Location: Children's Nutrition Research CenterTitle: Phenylbutyrate improves nitrogen disposal via alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylace-deficient patients) Author
Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/15/2011
Publication Date: 4/13/2011
Citation: Marini, J.C., Lanpher, B.C., Scaglia, F., O'Brien, W.E., Sun, Q., Garlick, P.J., Jahoor, F., Lee, B. 2011. Phenylbutyrate improves nitrogen disposal via alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylace-deficient patients patients. American Journal of Clinical Nutrition. 93(6):1248-1254. Interpretive Summary: Phenylbutyrate is a drug that elicits secondary pathways for the disposal of nitrogen and for this reason is used for the metabolic control of urea cycle disorders. The observation that phenylbutyrate reduces plasma concentrations of branched chain amino acids suggested that protein metabolism could be compromised. In the present article we showed that although branched chain amino acids are decreased when phenylbutyrate is administered, it was not accompanied by an increase in protein breakdown or amino acid oxidation. This is important because the reduction in branched chain amino acids was of great concern in the current metabolic management of urea cycle disorders.
Technical Abstract: Phenylbutyrate (PB) is a drug used in urea cycle disorder patients to elicit alternative pathways for nitrogen disposal. However, PB decreases plasma branched chain amino acid (BCAA) concentrations and prior research suggests that PB may increase leucine oxidation, indicating increased protein degradation and net protein loss. To investigate the effects of PB administration on whole body protein metabolism, glutamine, leucine and urea kinetics in healthy and ornithine transcarbamylase deficient (OTCD) subjects, and the possible benefits of BCAA supplementation during PB therapy. Seven healthy control and 7 partial OTCD subjects received either PB or no treatment in a crossover design. Additionally, the partial OTCD and 3 null OTCD subjects received PB and PB plus BCAA supplementation. A multitracer protocol was used to determine the whole-body fluxes of urea and the amino acids of interest. PB reduced ureagenesis by approximately 15% without affecting the fluxes of leucine, tyrosine, phenylalanine or glutamine, and the oxidation of leucine or phenylalanine. The transfer of 15N from glutamine to urea was reduced by 35%. However, a reduction in the plasma concentrations of the BCAA was observed due to PB treatment. BCAA supplementation did not alter the respective baseline fluxes.