Identification of novel reaction products of methylene-bis-phenylisocyanate ("MDI") with oxidized glutathione in aqueous solution and also during incubation of MDI with a murine hepatic S9 fraction.
Identification of novel reaction products of methylene-bis-phenylisocyanate ("MDI") with oxidized glutathione in aqueous solution and also during incubation of MDI with a murine hepatic S9 fraction.
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鉴定亚甲基双苯基异氰酸酯（“MDI”）与氧化型谷胱甘肽在水溶液中以及在 MDI 与鼠肝 S9 级分孵育期间的新反应产物。
DOI：
10.1016/j.tiv.2016.07.011
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Nassar,AF
中科院分区：
文献类型：
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作者：
Wisnewski,AV;Liu,J;Nassar,AF
亚甲基二苯基二异氰酸酯（MDI）是一种重要的工业化学品和哮喘呼吸道敏化剂，但其代谢仍不清楚。在本研究中，我们使用 LC-MS 和 LC-MS/MS 鉴定了 MDI 与氧化型谷胱甘肽 (GSSG) 的新型反应产物，包括对应于 GSSG 与部分水解的 MDI 结合（通过其 N 末端之一）的 837m/z[M + H]+ 离子，以及对应于 MDI 交联的 GSSG 的 863m/z[M + H]+ 离子（通过其两个γ-谷氨酰胺 N 端）。对重同位素标记和天然还原型谷胱甘肽 (GSH) 的进一步研究确定了与先前描述的单 (GSH)-MDI 相对应的 [M + H]+ 离子，以及“寡聚”GSH-MDI 缀合物的证据。本研究还研究了与小鼠肝脏制备的 S9 级分孵育后 MDI 的转化变化。 S9 反应产物的 LC-MS 分析揭示了 [M + H]+ 离子的形成，其 m/z 和保留时间与新描述的 GSSG-MDI（837 和 863）缀合物和先前描述的单（GSH）-MDI 缀合物相同。这些数据共同确定了 MDI 的新生物转化，这可能对与暴露相关的健康影响产生影响，并可能有助于瞄准未来的体内代谢研究。
Methylene diphenyl diisocyanate (MDI) is an important industrial chemical and asthmagenic respiratory sensitizer, however its metabolism remains unclear. In this study we used LC-MS and LC-MS/MS to identify novel reaction products of MDI with oxidized glutathione (GSSG), including an 837m/z[M + H]+ion corresponding to GSSG bound (via one of its N-termini) to partially hydrolyzed MDI, and an 863m/z[M + H]+ion corresponding to GSSG cross-linked by MDI (via its two γ-glutamine N-termini). Further studies with heavy isotope labeled and native reduced glutathione (GSH) identified an [M + H]+ion corresponding to previously described mono(GSH)-MDI, and evidence for “oligomeric” GSH-MDI conjugates. This study also investigated transformational changes in MDI after incubation with an S9 fraction prepared from murine liver. LC-MS analyses of the S9 reaction products revealed the formation of [M + H]+ions withm/z's and retention times identical to the newly described GSSG-MDI (837 and 863) conjugates and the previously described mono(GSH)-MDI conjugate. Together the data identify novel biological transformations of MDI, which could have implications for exposure-related health effects, and may help target future in vivo studies of metabolism.