Frequent occurrence of triclosan hydroxylation in mammals: A combined theoretical and experimental investigation.
Frequent occurrence of triclosan hydroxylation in mammals: A combined theoretical and experimental investigation.
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DOI：
10.1016/j.jhazmat.2020.124803
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发表时间：
2020-12
影响因子：
13.6
通讯作者：
Hongna Zhang;Katherine Z. Sanidad;Lin Zhu;J. Parsonnet;T. Haggerty;Guodong Zhang;Z. Cai
中科院分区：
文献类型：
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作者：
Hongna Zhang;Katherine Z. Sanidad;Lin Zhu;J. Parsonnet;T. Haggerty;Guodong Zhang;Z. Cai
三氯生（TCS）是一种广泛使用的抗菌剂，具有许多不良健康风险。其肝毒性总是指向组成型雄甾受体（CAR）的激活，该受体调节细胞色素P450 （CYP）基因，这些基因对氧化代谢至关重要。在此，我们提供了理论和实验证据，表明TCS在哺乳动物中经常通过芳香羟基化发生代谢激活。cypp介导的氧化预计发生在每个芳香族C-H键上。分子对接和体外实验表明，car调控的CYP2B6酶可以有效地催化氧化反应。利用平行反应监测（PRM）高分辨率质谱法鉴定和分析配对小鼠肝脏、胆汁、粪便、血浆和尿液中的TCS氧化代谢物。我们发现了多个羟基化异构体，包括通过NIH氯转移产生的产物，以及它们随后的偶联物。这些代谢物在小鼠体内表现出同分异构体特异性滞留。葡萄糖醛酸缀合物比硫酸盐更容易排出体外。此外，首次在使用含tcs的家用和个人护理产品的人类受试者的尿液和粪便中检测到同分异体羟基化代谢物。总的来说，这些发现表明羟基化是一个重要的，但经常被低估的因素，值得考虑充分评估TCS的生物学命运和健康风险。
Triclosan (TCS) is a widespread antimicrobial agent with many adverse health risks. Its hepatoxicity invariably points to the activation of constitutive androstane receptor (CAR), which regulates cytochrome P450 (CYP) genes that are critical for oxidative metabolism. Here, we provide the theoretical and experimental evidences showing that metabolic activation of TCS frequently occurs through aromatic hydroxylation in mammals. CYP-mediated oxidation was predicted to take place at each aromatic C‒H bond. Molecular docking andin vitroapproaches reveal oxidative reaction could be efficiently catalyzed by CAR-regulated CYP2B6 enzyme. Parallel reaction monitoring (PRM) high-resolution mass spectrometry was utilized to identify and profile TCS oxidative metabolites in paired mouse liver, bile, feces, plasma and urine. We found multiple hydroxylated isomers including the products generatedviathe NIH shift of chlorine, as well as their subsequent conjugates. These metabolites showed isomer-specific retention in mice. Glucuronide conjugates are more readily excreted than the sulfates. Moreover, for the first time, isomeric hydroxylated metabolites were detected in the urine and stool of human subjects used TCS-contained household and personal care products. Collectively, these findings suggest that hydroxylation is an important, yet often underestimated element that worth considering to fully evaluate the biological fates and health risks of TCS.