Metabonomic investigations into the global biochemical sequelae of exposure to the pancreatic toxin 1-cyano-2-hydroxy-3-butene in the rat

Eszter Bohus, Ákos Rácz, Béla Noszál, Muireann Coen, Olaf Beckonert, Hector C. Keun, Timothy M.D. Ebbels, Glenn H. Cantor, John A. Wijsman, Elaine Holmes, John C. Lindon, Jeremy K. Nicholson

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Abstract

The time-related metabolic effects of 1-cyano-2-hydroxy-3-butene (CHB, crambene), a naturally occurring nitrile and experimental modeltoxin causing exocrine pancreatitis, have been investigated inratsusing high-resolution NMR spectroscopy of urine and serum in combination with pattern recognition analysis. Rats were administered CHB subcutaneously in two doses, 15 mg/kg dose (n = 10) and 150 mg/kg (n = 10), and conventional histopathology and clinical chemistry assessments were performed. Urine samples were collected at -16 and 0, 8, 24, 48, 72, 96, 120, 144 and 168 h postdosing and serum samples were collected at 48 and 168 h postdosing; these were analyzed using a range of 1D and 2D NMR spectroscopic methods. The metabolic profile perturbations seen throughout the time-course of the study are described, and the application of the spectral correlation technique Statistical TOtal Correlation Spectroscop Y (STOCSY) to detect both structural and novel toxicological connectivities between xenobiotic and endogenous metabolite signals is illustrated for the first time. As a result, it is suggested that the STOCSY approach may be of wider application in the identification of toxic versus nontoxic metabolites in drug metabolism studies.

Original languageEnglish
Pages (from-to)S26-S35
JournalMagnetic Resonance in Chemistry
Volume47
Issue numberSUPPL. 1
DOIs
Publication statusPublished - Dec 1 2009

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Keywords

  • 1-cyano-2-hydroxy-3-butene
  • 2′-deoxycytidine
  • Crambene
  • Metabonomics
  • NMR
  • Pancreatic toxicity
  • Pattern recognition
  • STOCSY

ASJC Scopus subject areas

  • Chemistry(all)
  • Materials Science(all)

Cite this

Bohus, E., Rácz, Á., Noszál, B., Coen, M., Beckonert, O., Keun, H. C., Ebbels, T. M. D., Cantor, G. H., Wijsman, J. A., Holmes, E., Lindon, J. C., & Nicholson, J. K. (2009). Metabonomic investigations into the global biochemical sequelae of exposure to the pancreatic toxin 1-cyano-2-hydroxy-3-butene in the rat. Magnetic Resonance in Chemistry, 47(SUPPL. 1), S26-S35. https://doi.org/10.1002/mrc.2485