State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China.
State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China; Guangdong-Hong Kong-Macao Joint Laboratory for Environmental Pollution and Control, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China; CAS Center for Excellence in Deep Earth Science, Guangzhou 510640, China.
Ecotoxicol Environ Saf. 2024 Sep 15;283:116748. doi: 10.1016/j.ecoenv.2024.116748. Epub 2024 Jul 26.
Organophosphorus flame retardants (PFRs) are a class of flame retardants and environmental pollutants with various biological effects. Recentstudies have evidenced activation of some PFRs by human CYP enzymes (including CYP2E1) for genotoxic effects. However, the activity of CYPs in fish species toward PFR metabolism remains unclear. This study was aimed on comparing the metabolism of triphenyl phosphate (TPHP) and 4-OH-TPHP in human, rat, and common carp, and the involvement of human CYP2E1 and its orthologs in the metabolism, by using fomepizole (4-MP, CYP2E1 inhibitor) as a modulator, in silico molecular docking and dynamics analyses. The rate of TPHP metabolism was apparently faster with human and rat, microsomes than with fish microsomes, the major metabolites were phosphodiester and hydroxylated phosphate, with 30-80 % of TPHP forming unidentified metabolites in the system of each species. 4-OH-TPHP was readily metabolized by both human and rat microsomes, whereas it was hardly metabolized in carp assays. Meanwhile, with 4-MP the transformation of TPHP to 4-OH-TPHP was enhanced in the human/rat systems while suppressed in the carp system. Moreover, the formation of unidentified metabolites in human and rat systems was mostly inhibited by 4-MP. Through molecular dynamics analysis TPHP and its primary metabolites showed high affinity for human and rat CYP2E1, as well as the carp ortholog (CYP2G1-like enzyme), however, the 4-OH-TPHP bond to the latter was too far from the heme to permit a biochemical reaction. This study suggests that the metabolism/activation of TPHP might be favored in mammals rather than carp, a fish species.
有机磷阻燃剂 (PFRs) 是一类具有多种生物学效应的阻燃剂和环境污染物。最近的研究表明，一些 PFRs 可被人类 CYP 酶（包括 CYP2E1）激活产生遗传毒性。然而，鱼类 CYP 酶对 PFR 代谢的活性仍不清楚。本研究旨在比较三苯基磷酸酯 (TPHP) 和 4-OH-TPHP 在人、大鼠和鲤鱼中的代谢情况，并通过使用 fomepizole (4-MP，CYP2E1 抑制剂) 作为调节剂，在体外进行分子对接和动力学分析，研究人 CYP2E1 及其同源物在代谢中的作用。TPHP 的代谢速度在人源和鼠源微粒体中明显快于鱼源微粒体，主要代谢产物为磷酸二酯和羟基化磷酸盐，在每个物种的系统中，有 30-80%的 TPHP 形成未鉴定的代谢物。4-OH-TPHP 易被人源和鼠源微粒体代谢，而在鲤鱼试验中则难以代谢。同时，在 4-MP 存在的情况下，TPHP 向 4-OH-TPHP 的转化在人/鼠系统中增强，而在鲤鱼系统中受到抑制。此外，4-MP 主要抑制人源和鼠源系统中未鉴定代谢物的形成。通过分子动力学分析，TPHP 及其主要代谢产物与人源和鼠源 CYP2E1 以及鲤鱼同源物（CYP2G1 样酶）具有高亲和力，但 4-OH-TPHP 与后者的结合距离太远，无法进行生化反应。本研究表明，TPHP 的代谢/激活可能在哺乳动物中更为有利，而不是在鲤鱼等鱼类中。
