To investigate the effect of aging on ethanol metabolism, 24 male and female F344 rats aged 2 and 12 mo that were fed a laboratory diet received ethanol (1.2 and 2.5 g/kg body wt) intraperitoneally. In male rats, in vivo ethanol elimination significantly decreased according to age both at high (436 +/- 38 vs. 294 +/- 27 mg/kg.h; p less than 0.01) and low (365 +/- 19 vs. 261 +/- 8 mg/kg.h; p less than 0.01) blood ethanol concentrations. Age did not influence the specific activity of hepatic or gastric alcohol dehydrogenase, whereas the activity was significantly decreased with age in the liver (p less than 0.05) and in the stomach (p less than 0.001) when related to body weight. In addition, the activity of the hepatic microsomal ethanol oxidizing system decreased significantly according to age (8.7 +/- 0.5 vs. 6.00 +/- 0.3 nmol/min.mg micr. protein; p less than 0.001). To study the response of ethanol-metabolizing enzymes to chronic ethanol ingestion, 2- and 19-mo-old male F344 rats were pair-fed nutritionally adequate liquid diets containing 36% of total calories either as ethanol or isocaloric carbohydrate for 3 wk. In this experiment specific alcohol dehydrogenase activity was not significantly affected by age, whereas the hepatic microsomal function estimated by the determination of cytochrome P450, microsomal ethanol oxidizing system, and aniline hydroxylation as well as hepatic mitochondrial low Km-acetaldehyde dehydrogenase activity was found to be markedly depressed with age (p less than 0.01). Chronic ethanol consumption increased microsomal enzyme activities in older rats to levels comparable to those observed in young animals prior to ethanol administration. Chronic ethanol feeding also resulted in an increased hepatic fat accumulation, which was significantly enhanced in older rats. In contrast to male rats, in vivo ethanol metabolism was practically identical for 2- and 12-mo-old female rats. These data demonstrate an enhanced toxicity of alcohol in older compared to younger male but not female rats associated with a delay in alcohol elimination both at high and low ethanol blood concentrations and a decrease in ethanol- and acetaldehyde-metabolizing enzyme activities.