In this study, we performed the metabolism of endosulfan sulfate in human liver preparations (human liver microsomes, S9 fractions and hepatocytes) to identify new metabolites using liquid chromatography-high resolution mass spectrometry (LC-HRMS). Endosulfan sulfate is a major oxidized metabolite of the organochlorine insecticide endosulfan, and it exhibits a similar toxicity to endosulfan. Six metabolites, including 5 novel metabolites of endosulfan sulfate, were identified in the three different human liver reaction mixtures and metabolic pathways of endosulfan sulfate were proposed. The phase I metabolites M1 and M2 were observed in human liver microsomes, S9 fractions and hepatocytes. M1 was suggested to be an endosulfan diol monosulfate and M2 was identified as (1,4,5,6,7,7-hexachloro-3-formylbicyclo[2,2,1]hept-5-en-2-yl)methyl hydrogen sulfate through the interpretation of the HRMS spectrum. The phase II metabolite M3 was produced as an endosulfan sulfate-GSH conjugate in those three liver preparations and transformed to M5 (dipeptide) in S9 fractions and hepatocytes. M3 was the most predominant metabolite identified in the three liver preparations. M4 was only detected in microsomes as an M2-GSH conjugate and was metabolized to M6 (monopeptide) in hepatocytes. These results are different from the metabolic pathway of endosulfan and suggest the possible detoxification metabolic reaction of endosulfan sulfate in living organisms.

中文翻译：

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液相色谱-高分辨率质谱分析三种人肝制剂中硫酸硫丹的代谢物并进行鉴定。

在这项研究中，我们进行了人类肝脏制剂（人类肝脏微粒体，S9级分和肝细胞）中硫酸硫丹的代谢，以使用液相色谱-高分辨率质谱（LC-HRMS）识别新的代谢物。硫酸硫丹是有机氯杀虫剂硫丹的主要氧化代谢产物，与硫丹具有相似的毒性。在三种不同的人肝反应混合物中鉴定出6种代谢物，包括5种新的硫丹硫酸盐代谢物，并提出了硫丹硫酸盐的代谢途径。在人肝微粒体，S9级分和肝细胞中观察到I期代谢物M1和M2。M1被认为是硫丹二醇单硫酸盐，M2被确定为（1,4,5,6,7,7-六氯-3-甲酰基双环[2,2，通过HRMS光谱的解释，得到1]庚-5-烯-2-基）甲基硫酸氢盐。在这三种肝脏制剂中，II期代谢产物M3以硫丹硫酸盐-GSH缀合物的形式产生，并在S9级分和肝细胞中转化为M5（二肽）。在三种肝制剂中，M3是最主要的代谢产物。M4仅在微粒体中作为M2-GSH偶联物检测到，并在肝细胞中代谢为M6（单肽）。这些结果与硫丹的代谢途径不同，表明硫酸硫丹在活生物体中可能发生解毒代谢反应。在这三种肝脏制剂中，II期代谢产物M3以硫丹硫酸盐-GSH缀合物的形式产生，并在S9级分和肝细胞中转化为M5（二肽）。在三种肝制剂中，M3是最主要的代谢产物。M4仅在微粒体中作为M2-GSH偶联物检测到，并在肝细胞中代谢为M6（单肽）。这些结果与硫丹的代谢途径不同，表明硫酸硫丹在活生物体中可能发生解毒代谢反应。在这三种肝脏制剂中，II期代谢产物M3以硫丹硫酸盐-GSH缀合物的形式产生，并在S9级分和肝细胞中转化为M5（二肽）。在三种肝制剂中，M3是最主要的代谢产物。M4仅在微粒体中作为M2-GSH偶联物检测到，并在肝细胞中代谢为M6（单肽）。这些结果与硫丹的代谢途径不同，表明硫酸硫丹在活生物体中可能发生解毒代谢反应。