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。
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.