在体外肝脏新陈代谢输入参数支持从β-同位素烯糖醇甲基乙醇中形成甲基酸的毒动学模拟
Sophie Werner1,2,3, Lucie Hegg3,4, Nancy B Hopf3,4
1School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland.
Pharmacology research & perspectives
|December 10, 2024
概括
这项研究使用体外肝脏模型量化烯基醇甲基乙醇β-异构体代谢. 毒动力学模型准确地预测了代谢物度,支持3D HepaRG细胞进行长期暴露评估.
科学领域:
- 毒理学 毒理学 毒理学
- 代谢研究 代谢研究
- 在 Vitro 模型中
背景情况:
- 乙醇乙烯 (PGEs) 是一种常见的有机溶剂.
- PGEs的β-异构体的新陈代谢可以产生有害的代谢产物.
- 对于许多PGEs存在有限的动力数据,这阻碍了暴露评估.
研究的目的:
- 为了在体外生成甘甲基乙β-异构体 (β-PGME) 和其代谢物2-MPA的肝脏内在清除数据.
- 将这些数据整合到一个in silico毒动力学 (TK) 模型中.
- 评估3DHepaRG细胞和S9肝部份对β-PGME代谢的预测能力.
主要方法:
- 使用了体外3DHepaRG细胞培养和人类S9肝脏部分.
- 评估了酒精脱酶 (ADH) 和化脱酶 (ALDH) 的活性.
- 在TK模型中测量了2-MPA的形成和集成的空隙值.
主要成果:
- 在HepaRG和S9系统中表现出ADH和ALDH活性和2-MPA形成 (缓慢至中速).
- 该TK模型成功地预测了尿液中的2-MPA度,其误差为两倍.
- 这两种体外系统都可靠地预测了β-PGME的肝脏清除.
结论:
- 3D HepaRG 细胞和 S9 分数可以可靠地预测β-PGME的肝清除.
- 3D HepaRG 模型为长期代谢研究提供了持续的代谢能力.
- 这项研究为评估PGE暴露和毒性提供了关键的动力学数据.
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