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在初级人类肝细胞3D球形体中,OCT1 (SLC22A1) 载体动力学和调节
Evgeniya Mickols1, Alina Meyer1, Niklas Handin1
1Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Scientific reports
|July 27, 2024
概括
三维初级人类肝细胞球形有效模拟药物输送器动力学和调节. 有机阴离子载体1 (OCT1) 功能在这些球体中保持稳定,支持它们在药物发现中的使用.
科学领域:
- 肝细胞生物学 肝细胞生物学
- 毒品运输商研究研究
- 在体外毒理学.
背景情况:
- 初级人类肝细胞的3D球体 (3D PHH) 保持差异化的表型和代谢功能.
- 3D PHH越来越多地用于肝脏平衡研究和体外到体外抽取 (IVIVE) 在药物发现中.
- 然而,3D PHH中的药物载体动力学和调节仍未得到充分研究.
研究的目的:
- 在3D PHH中评估有机阴离子载体1 (OCT1/SLC22A1) 的动力学和长期调节.
- 验证3D PHH作为研究载体功能和对异生菌的反应的模型.
主要方法:
- 在个体3D PHH中使用光基质ASP+和抑制剂研究了OCT1动力学.
- 在对3D PHH进行了为期七天的异生物治疗后,评估了OCT1蛋白表达和功能.
- 利用全球蛋白质组分析来监测肝脏表型和其他药物代谢蛋白的变化.
主要成果:
- 在3D PHH中,OCT1表现出完全功能性的动力学,Km为14±4.0μM.
- 已知的OCT1抑制剂减少了ASP+吸收的35-52%.
- 在激活核受体信号或暴露于炎症/毒性化合物时,OCT1的功能和表达保持稳定.
结论:
- 3D PHH球体表达生理上相关的,完全活跃的OCT1,使准确的动力学研究成为可能.
- 在影响其他药物载体和酶的关键代谢通路的激活过程中,OCT1表现出稳定性.
- 这些发现扩大了3D PHH对综合药物载体和代谢研究的实用性.
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