Induction of 5-oxoprolinuria in the rat following chronic feeding with N-acetyl 4-aminophenol (paracetamol).
The urine of rats fed on 1% paracetamol in the diet for up to 10 weeks was analysed using 500 MHz 1H NMR spectroscopy. After 3 weeks, paracetamol-dosed rats were found to excrete massive quantities of an unknown metabolite in the urine. Using a range of 1 and 2 dimensional 1H NMR spectroscopic techniques, solid phase extraction and mass spectrometry, the metabolite was identified at 5-oxoproline (5OXP, pyroglutamic acid). Rats fed paracetamol plus methionine, which prevents the depletion of sulphur-containing amino acids, did not develop 5OXP-uria during the study period. Quantitative 1H NMR spectroscopy of whole urine showed that no 5OXP appeared in the urine in the first 2 weeks of feeding paracetamol to the animals, but urinary concentrations then rose rapidly up to 1 M in some animals. This unusually high concentration of 5OXP in the urine and its prevention by methionine indicates that chronic high level paracetamol dosing leads to severe depletion of sulphur-containing amino acids including cysteine with consequent disruption of the glutathione cycle.
Department of Chemistry, Birkbeck College, University of London, U.K.
F Y
FY
Ghauri
A E
AE
McLean
D
D
Beales
I D
ID
Wilson
J K
JK
Nicholson
D000082:Acetaminophen / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine; D000111:Acetylcysteine / Q000652:urine; D000818:Animals; D005965:Glucuronates / Q000652:urine; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D011761:Pyrrolidonecarboxylic Acid / Q000652:urine*; D051381:Rats; D017208:Rats, Wistar; D013431:Sulfates / Q000652:urine
D005965:Glucuronates; D013431:Sulfates; D000082:Acetaminophen; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine