肝芯片模型和应用在药物的基因毒性和变异性预测中的应用
B Kopp1, A Khawam1, K Di Perna1
1Charles River Laboratories Montreal ULC, Canada.
概括
这项研究开发了一种无动物肝芯片模型来评估基因毒性,成功识别了来自各种化学物质的DNA损伤和突变.
科学领域:
- 毒理学 毒理学 毒理学
- 生物技术是生物技术.
- 药品安全 药品安全
背景情况:
- 目前的基因毒性测试缺乏全面的体外/体内系统,用于临床前药物安全.
- 需要精简,无动物方法,具有强大的人类代谢活动.
研究的目的:
- 开发一种用于综合性基因毒性评估的新型体外模型.
- 为药物安全性评估创建一个没有动物的系统,并整合了人类代谢活动.
主要方法:
- 在微生理系统 (MPS) 中使用初级人类肝细胞或HepaRG细胞创建了肝芯片 (LOC) 模型.
- LOC模型与TK6细胞共同培养,用于分析DNA链断裂,染色体损伤 (微核分析) 和突变 (双重测序).
- 该系统暴露于直接的基因毒剂 (MMS,EMS) 和需要代谢激活的基因毒剂 (B[a]P,CP).
主要成果:
- 通过各种生化评估,LOC-MPS系统证明了功能代谢能力.
- 对MMS和EMS的所有终点观察到基因毒性.
- 通过观察CP的微核和突变频率增加,以及B[a]P的%尾巴DNA,证实了代谢激活.
结论:
- 芯片上的肝脏微生理系统 (LOC-MPS) 是一个有前途的工具,用于在体外基因毒剂危害识别.
- 这项原则证明研究突出了简化,无动物基因毒性测试方法的潜力.
- 对于某些基因毒性物质 (如B[a]P) 可能需要进一步优化,以完全捕捉所有基因毒性终点.
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