Academic journal article Alcohol Research

Oxidation of Ethanol in the Brain and Its Consequences

Academic journal article Alcohol Research

Oxidation of Ethanol in the Brain and Its Consequences

Article excerpt

Acetaldehyde, a toxic byproduct of alcohol (i.e., ethanol) metabolism, has long been suspected of causing at least some of the central nervous system actions of ethanol. However, the data to support such a hypothesis have been difficult to obtain. One roadblock is the very low blood levels of 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. …

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