School of Environmental Science and Engineering, China-America CRC for Environment & Health, Shandong University, Qingdao, 266237, China.
School of Chemistry and Materials Science, Ludong University, Yantai, 264025, China.
Water Res. 2024 Jun 1;256:121562. doi: 10.1016/j.watres.2024.121562. Epub 2024 Apr 1.
Halophenylacetamides (HPAcAms) have been identified as a new group of nitrogenous aromatic disinfection byproducts (DBPs) in drinking water, but the toxicity mechanisms associated with HPAcAms remain almost completely unknown. In this work, the cytotoxicity of HPAcAms in human hepatoma (HepG2) cells was evaluated, intracellular oxidative stress/damage levels were analyzed, their binding interactions with antioxidative enzyme were explored, and a quantitative structure-activity relationship (QSAR) model was established. Results indicated that the EC values of HPAcAms ranged from 2353 μM to 9780 μM, and the isomeric structure as well as the type and number of halogen substitutions could obviously induce the change in the cytotoxicity of HPAcAms. Upon exposure to 2-(3,4-dichlorophenyl)acetamide (3,4-DCPAcAm), various important biomarkers linked to oxidative stress and damage, such as reactive oxygen species, 8‑hydroxy-2-deoxyguanosine, and cell apoptosis, exhibited a significant increase in a dose-dependent manner. Moreover, 3,4-DCPAcAm could directly bind with Cu/Zn-superoxide dismutase and induce the alterations in the structure and activity, and the formation of complexes was predominantly influenced by the van der Waals force and hydrogen bonding. The QSAR model supported that the nucleophilic reactivity as well as the molecular compactness might be highly important in their cytotoxicity mechanisms in HepG2 cells, and 2-(2,4-dibromophenyl)acetamide and 2-(3,4-dibromophenyl)acetamide deserved particular attention in future studies due to the relatively higher predicted cytotoxicity. This study provided the first comprehensive investigation on the cytotoxicity mechanisms of HPAcAm DBPs.
卤代苯乙酰胺（HPAcAms）已被确定为饮用水中一类新的含氮芳香族消毒副产物（DBPs），但其与 HPAcAms 相关的毒性机制仍几乎完全未知。在这项工作中，评估了 HPAcAms 对人肝癌（HepG2）细胞的细胞毒性，分析了细胞内氧化应激/损伤水平，探讨了其与抗氧化酶的结合相互作用，并建立了定量构效关系（QSAR）模型。结果表明，HPAcAms 的 EC 值范围为 2353 μM 至 9780 μM，其同分异构结构以及卤素取代的类型和数量明显会引起 HPAcAms 细胞毒性的变化。在暴露于 2-(3,4-二氯苯基)乙酰胺（3,4-DCPAcAm）后，各种与氧化应激和损伤相关的重要生物标志物，如活性氧、8-羟基-2-脱氧鸟苷和细胞凋亡，均呈剂量依赖性显著增加。此外，3,4-DCPAcAm 可直接与 Cu/Zn-超氧化物歧化酶结合并诱导其结构和活性的改变，复合物的形成主要受范德华力和氢键的影响。QSAR 模型表明亲核反应性和分子紧凑性可能在其对 HepG2 细胞的细胞毒性机制中非常重要，并且 2-(2,4-二溴苯基)乙酰胺和 2-(3,4-二溴苯基)乙酰胺由于相对较高的预测细胞毒性而值得在未来的研究中特别关注。这项研究首次全面调查了 HPAcAm DBPs 的细胞毒性机制。
