title: 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.
  
  
  METHODS
  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.affiliation: US Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Marini
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Lanpher
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
authors.forename: William E
authors.initials: WE
authors.lastname: O'Brien
authors.forename: Qin
authors.initials: Q
authors.lastname: Sun
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Garlick
authors.forename: Farook
authors.initials: F
authors.lastname: Jahoor
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology; D000597:Amino Acids, Branched-Chain / Q000097:blood* / Q000494:pharmacology; D002648:Child; D005260:Female; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008875:Middle Aged; D009584:Nitrogen / Q000378:metabolism*; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000188:drug therapy / Q000378:metabolism*; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use; D011506:Proteins / Q000378:metabolism*; D014508:Urea / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000596:Amino Acids; D000597:Amino Acids, Branched-Chain; D010654:Phenylbutyrates; D011506:Proteins; D005973:Glutamine; D014508:Urea; D009584:Nitrogen