...acetaldehyde following ethanol intake and the finding that even elevated acetaldehyde levels in the blood do not easily gain access to the brain. The recent discovery of the oxidation of ethanol to acetaldehyde in the adult brain may help explain the acute effects of ethanol. KEY WORDS: Ethanol metabolism; ethanol-to-acetaldehyde metabolism; acetaldehyde; acetate; aldehyde dehydrogenase (ALDH); central nervous system; brain; catalase; cytochrome P450; alcohol dehydrogenase (ADH); ethanol oxidation; behavior; ethanol preference

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This article reviews studies of a potential role for acetaldehyde, a toxic byproduct of alcohol (i.e., ethanol) metabolism, in ethanol's effects in the central nervous system (CNS); the metabolism of ethanol to acetaldehyde in the brain; the metabolism of acetaldehyde in brain cells; the results of ethanol oxidation to form acetaldehyde; and acetaldehyde's effects on behavior. The studies cited primarily are those dealing with acute or very short-term administration of ethanol. The role of acetaldehyde in tolerance and dependence or in the peripheral effects of ethanol is not covered.

ACETALDEHYDE'S ROLE IN ETHANOL'S EFFECTS

Acetaldehyde, a toxic byproduct of ethanol metabolism, may be at least partially responsible for ethanol's actions in the CNS (Hunt 1996; Hashimoto et al. 1989; Bergamaschi et al. 1988; Zimatkin and Deitrich 1997; Thadani and Truitt 1977; Collins et al. 1988; Heap et al. 1995). However, several factors cast doubt on this hypothesis. First, avid metabolism of acetaldehyde by the liver keeps blood levels of acetaldehyde following ethanol ingestion extremely low (Sippel and Eriksson 1975). The levels of acetaldehyde in most people after ethanol ingestion are nearly undetectable in the blood, on the order of one micromole. (1) Second, even if the blood acetaldehyde levels are significant, either because of genetic variation in alcohol-metabolizing enzymes or the presence of drugs that allow build-up of acetaldehyde, acetaldehyde does not seem to be able to penetrate blood vessels into the brain (i.e., the blood-brain barrier), and substantial blood levels are required before acetaldehyde levels increase in the brain (Tabakoff et al. 1976; Westcott et al. 1980; Sippel 1974; Zimatkin and Pronko 1995). This is attributed primarily to the presence of the enzyme that converts acetaldehyde to acetate (i.e., aldehyde dehydrogenase [ALDH]) in the blood-brain barrier, which may help keep brain acetaldehyde levels low (Petersen 1985; Tampier et al. 1993). Third, although one could use the compound pyrazole to inhibit the reaction by which the enzyme alcohol dehydrogenase (ADH) breaks down ethanol (i.e., oxidation), and thus inhibit the formation of acetaldehyde, intoxication still would result, suggesting that acetaldehyde does not play a significant role in ethanol's effects on the brain. Indeed, Goldstein and Zaechelein (1983) used pyrazole to study intoxication in mice using a vapor chamber method. In this method, the metabolism of inhaled ethanol is slowed, providing for more prolonged and consistent blood levels of ethanol, producing physical dependence in mice.

Metabolism of Ethanol to Acetaldehyde in the Brain

These considerations would be irrelevant if the brain could produce its own acetaldehyde from ethanol. Although there had been several reports of the oxidation of ethanol in the brain (Sutherland et al. 1958; Raskin 1973; Raskin and Sokoloff 1974; Raskin and Sokoloff 1968; Raskin and Sokoloff 1970a, b; Raskin and Sokoloff 1972a, b), this idea largely was dismissed by the findings of Mukherji and colleagues (1975), whose studies showed that ethanol did not break down to acetaldehyde in the brain.

Catalase. Catalase, the enzyme that facilitates the breakdown of hydrogen peroxide to oxygen and water, may play a role in the production of acetaldehyde from ethanol in the brain. Cohen and colleagues (1980) demonstrated that catalase in conjunction with hydrogen peroxide will oxidize ethanol in the brain. Although the authors did not directly demonstrate the production of acetaldehyde (and thus the metabolism of ethanol), in this system, they did provide impetus to other investigators' attempts. Researchers initially were thwarted in their attempts to document metabolism of ethanol in the brain when they discovered nonenzymatic (i.e., artifactual) production of acetaldehyde. It was determined that the iron typically found in red blood cells (i.e., hemoglobin) caused this nonenzymatic formation of acetaldehyde from ethanol, thus masking any enzymatic production of acetaldehyde. Two groups, nearly simultaneously, overcame these problems. Aragon and colleagues (1992) demonstrated that acetaldehyde was produced from ethanol in rat brains with all blood removed. Gill and colleagues (1992) were able to prevent the artifactual formation of acetaldehyde and show the production of acetaldehyde from ethanol in rat brain tissue. In both studies, inhibitors of catalase also were effective in inhibiting the production of acetaldehyde. On the other hand, inhibitors of the enzymes cytochrome P450 and ADH--key enzymes involved in alcohol metabolism--were ineffective. Other investigators quickly confirmed these findings (Hamby-Mason et al. 1997; Aspberg et al. 1993; Zimatkin et al. 1999). In studies of cells from all parts of the brain (i.e., whole-brain homogenates), the intensity of ethanol oxidation is comparatively low but may be much higher in the specific structures and cells known for their increased catalase activity (Zimatkin and Lindros 1996).

Cytochrome P450. Cytochrome P450 enzymes, which are involved in ethanol metabolism in the liver, have been implicated in the metabolism of ethanol in the brain. First, Warner and Gustafsson (1994) demonstrated the presence of cytochrome P450 in rat brain and its induction by ethanol. Cytochrome P450 2E1, a variant of cytochrome P450 (i.e., isozyme) that is capable of oxidizing ethanol efficiently in other tissues, also was found in the brain (Hansson et al. 1990). Its protein, messenger RNA (mRNA), specific activity, and induction by ethanol were found in nerve cells (i.e., neurons) and support cells (i.e., glial cells) in the following brain regions: cerebellum, cerebral cortex, thalamus, and hippocampus (Sohda et al. 1993; Tindberg and Ingelman-Sundberg 1996; Upadhya et al. 2000). Cytochrome P450 also has been found in prenatal human brain cells (Khalighi et al. 1999). In addition, a recent study in rats and mice has reinforced the possibility that cytochrome P450...

NOTE: All illustrations and photos have been removed from this article.



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