the ing, thereby reducing these people’s periphery produces a pattern of effects susceptibility to develop alcohol abuse The hypothesis that acetaldehyde commonly defined by the term “alco­ or dependence. mediates or contributes to the effects of hol sensitivity” because these symptoms The causal role of acetaldehyde in ethanol implies that acetaldehyde itself most often are observed when people the alcohol sensitivity reaction has been can exert effects similar to those observed with deficient ALDH activity drink supported further by studies of people after alcohol administration. Therefore, alcohol (Eriksson 2001). These typical who carry the deficient ALDH2*2 the first step to support such a theory is physiological effects include peripheral allele or in whom ALDH activity had widening of the blood vessels (i.e., to demonstrate acetaldehyde’s direct been pharmacologically inhibited. vasodilation), resulting in increased pharmacological and behavioral effects. Investigators treated these people with Because acetaldehyde is highly toxic, skin temperature and facial flushing; the compound 4-methylpyrazole—an however, most studies using direct increased heart and respiration rates; administration of acetaldehyde have pounding or racing of the heart (i.e., inhibitor of the ADH enzyme that pre­ been carried out in laboratory animals, palpitations); lowered blood pressure; vents acetaldehyde production in the particularly rodents. In humans, most narrowing of the airways (i.e., bron­ periphery. This treatment prevented or of the knowledge