Ghauri F Y, McLean A E, Beales D, Wilson I D, Nicholson J K
Department of Chemistry, Birkbeck College, University of London, U.K.
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.
采用500兆赫的氢核磁共振波谱法，对以含1%扑热息痛的饲料喂养长达10周的大鼠尿液进行了分析。3周后，发现服用扑热息痛的大鼠尿液中大量排泄一种未知代谢物。运用一系列一维和二维氢核磁共振波谱技术、固相萃取和质谱分析，该代谢物被鉴定为5-氧代脯氨酸（5OXP，焦谷氨酸）。在研究期间，给服用扑热息痛的大鼠补充蛋氨酸（可防止含硫氨基酸的消耗），大鼠未出现5OXP尿症。对全尿进行的定量氢核磁共振波谱分析表明，在给动物喂食扑热息痛的前两周，尿液中未出现5OXP，但在一些动物中，随后尿液浓度迅速上升至1摩尔。尿液中5OXP的这种异常高浓度以及蛋氨酸对其的预防作用表明，长期高剂量服用扑热息痛会导致包括半胱氨酸在内的含硫氨基酸严重消耗，从而导致谷胱甘肽循环中断。
