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Metabonomic investigations into the global biochemical sequelae of exposure to the pancreatic toxin 1‐cyano‐2‐hydroxy‐3‐butene in the rat
Author(s) -
Bohus Eszter,
Rácz Ákos,
Noszál Béla,
Coen Muireann,
Beckonert Olaf,
Keun Hector C.,
Ebbels Timothy M. D.,
Cantor Glenn H.,
Wijsman John A.,
Holmes Elaine,
Lindon John C.,
Nicholson Jeremy K.
Publication year - 2009
Publication title -
magnetic resonance in chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.483
H-Index - 72
eISSN - 1097-458X
pISSN - 0749-1581
DOI - 10.1002/mrc.2485
Subject(s) - chemistry , metabolite , urine , toxin , nuclear magnetic resonance spectroscopy , metabolism , pharmacology , chromatography , stereochemistry , biochemistry , medicine
The time‐related metabolic effects of 1‐cyano‐2‐hydroxy‐3‐butene (CHB, crambene), a naturally occurring nitrile and experimental model toxin causing exocrine pancreatitis, have been investigated in rats using 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 SpectroscopY (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. Copyright © 2009 John Wiley & Sons, Ltd.