Accumulation of Acetaldehyde in Alcohol‐Sensitive Japanese: Relation to Ethanol and Acetaldehyde Oxidizing Capacity

Abstract

The metabolism of ethanol and its oxidation product, acetaldehyde, was studied in Japanese volunteers. Subjects who responded by facial flushing and tachycardia were found to accumulate acetaldehyde during ethanol intoxication, in contrast to the near absence of blood acetaldehyde in nonflushing subjects. There were large individual variations in acetaldehyde accumulation observed in the former group, and this accumulation correlated well with the intensity of the physiological responses, but not with rate of ethanol elimination. Oral pretreatment with the alcohol dehydrogenase inhibitor, 4-methylpyrazole, reduced ethanol elimination by 15-25% and strongly suppressed acetaldehyde accumulation. However, here too there was no relation between individual ethanol elimination rate and acetaldehyde accumulation. Furthermore, the change in the blood lactate/pyruvate concentration ratio after ethanol intake was apparently unrelated to the degree of acetaldehyde accumulation. These results, combined with our previous observation of a strong negative correlation between increase in heart rate and activity of cytosolic aldehyde dehydrogenase in erythrocytes, suggest that in flushing Orientals lacking the low-Km aldehyde dehydrogenase isozyme, the alternative cytosolic enzyme is responsible for acetaldehyde oxidation, and its activity probably determines the individual variation of acetaldehyde-mediated physiological responses.

Suppression of Acetaldehyde Accumulation by 4-Methylpyrazole in Alcohol-Hypersensitive Japanese

“…2). When the same flushing subjects were tested with the same ethanol dose 1 hr after oral administration of 10 mg/kg 4-MP, both AcH accumulation and associated physio logical responses were effectively suppressed through a 20.4+4.2% reduction of ethanol elimination rate (18). Though peak AcH levels observed after 30 min again showed large individual variation in a range between 15-55 i M (Table 1), the physiological sensitivity to AcH was apparently lowered.…”

“…Partial inhibition of ethanol elimination by infusing a small dose of 4 methylpyrazole (4-MP), a specific inhibitor of alcohol dehydrogenase (13) with low toxicity (14,15), to cyanamide (another ALDH inhibitor)-treated subjects lead to a rapid fall in the level of AcH and associated responses (16,17). During the course of our previous experiment investigating AcH ac cumulation in relation to ethanol and AcH oxidizing capacity, 4-MP was found to be highly effective in reducing AcH levels also in flushing Orientals (18).…”

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

“…Preliminary studies failed to show a difference in alcohol elimination rates between flushers and non-flushers (Mizoi et al 1979;Inoue et al 1984), but a subsequent study detected reduced rates of elimination in individuals with ALDH2 deficiency when controlled for ADH genotype (Mizoi et al 1994). This finding would be consistent with product inhibition of ADH by elevated intrahepatic acetaldehyde levels.…”

Influence du site de prélèvement sur l’étude cinétique et métabolique de l’éthanol

“…Une action inhibitrice de l'éthanol sur l'alcool-déshydrogénase soit directe, soit par l'intermédiaire de son premier métabolite, l'acétaldéhyde, a été rapportée [37,[39][40][41]. Cependant la vitesse d'élimina-tion de l'éthanol ne semble pas corrélée aux concentrations d'acétaldéhyde [42] et la consommation des cofacteurs enzymatiques ne semblent pas, non plus, limiter le métabolisme de l'éthanol [37]. Plus récemment, l'hypothèse que l'alcool déshydrogénase puis l'aldéhyde déshydrogénase puissent limiter le métabolisme de l'éthanol a été avancée [38].…”