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 H-1 NMR spectroscopy. After 3 weeks, parac etamol-dosed rats were found to excrete massive quantities of an unkno wn metabolite in the urine. Using a range of 1 and 2 dimensional H-1 N MR spectroscopic techniques, solid phase extraction and mass spectrome try, the metabolite was identified at 5-oxoproline (5OXP, pyroglutamic acid). Rats fed paracetamol plus methionine, which prevents the deple tion of sulphur-containing amino acids, did not develop 50XP-uria duri ng the study period. Quantitative H-1 NMR spectroscopy of whole urine showed that no 50XP appeared in the urine in the first 2 weeks of feed ing paracetamol to the animals, but, urinary concentrations then rose rapidly up to 1 M in some animals. This unusually high concentration o f 50XP in the urine and its prevention by methionine indicates that ch ronic high level paracetamol dosing leads to severe depletion of sulph ur-containing amino acids including cysteine with consequent disruptio n of the glutathione cycle.