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-Keto and -Hydroxy Branched-Chain Acid Interrelationships in Normal Humans^1,2,

McGill Nutrition and Food Science Centre, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada ^* McGill University-Medical Research Council of Canada, Biomedical Mass Spectrometry Unit, Montreal, Quebec H3A 1A3, Canada

Plasma concentrations of the branched-chain amino acids leucine, isoleucine and valine, and those of leucine's and isoleucine's transamination products -ketoisocaproic acid (KICA) and -keto-ß-methylvaleric acid (KMVA), respectively, are known to increase after a protein meal or during extended fasting, but little or no increase in the concentration of valine's transamination product, -ketoisovaleric acid (KIVA), has been observed under these conditions. To determine whether this could be explained by the conversion of KIVA to its -hydroxy analogue, we measured the plasma concentrations of KICA, KMVA and KIVA, as well as their -hydroxy analogues [-hydroxyisocaproic acid (HICA), -hydroxy-ß-methylvaleric acid (HMVA) and -hydroxyisovaleric acid (HIVA)], in normal volunteers immediately after a protein meal or during a 60-h fast. We also determined the oxidoreduction equilibrium constants for HIVA/KIVA and HICA/KICA and their extent of plasma protein binding. In subjects in the postabsorptive state, the plasma concentrations of KICA and KMVA were 100 times those of HICA and HMVA, whereas that of KIVA was only twice that of HIVA. Shortly after a protein meal, KICA and KMVA concentrations increased significantly by 30 and 60%, respectively, whereas that of KIVA decreased by 25% (P < 0.05). HICA, HMVA and HIVA concentrations did not change. During prolonged fasting the plasma concentrations of all six metabolites increased gradually. The high plasma keto/hydroxy acid ratios were not related to their K_eq, which favored -hydroxy analogue formation. The reduction of the branched-chain -keto acids to their -hydroxy analogues seems to take place too slowly to attain thermodynamic equilibrium. The acute decrease in plasma KIVA after a protein meal may be due to a lower rate of valine intracellular transport or transamination in the presence of increased plasma leucine and isoleucine concentrations.

KEY WORDS: • branched-chain amino acids • humans • branched-chain keto acids

¹ Supported by the Medical Research Council of Canada. LJH was recipient of a scholarship from the Fonds de la Recherche en Santé du Québec and AT of a postdoctoral fellowship from the Research Institute of the Montreal General Hospital.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ To whom correspondence and reprint requests should be addressed.

Manuscript received 30 November 1992. Revision accepted 26 April 1993.