Phenylbutyrate improves nitrogen disposal via an alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylase-deficient patients.

Abstract

BACKGROUND:

Phenylbutyrate is a drug used in patients with urea cycle disorder to elicit alternative pathways for nitrogen disposal. However, phenylbutyrate administration decreases plasma branched-chain amino acid (BCAA) concentrations, and previous research suggests that phenylbutyrate administration may increase leucine oxidation, which would indicate increased protein degradation and net protein loss.

OBJECTIVE:

We investigated the effects of phenylbutyrate 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 phenylbutyrate therapy.

DESIGN:

Seven healthy control and 7 partial-OTCD subjects received either phenylbutyrate or no treatment in a crossover design. In addition, the partial-OTCD and 3 null-OTCD subjects received phenylbutyrate and phenylbutyrate plus BCAA supplementation. A multitracer protocol was used to determine the whole-body fluxes of urea and amino acids of interest.

RESULTS:

Phenylbutyrate administration reduced ureagenesis by ≈15% without affecting the fluxes of leucine, tyrosine, phenylalanine, or glutamine and the oxidation of leucine or phenylalanine. The transfer of (15)N from glutamine to urea was reduced by 35%. However, a reduction in plasma concentrations of BCAAs due to phenylbutyrate treatment was observed. BCAA supplementation did not alter the respective baseline fluxes.

CONCLUSIONS:

Prolonged phenylbutyrate administration reduced ureagenesis and the transfer of (15)N from glutamine to urea without parallel reductions in glutamine flux and concentration. There were no changes in total-body protein breakdown and amino acid catabolism, which suggests that phenylbutyrate can be used to dispose of nitrogen effectively without adverse effects on body protein economy.

• Authors: Juan C Marini, Brendan C Lanpher, Fernando Scaglia, William E O'Brien, Qin Sun, Peter J Garlick, Farook Jahoor, Brendan Lee
• Journal: The American journal of clinical nutrition (Am J Clin Nutr) Vol. 93 Issue 6 Pg. 1248-54 (Jun 2011) ISSN: 1938-3207 [Electronic] United States
• PMID: 21490144 (Publication Type: Controlled Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amino Acids
• Amino Acids, Branched-Chain
• Phenylbutyrates
• Proteins
• Glutamine
• Urea
• Nitrogen

Topics

• Adolescent
• Adult
• Aged
• Amino Acids (metabolism, pharmacology)
• Amino Acids, Branched-Chain (blood, pharmacology)
• Child
• Female
• Glutamine (metabolism)
• Humans
• Male
• Metabolic Networks and Pathways (drug effects)
• Middle Aged
• Nitrogen (metabolism)
• Ornithine Carbamoyltransferase Deficiency Disease (drug therapy, metabolism)
• Phenylbutyrates (pharmacology, therapeutic use)
• Proteins (metabolism)
• Urea (metabolism)
• Young Adult