title: L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway.
abstract: Glycine is an important ammoniagenic amino acid, which is increased in acute liver failure (ALF). We have previously shown that L-ornithine phenylacetate (OP) attenuates ammonia rise and intracranial pressure in pigs suffering from ALF but failed to demonstrate a stoichiometric relationship between change in plasma ammonia levels and excretion of phenylacetylglutamine in urine. The aim was to investigate the impact of OP treatment on the phenylacetylglycine pathway as an alternative and additional ammonia-lowering pathway. A well-validated and -characterized large porcine model of ALF (portacaval anastomosis, followed by hepatic artery ligation), which recapitulates the cardinal features of human ALF, was used. Twenty-four female pigs were randomized into three groups: (1) sham operated + vehicle, (2) ALF + vehicle, and (3) ALF + OP. There was a significant increase in arterial glycine concentration in ALF (P < 0.001 compared with sham), with a three-fold increase in glycine release into the systemic circulation from the kidney compared with the sham group. This increase was attenuated in both the blood and brain of the OP-treated animals (P < 0.001 and P < 0.05, respectively), and the attenuation was associated with renal removal of glycine through excretion of the conjugation product phenylacetylglycine in urine (ALF + vehicle: 1,060 ± 106 μmol/l; ALF + OP: 27,625 ± 2,670 μmol/l; P < 0.003). Data from this study provide solid evidence for the existence of a novel, additional pathway for ammonia removal in ALF, involving glycine production and removal, which is targeted by OP.
authors.affiliation: Department of Anesthesiology, University Hospital of North Norway and UiT The Arctic University of Norway, Tromsø, Norway; rune_ga_kri@outlook.com.
authors.forename: Rune Gangsøy
authors.initials: RG
authors.lastname: Kristiansen
authors.affiliation: Hepato-Neuro Laboratory, The University of Montreal Hospital Research Centre, Université de Montréal, Québec, Canada;
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Rose
authors.affiliation: Department of Clinical Pharmacology, University Hospital of North Norway and UiT The Arctic University of Norway, Tromsø, Norway;
authors.forename: Ole-Martin
authors.initials: OM
authors.lastname: Fuskevåg
authors.affiliation: Norwegian College of Fishery Science, UiT The Arctic University of Norway, Tromsø, Norway;
authors.forename: Hanne
authors.initials: H
authors.lastname: Mæhre
authors.affiliation: Department of Digestive Surgery, University Hospital of North Norway and UiT The Arctic University of Norway, Tromsø, Norway; and.
authors.forename: Arthur
authors.initials: A
authors.lastname: Revhaug
authors.affiliation: Liver Failure Group, University College London Institute for Liver and Digestive Health, Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
authors.affiliation: Department of Anesthesiology, University Hospital of North Norway and UiT The Arctic University of Norway, Tromsø, Norway;
authors.forename: Lars Marius
authors.initials: LM
authors.lastname: Ytrebø
mesh_terms: D000641:Ammonia / Q000097:blood / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D022124:Hyperammonemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D017114:Liver Failure, Acute / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011897:Random Allocation; D013552:Swine; D013997:Time Factors
chemical_list: D015415:Biomarkers; C022050:phenylacetylglycine; D000641:Ammonia; C572232:ornithine phenylacetate; D009952:Ornithine; D005998:Glycine
keywords: L-ornithine-phenylacetate, phenylacetylglycine; ammonia; glycine