The purpose of this study was to investigate the cytotoxic effects of tributylphosphate (TBP) and tris (2-butoxyethyl) phosphate (TBEP), and to explore the underlying molecular mechanism focusing on oxidative stress, apoptosis, and cell cycle arrest. The results showed that TBP and TBEP could inhibit cell proliferation, induce cellular reactive oxidative stress, and suppress the mitochondrial membrane potential in HepG2 cells. TBP and TBEP could induce both mitochondrial and p53 mediated apoptosis through different mitogen-activated protein kinase (MAPK) signal pathways. TBP activated the c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases (ERK1/2) pathways, while TBEP activated the JNK pathway. Furthermore, TBP and TBEP caused a concentration-dependent decrease of cyclin D1 expression and increase of cyclin-dependent kinase (CDK) inhibitor proteins such as p21 and p27, resulting in significant cell cycle arrest at the G0/G1 phase. Taken together, the toxicity of TBP and TBEP on the HepG2 cells was associated with apoptosis and cell cycle arrest induced by oxidative stress.

中文翻译：

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磷酸三丁酯（TBP）和磷酸三（2-丁氧基乙基）酯（TBEP）诱导HepG2细胞凋亡和细胞周期停滞

这项研究的目的是研究磷酸三丁酯（TBP）和磷酸三（2-丁氧基乙基）酯（TBEP）的细胞毒性作用，并探索着重于氧化应激，细胞凋亡和细胞周期停滞的潜在分子机制。结果表明，TBP和TBEP可以抑制HepG2细胞的增殖，诱导细胞反应性氧化应激，并抑制线粒体膜电位。TBP和TBEP可以通过不同的促分裂原活化蛋白激酶（MAPK）信号通路诱导线粒体和p53介导的细胞凋亡。TBP激活c-Jun N端激酶（JNK）和细胞外调节蛋白激酶（ERK1 / 2）途径，而TBEP激活JNK途径。此外，TBP和TBEP引起细胞周期蛋白D1表达的浓度依赖性降低和细胞周期蛋白依赖性激酶（CDK）抑制剂蛋白（例如p21和p27）的浓度依赖性升高，从而导致细胞周期明显停滞在G0 / G1期。两者合计，TBP和TBEP对HepG2细胞的毒性与氧化应激诱导的细胞凋亡和细胞周期停滞有关。