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在人类和的原发性肝细胞中,由八种亚胺诱导的DNA损伤的比较

Ji-Eun Seo¹, Xiaobo He², Matthew Bryant²

¹Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA; Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.

Chemico-biological interactions

|May 4, 2025

概括

八种亚胺在人类和的细胞中引起DNA损伤. 的细胞显示出更高的损伤,但人类细胞具有更大的可变性,这表明代谢酶活性差异影响基因毒性.

科学领域:

毒理学毒理学毒理学
基因毒性测试是指基因毒性测试.
药物安全评估药物安全评估

背景情况:

人类药物中越来越多地发现N-尼托胺,造成突变致病和致癌风险.
之前的研究使用HepaRG细胞评估了基因毒性,因此需要对原始人体细胞进行进一步的研究.

研究的目的:

评估八种亚胺在原始人肝细胞 (PHHs) 和原始肝细胞 (PMHs) 中诱导的DNA损伤.
为了比较PHHs和PMHs之间的代谢酶表达和活性.
在PMH中分析DNA损伤和亡生物标志物.

主要方法:

彗星测定检测PHH和PMH暴露于八种尼托胺的DNA损伤.
对I阶段和II阶段代谢酶的基因表达分析.
酶活性测定. 酶活性测定.
西方斑对于DNA损伤和亡的生物标志物.

主要成果:

所有八种尼托胺都在PHH和PMH中诱导了显著的DNA损伤.
一般来说,PMHs比PHHs显示出更高的DNA损伤 (%尾巴DNA),除了NDMA.
与PMH相比,PHHs在基因表达,酶活性和DNA损伤反应方面表现出更大的个体间变异性.
来自PMHs和3D HepaRG球体的DNA损伤数据与PHH数据相对应得很好.
乙基存在可能会影响DNA损伤和亡途径中的蛋白质表达.

结论:

这项研究为八种尼托胺提供了与人类相关的基因毒性数据.
PHHs和PMHs之间基因毒性强度的差异可能与细胞染色体P450 (CYP) 酶活性的变化有关.
PMHs可以作为基因毒性评估的有价值模型,补充人类细胞研究.

关键词:

造成的DNA损伤是DNA损伤.亚胺酸盐的含量是多少主要的人类肝细胞主要的肝细胞是的肝细胞.

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