Biotransformation of methyl isocyanate in the rat. Evidence for glutathione conjugation as a major pathway of metabolism and implications for isocyanate-mediated toxicities

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Abstract

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.

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