Discovery of a widespread metabolic pathway within and among phenolic xenobiotics

Abstract

Metabolism is an organism's primary defense against xenobiotics, yet it also increases the production of toxic metabolites. It is generally recognized that phenolic xenobiotics, a group of ubiquitous endocrine disruptors, undergo rapid phase II metabolism to generate more water-soluble glucuronide and sulfate conjugates as a detoxification pathway. However, the toxicological effects of the compounds invariably point to the phase I metabolic cytochrome P450 enzymes. Here we show that phenolic xenobiotics undergo an unknown metabolic pathway to form more lipophilic and bioactive products. In a nontargeted screening of the metabolites of a widely used antibacterial ingredient: triclosan (TCS), we identified a metabolic pathway via in vitro incubation with weever, quail, and human microsomes and in vivo exposure in mice, which generated a group of products: TCS-O-TCS. The lipophilic metabolite of TCS was frequently detected in urine samples from the general population, and TCS-O-TCS activated the constitutive androstane receptor with the binding activity about 7.2 times higher than that of the parent compound. The metabolic pathway was mediated mainly by phase I enzymes localized on the microsomes and widely observed in chlorinated phenols, phenols, and hydroxylated aromatics. The pathway was also present in different phenolic xenobiotics and formed groups of unknown pollutants in organisms (e.g., TCS-O-bisphenol A and TCS-O-benzo()pyrene), thus providing a cross-talk reaction between different phenolic pollutants during metabolic processes in organisms.

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

“…CYP1A1 is considered as playing a key role in B[a]P metabolism involving both BPDE formation and reduction [55]. Further, abnormal activation of phase I enzymes may have an adverse effect by inducing toxicity and causing cancer in the body [56]. Our results showed that co-treatment with silymarin reduced CYP1A1 and CYP1B1 protein level compared to B[a]P treatment alone ( Figure 3A,C).…”

Metabolism of typical halogenated organic pollutants in plants

“…[61,62] . 这类二聚反应在动 物体内也得到了证实, 对动物和人的微粒体以及 C57BL/6小鼠暴露TCS, 可以发现TCS-O-TCS的二聚 产物, 这一过程中CYP450酶起主导作用 [63] . 这些研究 预示酚类物质在生物体内的二聚反应也许也是一个普 遍的代谢途径.…”

RNA sequencing indicates that atrazine induces multiple detoxification genes in Daphnia magna and this is a potential source of its mixture interactions with other chemicals

“…Triclosan generates ROS and is primarily detoxified via glucuronidation with some sulfation (Ashrap et al, 2017; Binelli et al, 2009; Wu et al, 2010). RNAseq confirmed that several GSTs and UDPGTs were induced, which may detoxify triclosan or mitigate its toxic effects from ROS generation.…”