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首页> 外文期刊>Toxicology: An International Journal Concerned with the Effects of Chemicals on Living Systems >Influence of CLOCK on cytotoxicity induced by diethylnitrosamine in mouse primary hepatocytes.
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Influence of CLOCK on cytotoxicity induced by diethylnitrosamine in mouse primary hepatocytes.

机译：CLOCK对二乙基亚硝胺在小鼠原代肝细胞中诱导的细胞毒性的影响。

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摘要

The Clock gene is a core clock factor that plays an essential role in generating circadian rhythms. In the present study, it was investigated whether the Clock gene affects the response to diethylnitrosamine (DEN)-induced cytotoxicity using mouse primary hepatocytes. DEN-induced cytotoxicity, after 24h exposure, was caused by apoptosis in hepatocytes isolated from wild-type mouse. On the other hand, Clock mutant mouse (Clk/Clk) hepatocytes showed resistance to apoptosis. Because apoptosis is an important pathway for suppressing carcinogenesis after genomic DNA damage, the mechanisms that underlie resistance to DEN-induced apoptosis were examined in Clk/Clk mouse hepatocytes. The mRNA levels of metabolic enzymes bioactivating DEN and apoptosis-inducing factors before DEN exposure were lower in Clk/Clk cells than in wild-type cells. The accumulation of p53 and Ser15 phosphorylated p53 after 8h DEN exposure was seen in wild-type cells but not in Clk/Clk cells. Caspase-3/7 activity was elevated during 24h DEN exposure in wild-type cells but not in Clk/Clk cells. In addition, resistance to DEN-induced apoptosis in Clk/Clk cells affected the cell viability. These studies suggested that the lower expression levels of metabolic enzymes bioactivating DEN and apoptosis inducing factors affected the resistance to DEN-induced apoptosis in Clk/Clk cells, and the Clock gene plays an important role in cytotoxicity induced by DEN.
机译：Clock基因是一个核心时钟因子，在产生昼夜节律中起着至关重要的作用。在本研究中，研究了Clock基因是否影响对二乙基亚硝胺（DEN）诱导的使用小鼠原代肝细胞的细胞毒性的反应。暴露24小时后，DEN诱导的细胞毒性是由从野生型小鼠分离的肝细胞凋亡引起的。另一方面，Clock突变小鼠（Clk / Clk）肝细胞显示出对凋亡的抗性。因为凋亡是抑制基因组DNA损伤后癌变的重要途径，所以在Clk / Clk小鼠肝细胞中研究了对DEN诱导的凋亡产生抗性的基础机制。与野生型细胞相比，Clk / Clk细胞在DEN暴露前可以生物活性地激活DEN的代谢酶的mRNA水平和凋亡诱导因子均低于野生型细胞。 DEN暴露8h后p53和Ser15磷酸化的p53的积累在野生型细胞中可见，而在Clk / Clk细胞中则没有。 Caspase-3 / 7活性在DEN暴露24h期间在野生型细胞中升高，但在Clk / Clk细胞中没有升高。另外，对DEN诱导的Clk / Clk细胞凋亡的抗性影响细胞活力。这些研究表明，生物激活DEN的代谢酶的低表达水平和凋亡诱导因子会影响DEN诱导的Clk / Clk细胞凋亡的抗性，而Clock基因在DEN诱导的细胞毒性中起重要作用。

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