Temporal metabonomic modeling of L-arginine-lnduced exocrine pancreatitis

Eszter Bohus, Muireann Coen, Hector C. Keun, Timothy M.D. Ebbels, Oiaf Beckonert, John C. Lindon, Elaine Holmes, Béla Noszal, Jeremy K. Nicholson

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The time-related metabolic responses to L-arginine (ARG)-induced exocrine pancreatic toxicity were investigated using single ip doses of 1000 and 4000 mg/kg body weight over a 7 day experimental period in male Sprague-Dawley rats. Sequential timed urine and plasma samples were analyzed using high resolution 1H NMR spectroscopy together with complementary clinical chemistry and histopathology analyses. Principal components analysis (PCA) and orthogonal projection on latent structures discriminant analysis (O-PLS-DA) were utilized to analyze the 1H NMR data and to extract and identify candidate biomarkers and to construct metabolic trajectories post ARG administration. Low doses of ARG resulted in virtually no histopathological damage and distinct reversible metabolic response trajectories. High doses of ARG caused pancreatic acinar degeneration and necrosis and characteristic metabolic trajectory profiles with several distinct phases. The initial trajectory phase (0-8 h) involved changes in the urea cycle and transamination indicating a homeostatic response to detoxify excess ammonia generated from ARG catabolism. By 48 h, there was a notable enhancement of the excretion of the gut microbial metabolites, phenylacetylglycine (PAG), 4-cresol-glucuronide and 4-cresol-sulfate, suggesting that compromised pancreatic function impacts on the activity of the gut microbiota giving potential rise to a novel class of surrogate extragenomic biomarkers of pancreatic injury. The implied compromise of microbiotal function may also contribute to secondary hepatic and pancreatic toxic responses. We show here for the first time the value of metabonomic studies in investigating metabolic disruption due to experimental pancreatitis. The variety of observed systemic responses suggests that this approach may be of general value in the assessment of other animal models or human pancreatitis.

Original languageEnglish
Pages (from-to)4435-4445
Number of pages11
JournalJournal of Proteome Research
Volume7
Issue number10
DOIs
Publication statusPublished - Oct 1 2008

Keywords

  • Cresols
  • Gu microbiota
  • L-arginine
  • Metabonomics
  • NMR
  • Pancreatic toxicity
  • Pancreatitis
  • Pattern recognition
  • Surrogate biomarkers
  • Trajectory analysis

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

Fingerprint Dive into the research topics of 'Temporal metabonomic modeling of L-arginine-lnduced exocrine pancreatitis'. Together they form a unique fingerprint.

  • Cite this

    Bohus, E., Coen, M., Keun, H. C., Ebbels, T. M. D., Beckonert, O., Lindon, J. C., Holmes, E., Noszal, B., & Nicholson, J. K. (2008). Temporal metabonomic modeling of L-arginine-lnduced exocrine pancreatitis. Journal of Proteome Research, 7(10), 4435-4445. https://doi.org/10.1021/pr800407j