Conjugation of Di-n-butyl Phthalate Metabolites in Arabidopsis thaliana and Potential Deconjugation in Human Microsomes
Conjugation of Di-n-butyl Phthalate Metabolites in Arabidopsis thaliana and Potential Deconjugation in Human Microsomes
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拟南芥中邻苯二甲酸二正丁酯代谢物的结合和人微粒体中的潜在解结合
DOI：
10.1021/acs.est.0c07232
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发表时间：
2021-02-16
影响因子：
11.4
通讯作者：
Gan, Jay
中科院分区：
文献类型：
--
作者：
Cheng, Zhipeng;Sun, Hongwen;Gan, Jay
由于塑料的广泛使用，增塑剂在环境中普遍存在。废弃资源的再利用（如经过处理的废水、生物固体、动物粪便）以及其他做法（如塑料地膜覆盖）会将邻苯二甲酸酯引入农业生态系统。作为一种解毒机制，已知植物在吸收邻苯二甲酸酯后会将其转化为极性单邻苯二甲酸酯，随后还会发生进一步转化，包括与内源性生物分子结合。本研究有两个目标：一是通过一系列互补技术，包括稳定同位素标记、碳-14示踪和高分辨率质谱法，全面了解广泛使用的邻苯二甲酸二正丁酯（DnBP）的代谢情况；二是确定结合物在人微粒体中是否会发生去结合反应，从而释放出具有生物活性的代谢物。在拟南芥细胞中，DnBP的主要初始代谢物是邻苯二甲酸单正丁酯（MnBP），MnBP会通过羟基化、羧基化、糖基化和丙二酰化迅速代谢为七种转化产物。其中一种结合物，即MnBP-芳基-β-D-葡萄糖苷（MnBP-Glu），在人肝微粒体（HLM）和人肠微粒体（HIM）中进行孵育，发现其会快速发生转化。在HIM和HLM中，分别约有15%和10%的MnBP-Glu去结合为游离形式的MnBP。这些研究结果表明，作为二酯的邻苯二甲酸酯易水解形成单酯，而单酯在植物中可通过二期代谢轻易发生结合反应。结合物在被人体摄入后可能会发生去结合反应，释放出具有生物活性的化合物。因此，要准确评估邻苯二甲酸酯和其他污染物的饮食暴露情况，必须考虑植物代谢物，尤其是结合物，以便更好地预测它们对环境和人类健康的潜在风险。
Plasticizers, due to the widespread use of plastics, occur ubiquitously in the environment. The reuse of waste resources (e.g., treated wastewater, biosolids, animal waste) and other practices (e.g., plastic mulching) introduce phthalates into agroecosystems. As a detoxification mechanism, plants are known to convert phthalates to polar monophthalates after uptake, which are followed by further transformations, including conjugation with endogenous biomolecules. The objective of this study was 2-fold: to obtain a complete metabolic picture of the widely used di-n-butyl phthalate (DnBP) by using a suite of complementary techniques, including stable isotope labeling, C-14 tracing, and high-resolution mass spectrometry, and to determine if conjugates are deconjugated in human microsomes to release bioactive metabolites. In Arabidopsis thaliana cells, the primary initial metabolite of DnBP was mono-n-butyl phthalate (MnBP), and MnBP was rapidly metabolized via hydroxylation, carboxylation, glycosylation, and malonylation to seven transformation products. One of the conjugates, MnBP-aryl-beta-D-glucoside (MnBP-Glu), was incubated in human liver (HLM) and intestinal (HIM) microsomes and was found to undergo rapid transformations. Approximately 15% and 10% of MnBP-Glu were deconjugated to the free form MnBP in HIM and HLM, respectively. These findings highlight that phthalates, as diesters, are susceptible to hydrolysis to form monoesters that can be readily conjugated via a phase II metabolism in plants. Conjugates may be deconjugated to release bioactive compounds after human ingestion. Therefore, an accurate assessment of the dietary exposure of phthalates and other contaminants must consider plant metabolites, especially including conjugates, to better predict their potential environmental and human health risks.