Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China.
Environ Sci Technol. 2022 Mar 15;56(6):3634-3644. doi: 10.1021/acs.est.1c08141. Epub 2022 Mar 3.
It is generally recognized that phenol-containing molecules mainly undergo phase II metabolic reactions, whereas glucuronide and sulfate are conjugated to form water-soluble products. Here, we report direct reactions of phenolic pollutants (triclosan, alkylphenol, bisphenol A [BPA], and its analogues) and some endogenous metabolites (vitamin E [VE] and estradiol) to generate new lipophilic ether products (e.g., BPA-O-VEs and alkylphenol-O-estradiol). A nontargeted screening strategy was used to identify the products in human liver microsome incubations, and the most abundant products (BPA-O-VEs) were confirmed via exposure in mice. BPA-O-VEs were frequently detected in sera from the general population at levels comparable to those of glucuronide/sulfate-conjugated BPA. Recombinant human cytochrome P450s were applied to find that CYP3A4 catalyzed the formation of these newly discovered ether metabolites by linking the VE hydroxyl group to the BPA phenolic ring, leading to the significantly reduced antioxidative activities of BPA-O-VEs compared to VEs. The effects of the reaction on the homeostasis of reacted biomolecules were finally assessed by assay and mice exposures. The generation of BPA-O-VEs decreased the VE concentrations and increased the reactive oxygen species generation after exposure to BPA at environmentally relevant concentrations. The identified reactions provided an overlooked metabolic disruption pathway for phenolic pollutants.
人们普遍认为，含酚分子主要经历 II 相代谢反应，而葡萄糖醛酸和硫酸盐则与酚类结合形成水溶性产物。在这里，我们报告了酚类污染物（三氯生、烷基酚、双酚 A [BPA]及其类似物）和一些内源性代谢物（维生素 E [VE]和雌二醇）的直接反应，生成新的亲脂性醚产物（例如，BPA-O-VEs 和烷基酚-O-雌二醇）。我们采用非靶向筛选策略来鉴定人肝微粒体孵育物中的产物，并通过在小鼠中的暴露来确认最丰富的产物（BPA-O-VEs）。BPA-O-VEs 经常在普通人群的血清中检测到，其水平与葡萄糖醛酸/硫酸盐结合的 BPA 相当。应用重组人细胞色素 P450 发现，CYP3A4 通过将 VE 羟基连接到 BPA 酚环上催化这些新发现的醚代谢物的形成，导致 BPA-O-VEs 的抗氧化活性明显低于 VE。最后通过 试验和 暴露来评估反应对反应生物分子内稳态的影响。BPA-O-VEs 的生成降低了 VE 浓度，并增加了在环境相关浓度下暴露于 BPA 后的活性氧生成。所鉴定的反应为酚类污染物提供了一条被忽视的代谢破坏途径。
