Induction of 5-oxoprolinuria in the rat following chronic feeding with N-acetyl 4-aminophenol (paracetamol)

Biochem Pharmacol. 1993 Sep 1;46(5):953-7. doi: 10.1016/0006-2952(93)90506-r.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / administration & dosage
  • Acetaminophen / metabolism*
  • Acetaminophen / urine
  • Acetylcysteine / urine
  • Animals
  • Glucuronates / urine
  • Magnetic Resonance Spectroscopy / methods
  • Male
  • Pyrrolidonecarboxylic Acid / urine*
  • Rats
  • Rats, Wistar
  • Sulfates / urine


  • Glucuronates
  • Sulfates
  • Acetaminophen
  • Pyrrolidonecarboxylic Acid
  • Acetylcysteine