Noninvasive assessment of the effect of xenobiotics on mitochondrial function in human beings: studies with acetylsalicylic acid and ethanol with the use of the carbon 13-labeled ketoisocaproate breath test.

Studies in experimental animals and morphologic data in patients suggest that mitochondria are a prime target of the toxicity of ethanol and acetylsalicylic acid. However, the effects of socially consumed amounts of ethanol and therapeutic doses of acetylsalicylic acid on mitochondrial function in human beings are not known. Me α-ketoisocaproic acid (KICA) breath test noninvaslvely assesses a mitochondrial function, the decarboxylation of KICA, by following the exhalation of labeled carbon di-oxide after the administration of labeled KICA. The decarboxylation of I-[ 13 C]KICA was measured in two groups of eight healthy volunteers after ingestion of 0.5 gm/kg of ethanol or 30 mg/kg of acetylsalicylic acid, respectively. Breath samples were collected at intervals for the determination of [ 13 C]carbon dioxide in breath. The ingestion of ethanol resulted in peak concentrations of ethanol in plasma of 17.3 ±2.4 mmol/L (mean ± 95% confidence interval] and increased the lactate/pyruvate ratio in peripheral venous blood. Although the 13 C enrichment of circulating KICA and leucine were similar in the presence and absence of ethanol, the decarboxylation of KICA was significantly lower (p<0.01) at each time point in the presence of ethanol. The fraction decarboxylated in 2 hours was 6.3%±1.9% of the administered dose after administration of ethanol and 14.2%±3.9% (p<0.001) in the control period. In contrast, the ingestion of acetylsalicylic acid, which resulted in plasma concentrations of 0.9 mmol/L salicylate significantly increased the decarboxylation of KICA to 19.3%±3.1% of the administered dose exhaled in 2 hours. The present data indicate that the equivalent of two glasses of wine and therapeutic doses of acetylsalicylic acid interfere with mitochondrial function in human beings. Because it can detect subtoxic effecs of xenobiotics on mitochondria, the KICA breath test may provide a useful tool to assess effecs of new chemical entities on mitochondrial function in human beings. (J Lab Clin Med 1995;125:378-83)