Endoplasmic Reticulum Stress Induction and ERK1/2 Activation Contribute to Nefazodone-Induced Toxicity in Hepatic Cells.
Endoplasmic Reticulum Stress Induction and ERK1/2 Activation Contribute to Nefazodone-Induced Toxicity in Hepatic Cells.
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DOI：
10.1093/toxsci/kfw173
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Guo L
中科院分区：
文献类型：
--
作者：
Ren Z;Chen S;Zhang J;Doshi U;Li AP;Guo L
奈法唑酮是5-羟色胺受体的拮抗剂，已被用于治疗抑郁症。急性肝损伤已被证明与奈法唑酮的使用有关;然而，奈法唑酮诱导的肝毒性机制尚未明确。在这份报告中，使用生化和分子分析，我们的特点是奈法唑酮肝毒性的分子机制。我们发现奈法唑酮诱导HepG 2细胞的内质网应激，因为典型的内质网应激标志物，包括CHOP，ATF-4和p-eIF 2 α的表达显著增加，并观察到剪接的XBP 1。使用测量ER应激的Gaussia荧光素酶报告基因测定来评价奈法唑酮抑制的蛋白质分泌。ER应激抑制剂（4-苯丁酸酯和salubrinal）和ATF-4基因敲除可减轻奈法唑酮诱导的ER应激和细胞毒性。奈法唑酮激活MAPK信号通路，如JNK、ERK 1/2和p38磷酸化增加所示。抑制ERK 1/2可降低奈法唑酮引起的ER应激。总之，我们的研究结果表明，ER应激有助于奈法唑酮诱导的HepG 2细胞毒性，MAPK信号通路在ER应激中起着重要作用。
Nefazodone, an antagonist for the 5-hydroxytryptanine receptor, has been used for the treatment of depression. Acute liver injury has been documented to be associated with the use of nefazodone; however, the mechanisms of nefazodone-induced liver toxicity are not well defined. In this report, using biochemical and molecular analyses, we characterized the molecular mechanisms underlying the hepatotoxicity of nefazodone. We found that nefazodone induced endoplasmic reticulum (ER) stress in HepG2 cells, as the expression of typical ER stress markers, including CHOP, ATF-4, and p-eIF2α, was significantly increased, and splicing of XBP1 was observed. Nefazodone-suppressed protein secretion was evaluated using a Gaussia luciferase reporter assay that measures ER stress. The ER stress inhibitors (4-phenylbutyrate and salubrinal) and knockdown of ATF-4 gene attenuated nefazodone-induced ER stress and cytotoxicity. Nefazodone activated the MAPK signaling pathway, as indicated by increased phosphorylation of JNK, ERK1/2, and p38. Inhibition of ERK1/2 reduced ER stress caused by nefazodone. Taken together, our findings suggest that ER stress contributes to nefazodone-induced toxicity in HepG2 cells and that the MAPK signaling pathway plays an important role in ER stress.
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