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. The alpha-ketoisocaproic acid (KICA) breath test noninvasively assesses a mitochondrial function, the decarboxylation of KICA, by following the exhalation of labeled carbon dioxide after the administration of labeled KICA. The decarboxylation of I-[13C]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 [13C] 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 13C enrichment of circulating KICA and leucine were similar in the presence and absence of ethanol, the decarboxylation 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Lauterburg
B H
BH
Department of Clinical Pharmacology, University of Bern.
Grattagliano
I
I
Gmür
R
R
Stalder
M
M
Hildebrand
P
P
D000328:Adult; D001241:Aspirin / Q000494:pharmacology*; D001944:Breath Tests; D002247:Carbon Isotopes; D003653:Decarboxylation / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007651:Keto Acids / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D015262:Xenobiotics / Q000494:pharmacology*
D002247:Carbon Isotopes; D007651:Keto Acids; D015262:Xenobiotics; D000431:Ethanol; C013082:alpha-ketoisocaproic acid; D001241:Aspirin