OXIDATION OF LEUCINE AND ALPHA-KETOISOCAPROATE TO BETA-HYDROXY-BETA-METHYLBUTYRATE INVIVO

The oxidation of alpha-ketoisocaproate (KIC) to beta-hydroxy-beta-methylbutyrate (HMB) by the enzyme KIC dioxygenase has been previously described in rat and human liver; however, the importance of this pathway in normal leucine metabolism has not yet been assessed. A series of experiments was conducted in young lambs and pigs to determine whether HMB is produced from KIC in vivo and to estimate the importance of this pathway in leucine metabolism. In the first study, lambs were fed a bolus of KIC, and the change in plasma HMB concentration was monitored over a 24-h period. Administration of KIC increased plasma HMB from basal concentrations of 2 to approximately 7-mu-M 4 h after the supplementation. In the second experiment, lambs were infused with [6,6,6-H-2(3)]KIC into the duodenum, and the appearance of labeled [H-2(3)]HMB was measured. Under basal conditions, a minimum of 18% of the HMB was derived from KIC, but when unlabeled KIC was infused into the duodenum at a rate of 1.6-mu-mol.kg-1.min-1, plasma HMB concentration doubled, and essentially 100% of the HMB present was derived from KIC. In a third experiment, young pigs were infused with [6,6,6-H-2(3)]leucine. At steady state, [H-2(3)]-leucine and HMB enrichments were nearly identical, indicating that plasma HMB is derived solely from leucine. In a fourth experiment, both lambs and pigs were injected intravenously with 600 mg of HMB daily, and urinary HMB excretion was quantitated. In both lambs and pigs, only 34% of the HMB injected was recovered in the urine, suggesting that at least a portion of HMB is metabolized by the body and that HMB may not be a metabolic end product as suggested previously. The present studies indicate that HMB is a minor but normal metabolite of leucine in animals that can account for 2-10% of leucine oxidation in the postabsorptive state.