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一个增强的新陈代谢协议用于哺乳动物细胞中N-氨胺的体外基因毒性评估

M E Geijer¹, A M Gernaat¹, N Moelijker¹

¹Toxys B.V., Oegstgeest, the Netherlands.

Environmental and molecular mutagenesis

|March 28, 2025

概括

尼胺 (N-Nitrosamines,简称NAs) 是药品中可能存在的致癌物. 一个增强的代谢协议改进了使用ToxTracker的哺乳动物细胞中NAs的体外基因毒性测试.

科学领域:

毒理学毒理学毒理学
遗传学是一个遗传学.
药理学药理学是指药理学的学科.

背景情况:

尼胺 (N-Nitrosamines,NAs) 是可能的人类致癌物,并作为药品中的杂质被发现,引起了健康问题.
代谢激活是NA变异性所必需的,但使用标准S9肝提取物进行体外代谢往往对哺乳动物细胞遗传毒性测定无效.

研究的目的:

优化哺乳动物细胞中N-尼托拉胺 (NA) 的体外代谢协议.
通过优化方案和ToxTracker测定来评估各种NA的基因毒性潜力.

主要方法:

开发和优化了一个增强代谢协议 (EMP) 使用子S9肝提取物用于体外NA暴露.
利用ToxTracker试验,一种新的方法方法 (NAM),在EMP条件下评估NAs的基因毒性.
通过一系列已知变异性和非变异性NAs验证了EMP,包括NDMA,NDEA和NPRO.

主要成果:

增强代谢协议 (EMP) 与标准协议相比,增加了N-二甲基胺 (NDMA) 的基因毒性强度约200倍.
在使用EMP和毒素追踪器测试的7种突变性NA中,有6种被证实具有基因毒性.
两种NAs,N-nitrosobupropion (NBuPRO) 和N-nitrosoproline (NPRO),已被证实是无变异性的.

结论:

优化的增强代谢协议 (EMP) 在体外显著改善了NA基因毒性的检测.
结合EMP和ToxTracker试验,表明了在哺乳动物细胞中对NA相关的基因毒性进行强有力的研究的潜力.
这种方法有助于评估与制药中的NA杂质相关的健康风险.

关键词:

它们是N-氨酸胺.毒素追踪器毒素追踪器遗传毒性遗传毒性遗传毒性遗传毒性杂质杂质是指杂质的杂质.在体外代谢过程中的代谢.

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