Phenylbutyrate-induced glutamine depletion in humans: effect on leucine metabolism

The present study was designed to determine whether sodium phenylbutyrate (Phi B) acutely induces a decrease in plasma glutamine in healthy humans, and, if so, will decrease estimates of whole body protein synthesis. In a first group of three healthy subjects, graded doses (0, 0.18, and 0.36 g.kg(-1).day(-1)) of Phi B were administered for 24 h before study: postabsorptive plasma glutamine concentration declined in a dose-dependent manner, achieving an approximate to 25% decline for a dose of 0.36 g Phi B.kg(-1).day(-1). A second group of six healthy adults received 5-h infusions of L-[1-C-14]leucine and L-[1-C-13]glutamine in the postabsorptive state on two separate days: 1) under baseline conditions and 2) after 24 h of oral treatment with Phi B (0.36 g.kg(-1).day(-1)) in a randomized order. The 24-h phenylbutyrate treatment was associated with 1) an approximate to 26% decline in plasma glutamine concentration from 514 +/- 24 to 380 +/- 15 mu M (means +/- SE; P < 0.01 with paired t-test) with no change in glutamine appearance rate or de novo synthesis; 2) no change in leucine appearance rate (R-a), an index of protein breakdown (123 +/- 7 vs. 117 +/- 5 mu mol.kg(-1).h(-1); not significant); 3) an approximate to 22% rise in leucine oxidation (Ox) from 23 +/- 2 to 28 +/- 2 mu mol.kg(-1).h(-1) (P < 0.01), resulting in an approximate to 11% decline in nonoxidative leucine disposal (NOLD = R-a - Ox), an index of protein synthesis, from 100 +/- 6 to 89 +/- 5 mu mol.kg(-1).h(-1) (P < 0.05). The data suggest that, in healthy adults, 1) large doses of oral phenylbutyrate can be used as a "glutamine trap" to create a model of glutamine depletion; 2) a moderate decline in plasma glutamine does not enhance rates of endogenous glutamine production; and 3) a shortterm depletion of plasma glutamine decreases estimates of whole body protein synthesis.