Assessment of Mitochondrial Function in Vivo With A Breath Test Utilizing α—Ketoisocaproic Acid

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Abstract
A breath test to assess hepatic mitochondrial function in vivo was evaluated in rats. Following the i.p. administration of [1–14C]–α–ketoisocaproic acid, 14CO2 exhalation reached a peak within 10 to 20 min and then declined exponentially, with a half–life of 14.3 min. Control animals exhaled 38.6% of the administered radioactivity within 1 hr. In functionally anhepatic animals, 14CO2 in breath amounted to 23% of that in control animals, indicating that α–ketoisocaproic acid decarboxylation reflects mainly hepatic mitochondrial function in vivo. Ethanol (3 gm per kg) significantly decreased α–ketoisocaproic acid decarboxylation (21.8% of the dose appearing in breath in 1 hr), probably due to the ethanol–induced shift in the NAD+:NADH ratio. In contrast, an uncoupler of mitochondrial respiration, sodium salicylate (375 mg per kg), increased the decarboxylation of α—ketoisocaproic acid (56.3% of the dose recovered as 14CO2 in 1 hr). Mitochondrial damage induced by 4–pentenoic acid decreased the decarboxylation of α–ketoisocaproic acid but did not affect the microsomal metabolism of antipyrine. The present data indicate that the α–ketoisocaproic acid breath test provides a noninvasive estimate of hepatic mitochondrial function in vivo which, when applied to man, might yield clinically useful information.