Pascoe G A, Calleman C J, Baille T A
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Chem Biol Interact. 1988;68(1-2):85-98. doi: 10.1016/0009-2797(88)90008-7.
S-(2,5-Dihydroxyphenyl)-cysteine and S-(2,5-dihydroxyphenyl)-N-acetyl-cysteine [the cysteine- and N-acetyl-cysteine adducts, respectively, of hydroquinone (HQ)] were identified and quantified in the urine of mice administered [ring-U-14C]acetaminophen [14C]APAP, 200 mg kg-1, i.p.). Urine was collected for 24 h and fractionated by HPLC to isolate the above adducts. These conjugates were then converted to a common derivative, viz. O,O',S-tris-acetyl-3-thio-hydroquinone, which was characterized by GC/MS. Neither of the HQ adducts was detected in the urine of control mice which had not received APAP. Quantification of urinary HQ-cysteine and HQ-N-acetyl-cysteine was performed by HPLC techniques, which indicated that these conjugates accounted for approx. 1.5% of the administered dose of APAP after 24 h, a figure which is equivalent to 6.3% of the corresponding APAP-thiol conjugates in the urine. These findings provide strong indirect evidence that p-benzoquinone is formed as a reactive, but apparently non-hepatotoxic, metabolite of APAP in vivo.
在腹腔注射给予[环-U-¹⁴C]对乙酰氨基酚[¹⁴C]APAP（200 mg/kg）的小鼠尿液中，鉴定并定量了S-(2,5-二羟基苯基)-半胱氨酸和S-(2,5-二羟基苯基)-N-乙酰半胱氨酸[分别为对苯二酚（HQ）的半胱氨酸和N-乙酰半胱氨酸加合物]。收集尿液24小时，并通过高效液相色谱法（HPLC）进行分离以分离上述加合物。然后将这些缀合物转化为一种常见的衍生物，即O,O',S-三乙酰基-3-硫代对苯二酚，通过气相色谱/质谱联用仪（GC/MS）对其进行表征。在未接受APAP的对照小鼠尿液中未检测到任何一种HQ加合物。通过HPLC技术对尿液中的HQ-半胱氨酸和HQ-N-乙酰半胱氨酸进行定量，结果表明这些缀合物在24小时后约占给予APAP剂量的1.5%，这一数值相当于尿液中相应APAP-硫醇缀合物的6.3%。这些发现提供了强有力的间接证据，表明对苯醌是APAP在体内形成的一种具有反应活性但显然无肝毒性的代谢产物。
