对苯二胺类抗氧化剂体外代谢途径研究

In vitro metabolic pathway studies of p-phenylenediamine antioxidants

中文关键词: 对苯二胺类抗氧化剂  人肝微粒体  体外代谢  代谢产物鉴定  毒性预测

英文关键词: p-phenylenediamine antioxidants  human liver microsomes  in vitro metabolism  metabolites identification  toxicity prediction

中文摘要:

      轮胎橡胶抗氧化剂N，N′-取代对苯二胺(PPDs)是一类普遍存在的新污染物，因其在环境中被转化为高毒性醌类产物(PPDQs)而受到关注．然而，PPDs在人体内的代谢途径和产物尚不明确，限制了对其环境风险的准确认识．采用人肝微粒体孵育结合液相色谱-串联质谱检测，研究了3种PPDs(N-异丙基-N′-苯基对苯二胺(IPPD)、N-环己基-N′-苯基对苯二胺(CPPD)和N，N′-二苯基对苯二胺(DPPD))的Ⅰ相代谢过程．共鉴定得到47种代谢产物，脱氢、羟基化和N-脱烷基是主要的代谢途径．发现3种PPDs均能转化为PPDQs，苯基取代的DPPD比烷基取代的IPPD和CPPD的代谢产物种类少，但相对丰度高．毒性预测结果表明，脱氢、羟基化和N-脱烷基等主要产物具有潜在的致癌性．研究结果提供了PPDs人体代谢归趋和毒性的基础数据，有望用于PPDs的健康风险评价．

英文摘要:

      N,N′-substituted p-phenylenediamines (PPDs), a type of antioxidants used in tire rubber, are emerging pollutants of concern due to their transformation into highly toxic quinone products (PPDQs) in the environment. However, the metabolic pathways and products of PPDs in organisms are still unclear, hindering the accurate understanding of their environmental risks. The phase I metabolism of three PPDs (N-isopropyl-N′-phenyl-p-phenylenediamine (IPPD), N-cyclohexyl-N′-phenyl-p-phenylenediamine (CPPD), and N,N′-diphenyl-p-phenylenediamine (DPPD)) is investigated using human liver microsomes incubation combined with liquid chromatography-tandem mass spectrometry detection. A total of 47 metabolites are identified, with dehydrogenation, hydroxylation and N-dealkylation being the main metabolic pathways. It is found that all three PPDs can be transformed into PPDQs, and the phenyl-substituted DPPD possesses fewer but more abundant metabolites than alkylated IPPD and CPPD. Toxicity prediction results indicate that the main products such as dehydrogenation, hydroxylation and N-dealkylation metabolites have potential carcinogenicity. The results provide basic data for the metabolic fate and toxicity of PPDs in humans, thus benefit the health risk assessment of PPDs.