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

1998; American Physiological Society; Volume: 274; Issue: 5 Linguagem: Inglês

10.1152/ajpendo.1998.274.5.e801

1522-1555

Dominique Darmaun, Susan Welch, Annie Rini, Brenda Sager, Astride Altomare, Morey W. Haymond,

Cancer, Hypoxia, and Metabolism

The present study was designed to determine whether sodium phenylbutyrate (ΦB) 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 ΦB were administered for 24 h before study: postabsorptive plasma glutamine concentration declined in a dose-dependent manner, achieving an ≈25% decline for a dose of 0.36 g ΦB ⋅ kg −1 ⋅ day −1 . A second group of six healthy adults received 5-h infusions ofl-[1- 14 C]leucine andl-[1- 13 C]glutamine in the postabsorptive state on two separate days: 1) under baseline conditions and 2) after 24 h of oral treatment with ΦB (0.36 g ⋅ kg −1 ⋅ day −1 ) in a randomized order. The 24-h phenylbutyrate treatment was associated with 1) an ≈26% decline in plasma glutamine concentration from 514 ± 24 to 380 ± 15 μM (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 μmol ⋅ kg −1 ⋅ h −1 ; not significant); 3) an ≈22% rise in leucine oxidation (Ox) from 23 ± 2 to 28 ± 2 μmol ⋅ kg −1 ⋅ h −1 ( P < 0.01), resulting in an ≈11% decline in nonoxidative leucine disposal (NOLD = R a − Ox), an index of protein synthesis, from 100 ± 6 to 89 ± 5 μmol ⋅ 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 short-term depletion of plasma glutamine decreases estimates of whole body protein synthesis.