华南师范大学使用IPHASE肝微粒体在《Environment Pollution》上发表文章

近日，华南师范大学环境学院应光国教授、赵建亮研究员团队2021级硕士研究生张源源等人在《Environment Pollution》上发表了题为“In vitro metabolism of the emerging contaminant 6PPD-quinone in human and rat liver microsomes: Kinetics, pathways, and mechanism”的论文（DOI: 10.1016/j.envpol.2024.123514，IF=8.9）。该研究使用IPHASE肝微粒体产品以体外代谢反应体系探究了轮胎添加剂的抗氧化剂6PPD及其转化产物6PPD醌（6PPD-Q）的I相代谢情况，通过疑似筛查和非靶向的分析方法阐明了可能的转化产物及转化路径，结合表型分析实验与分子对接明确了代谢6PPD-Q的关键作用酶。

发表于《Science》上论文之前报道了6PPD-Q对银鲑鱼的急性致死效应，引起了世界范围的广泛关注，轮胎添加剂的安全性备受质疑。6PPD-Q是橡胶抗氧化剂6PPD经臭氧氧化的转化产物，广泛存在于各种环境介质中，可通过吸入、食入和皮肤接触等多种途径进入人体，进而进一步进入人体的代谢系统。本研究以肝微粒体体外孵育体系探究6PPD和6PPD-Q的生物转化情况，探讨6PPD-Q对人体健康可能的影响。

此项研究结果表明研究6PPD-Q 在较低浓度下代谢显著，但在高浓度下代谢程度降低。关键I 相代谢产物为单加氧和进一步氧化的产物。与6PPD相比，6PPD-Q所需的代谢时间相对较长，代谢40 μg/L 6PPD的半衰期（t1/2）为28.9 min，而代谢16 μg/L 6PPD-Q的 t1/2则需要29.6 min，代谢80 μg/L 6PPD-Q的 t1/2则要达到254 min。这也说明与轮胎添加剂母体相比，转化产物更难被人体所代谢，可能带来更大的环境健康问题。未来的研究应重点关注轮胎添加剂转化产物，特别是其他PPD-Qs的转化产物，以充分评估其对人类健康的影响。

摘    要

N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q) is an ozonation product of the rubber antioxidant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD). 6PPD-Q has recently been detected in various environmental media, which may enter the human body via inhalation and skin contact pathways. However, the human metabolism of 6PPD-Q has remained unknown. This study investigated the in vitro Cytochrome P450-mediated metabolism of 6PPD-Q in human and rat liver microsomes (HLMs and RLMs). 6PPD-Q was significantly metabolized at lower concentrations but slowed at high concentrations. The intrinsic clearance (CLint) of 6PPD-Q was 21.10 and 18.58 μL min− 1 mg− 1 protein of HLMs and RLMs, respectively, suggesting low metabolic ability compared with other reported pollutants. Seven metabolites and one intermediate were identified, and metabolites were predicted immunotoxic or mutagenic toxicity. Mono- and di-oxygenation reactions were the main phase I in vitro metabolic pathways. Enzyme inhibition experiments and molecular docking techniques were further used to reveal the metabolic mechanism. CYP1A2, 3A4, and 2C19, especially 

CYP1A2, play critical roles in 6PPD-Q metabolism in HLMs, whereas 6PPD-Q is extensively metabolized in RLMs. Our study is the first to demonstrate the in vitro metabolic profile of 6PPD-Q in HLMs and RLMs. The results will significantly contribute to future human health management targeting the emerging pollutant 6PPD-Q.

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