Assessment of mitochondrial function in vivo with a breath test utilizing alpha-ketoisocaproic acid.
A breath test to assess hepatic mitochondrial function in vivo was evaluated in rats. Following the i.p. administration of [1-14C]-alpha-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 alpha-ketoisocaproic acid decarboxylation reflects mainly hepatic mitochondrial function in vivo. Ethanol (3 gm per kg) significantly decreased alpha-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 alpha-ketoisocaproic acid (56.3% of the dose recovered as 14CO2 in 1 hr). Mitochondrial damage induced by 4-pentenoic acid decreased the decarboxylation of alpha-ketoisocaproic acid but did not affect the microsomal metabolism of antipyrine. The present data indicate that the alpha-ketoisocaproic acid breath test provides a noninvasive estimate of hepatic mitochondrial function in vivo which, when applied to man, might yield clinically useful information.
Michaletz
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PA
Division of Gastroenterology, Baylor College of Medicine, Houston, Texas 77030.
Cap
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Alpert
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Lauterburg
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BH
D000818:Animals; D001944:Breath Tests; D002250:Carbon Radioisotopes; D003653:Decarboxylation; D000431:Ethanol / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D006207:Half-Life; D007651:Keto Acids / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012980:Sodium Salicylate / Q000494:pharmacology
D002250:Carbon Radioisotopes; D005229:Fatty Acids, Monounsaturated; D007651:Keto Acids; D000431:Ethanol; C013082:alpha-ketoisocaproic acid; C009785:4-pentenoic acid; D012980:Sodium Salicylate