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The Capture of Cadmium by Reactive Polysulfides Attenuates Cadmium-Induced Adaptive Responses and Hepatotoxicity
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2017-11-20 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00278
Masahiro Akiyama 1 , Yasuhiro Shinkai 1 , Takamitsu Unoki 1 , Ilseob Shim 2 , Isao Ishii 3 , Yoshito Kumagai 1
Affiliation  

Cadmium (Cd) is an environmental electrophile that modifies protein nucleophiles, thereby modulating cellular signaling and toxicity. While reactive persulfides/polysulfides exhibit relatively high nucleophilic properties, their roles in the altered gene expression and toxicity caused by Cd remain unclear. Exposing primary mouse hepatocytes to Cd caused heat shock protein 70 (HSP70) and metallothionein (MT)-I/II to be upregulated and cytotoxicity to occur. These effects were blocked in the presence of polysulfide sodium tetrasulfide (Na2S4). Electrospray ionization mass spectrometry analysis indicated that cadmium sulfide (CdS) and cadmium thiosulfate (CdS2O3) were produced when Cd reacted with Na2S4. Authentic CdS did not cause cellular signaling responses to be activated or hepatotoxic effects, while CdS2O3 had effects similar to those of Cd. HSP70 and MT-I/II upregulation and hepatotoxicity caused by exposure to Cd were significantly enhanced by the deletion of cystathionine γ-lyase (CSE), which catalyzes the formation of reactive persulfides/polysulfides. Deleting CSE also exacerbated Cd-mediated liver injury, whereas little hepatic damage was found when CdS or Na2S4 along with Cd was administered. Overall, the results suggest that the persulfide/polysulfide-mediated formation of sulfur adducts of Cd such as CdS rather than CdS2O3 is, at least in part, involved in decreasing the level of Cd-mediated activation of cellular signaling and toxicity.

中文翻译:

反应性多硫化物对镉的捕获减弱了镉诱导的适应性反应和肝毒性。

镉(Cd)是一种环境亲电试剂,可修饰蛋白质亲核试剂,从而调节细胞信号传导和毒性。尽管反应性过硫化物/多硫化物表现出较高的亲核性质,但它们在由镉引起的基因表达改变和毒性中的作用仍不清楚。将原代小鼠肝细胞暴露于Cd会导致热休克蛋白70(HSP70)和金属硫蛋白(MT)-I / II上调,并发生细胞毒性。在多硫化钠四硫化钠(Na 2 S 4)的存在下,这些作用被阻止。电喷雾电离质谱分析表明,当Cd与Na 2 S反应时会生成硫化镉(CdS)和硫代硫酸镉(CdS 2 O 3)。4。真实的CdS不会引起细胞信号转导反应被激活或具有肝毒性作用,而CdS 2 O 3的作用与Cd相似。胱硫醚γ-裂合酶(CSE)的缺失可显着增强HSP70和MT-I / II的上调作用以及由于暴露于Cd引起的肝毒性,该酶可催化反应性过硫化物/多硫化物的形成。删除CSE还会加剧Cd介导的肝损伤,而与Cd一起使用CdS或Na 2 S 4时,对肝的损害很少。总体而言,该结果表明,过硫化物/多硫化物介导的Cd的硫加合物(如CdS而不是CdS 2 O 3)的形成 至少部分地参与降低Cd介导的细胞信号转导和毒性的水平。
更新日期:2017-11-20
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