Slatter J G, Rashed M S, Pearson P G, Han D H, Baillie T A
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Chem Res Toxicol. 1991 Mar-Apr;4(2):157-61. doi: 10.1021/tx00020a006.
S-(N-Methylcarbamoyl)-N-acetylcysteine (AMCC), a chemically labile mercapturic acid conjugate, was identified by liquid chromatography-mass spectrometry (LC-MS) in the urine of rats dosed intraperitoneally with methyl isocyanate (MIC; 45.2 mumol). The corresponding cysteine conjugate, however, was not detected in urine. Following methylation, urine extracts were analyzed by thermospray LC-MS and the AMCC methyl ester was quantified by means of a stable isotope dilution assay procedure which utilized S-(N-methylcarbamoyl)-N-[2H3]-acetylcysteine [( 2H3]AMCC) as internal standard. The results showed that the fraction of the injected dose of MIC which appeared in 24-h urine collections as AMCC was 24.8 +/- 1.9% (mean +/- SD, N = 4). Thus, conjugation of MIC with glutathione (GSH), followed by metabolism of the resulting adduct to AMCC, appears to represent a quantitatively important pathway of biotransformation of MIC in the rat. However, in view of the known carbamoylating properties and in vitro cytotoxicity of S-linked conjugates of MIC, it seems unlikely that the GSH pathway of metabolism fulfills a conventional detoxification role in the case of MIC. In contrast, it is proposed that carbamate thioester conjugates of MIC, which can revert spontaneously to free MIC under physiological conditions, may actually contribute to the multisystem adverse effects of this highly toxic isocyanate in vivo.
S-(N-甲基氨基甲酰基)-N-乙酰半胱氨酸（AMCC）是一种化学性质不稳定的硫醚氨酸结合物，通过液相色谱-质谱联用（LC-MS）在腹腔注射甲基异氰酸酯（MIC；45.2 μmol）的大鼠尿液中被鉴定出来。然而，相应的半胱氨酸结合物在尿液中未被检测到。甲基化后，通过热喷雾LC-MS分析尿液提取物，并利用S-(N-甲基氨基甲酰基)-N-[2H3]-乙酰半胱氨酸[2H3]AMCC作为内标，通过稳定同位素稀释分析程序对AMCC甲酯进行定量。结果表明，在24小时尿液收集物中以AMCC形式出现的MIC注射剂量的比例为24.8±1.9%（平均值±标准差，N = 4）。因此，MIC与谷胱甘肽（GSH）结合，随后将所得加合物代谢为AMCC，似乎是大鼠体内MIC生物转化的一个重要定量途径。然而，鉴于MIC的S-连接结合物已知的氨基甲酰化特性和体外细胞毒性，在MIC的情况下，GSH代谢途径似乎不太可能起到传统的解毒作用。相反，有人提出，MIC的氨基甲酸酯硫酯结合物在生理条件下可自发还原为游离MIC，实际上可能是这种剧毒异氰酸酯在体内产生多系统不良反应的原因。
