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首页> 外文期刊>Toxicology in vitro: an international journal published in association with BIBRA >Cellular mechanisms of the cytotoxic effects of the zearalenone metabolites α-zearalenol and β-zearalenol on RAW264.7 macrophages
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Cellular mechanisms of the cytotoxic effects of the zearalenone metabolites α-zearalenol and β-zearalenol on RAW264.7 macrophages

机译：玉米赤霉烯酮代谢产物α-玉米赤霉烯醇和β-玉米赤霉烯醇对RAW264.7巨噬细胞毒性作用的细胞机制

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摘要

Zearalenone (ZEN) and its metabolites are commonly found in many food commodities and are known to cause reproductive disorders and genotoxic effects. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). Although many studies have demonstrated the cytotoxic effects of these metabolites, the mechanisms by which α-ZOL or β-ZOL mediates their cytotoxic effects appear to differ according to cell type and the exposed toxins. We evaluated the toxicity of α-ZOL and β-ZOL on RAW264.7 macrophages and investigated the underlying mechanisms. β-ZOL not only more strongly reduced the viability of cells than did α-ZOL, but it also induced cell death mainly by apoptosis rather than necrosis. The ZEN metabolites induced loss of mitochondrial membrane potential (MMP), mitochondrial changes in Bcl-2 and Bax proteins, and cytoplasmic release of cytochrome c and apoptosis-inducing factor (AIF). Use of an inhibitor specific to c-Jun N-terminal kinase (JNK), p38 kinase or p53, but not pan-caspase or caspase-8, decreased the toxin-induced generation of reactive oxygen species (ROS) and also attenuated the α-ZOL- or β-ZOL-induced decrease of cell viability. Antioxidative enzyme or compounds such as catalase, acteoside, and (E)-1-(3,4-dihydroxyphenethyl)-3-(4-hydroxystyryl)urea suppressed the ZEN metabolite-mediated reduction of cell viability. Further, knockdown of AIF via siRNA transfection diminished the ZEN metabolite-induced cell death. Collectively, these results suggest that the activation of p53, JNK or p38 kinase by ZEN metabolites is the main upstream signal required for the mitochondrial alteration of Bcl-2/Bax signaling pathways and intracellular ROS generation, while MMP loss and nuclear translocation of AIF are the critical downstream events for ZEN metabolite-mediated apoptosis in macrophages.
机译：玉米赤霉烯酮（ZEN）及其代谢产物通常在许多食品中发现，并已知会引起生殖系统疾病和遗传毒性。 ZEN的主要代谢物是α-玉米赤霉烯醇（α-ZOL）和β-玉米赤霉烯醇（β-ZOL）。尽管许多研究表明这些代谢产物具有细胞毒性作用，但根据细胞类型和暴露的毒素，α-ZOL或β-ZOL介导其细胞毒性作用的机制似乎有所不同。我们评估了α-ZOL和β-ZOL对RAW264.7巨噬细胞的毒性，并研究了其潜在机制。 β-ZOL不仅比α-ZOL更强烈地降低了细胞活力，而且还主要通过凋亡而非坏死来诱导细胞死亡。 ZEN代谢物诱导线粒体膜电位（MMP）丢失，Bcl-2和Bax蛋白的线粒体变化以及细胞色素c和细胞凋亡诱导因子（AIF）的胞质释放。使用对c-Jun N末端激酶（JNK），p38激酶或p53有特异性的抑制剂，而不是泛半胱天冬酶或caspase-8，可以减少毒素诱导的活性氧（ROS）的产生，并减弱α -ZOL-或β-ZOL诱导的细胞活力降低。抗氧化酶或过氧化氢酶，肌苷，和（E）-1-（3,4-二羟基苯乙基）-3-（4-羟基苯乙烯基）脲等化合物可抑制ZEN代谢物介导的细胞活力降低。此外，通过siRNA转染的AIF敲低可减少ZEN代谢物诱导的细胞死亡。总的来说，这些结果表明，ZEN代谢物激活p53，JNK或p38激酶是线粒体Bcl-2 / Bax信号通路和细胞内ROS生成所需的主要上游信号，而MIF丢失和AIF的核易位是ZEN代谢物介导的巨噬细胞凋亡的关键下游事件。

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