罗利西丁类类化合物拉西奥卡因在试验室中损害了细胞周期的进展
Stefanie Hessel-Pras1, Marlena Beckschulte2, Antonia Peters2
1Department of Chemical and Product Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589, Berlin, Germany. stefanie.hessel-pras@bfr.bund.de.
Archives of toxicology
|September 16, 2025
概括
1,2-不和罗利胺类化合物 (PAs) 通过损害细胞循环进展而导致肝损伤. 拉西奥卡,一种PA,诱导DNA损伤和肝细胞中的G2逮捕,导致基因组不稳定.
科学领域:
- 毒理学 毒理学 毒理学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 1,2-不和罗利胺类化合物 (PAs) 是已知的肝毒素.
- 暴露于PA可以导致细胞循环受损,导致肝损伤.
研究的目的:
- 研究拉西奥卡 (PA) 对人类CYP3A4过度表达细胞系细胞周期进展的影响.
- 阐明PA诱导的细胞周期停止和肝毒性背后的分子机制.
主要方法:
- 细胞活力测试,流细胞计和显微镜被用于分析细胞周期进展和形态学.
- 研究了细胞周期调节蛋白的不同基因表达和蛋白质酸化模式.
- 在中国仓鼠肺纤维细胞 (V79) 和人类肝细胞母细胞瘤 (HepG2) 细胞系上进行了过度表达人类CYP3A4.4的实验.
主要成果:
- 拉西奥卡因以度依赖的方式降低了细胞活力.
- 暴露于拉西奥卡宾导致细胞和细胞核大小增加以及G2/M阶段细胞的积累.
- 基因表达分析显示细胞循环调节者的水平发生变化 (例如,WEE1减少,CHEK1增加,PAK1增加,ATM增加).
- 蛋白质酸化数据表明诱导DNA损伤反应和晚期G2停止.
结论:
- 拉西奥卡宾会影响细胞循环的进展,诱导G2停止.
- 观察到的效应与lasiocarpine的代谢激活相关,并且可能涉及DNA adduct的形成.
- 由PA诱导的细胞循环损伤会破坏细胞平衡,并导致基因组不稳定,导致肝毒性.
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