Metabonomic investigations into the global biochemical sequelae of exposure to the pancreatic toxin 1-cyano-2-hydroxy-3-butene in the rat.
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.
Bohus
Eszter
E
Department of Pharmaceutical Chemistry, Semmelweis University, Högyes Endre u. 9. Budapest 1092, Hungary. bohuse@gytk.sote.hu
Rácz
Akos
A
Noszál
Béla
B
Coen
Muireann
M
Beckonert
Olaf
O
Keun
Hector C
HC
Ebbels
Timothy M D
TM
Cantor
Glenn H
GH
Wijsman
John A
JA
Holmes
Elaine
E
Lindon
John C
JC
Nicholson
Jeremy K
JK
D000475:Alkenes / Q000506:poisoning*; D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics; D015394:Molecular Structure; D009570:Nitriles / Q000506:poisoning*; D009929:Organ Size; D046790:Pancreas, Exocrine / Q000473:pathology; D010195:Pancreatitis / Q000097:blood* / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards
D000475:Alkenes; D009570:Nitriles; C055903:1-cyano-2-hydroxy-3-butene