在试验室模型中,人类肝脏和脏中的转录组变化和线粒体毒性对急性和重复剂量治疗的反应
Tamara Meijer1, Bas Ter Braak2, Liesanne Loonstra-Wolters2
1Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands.
概括
布雷奎纳是一种DHODH抑制剂,在人体细胞中表现出差异性毒性. 细胞比肝细胞更敏感,特别是在重复暴露时,会影响线粒体呼吸.
科学领域:
- 药理学 药理学是指药理学的学科.
- 毒理学 毒理学 毒理学
- 细胞生物学 细胞生物学
背景情况:
- 布雷奎纳是一种强效的二基酸脱酶 (DHODH) 抑制剂,用于抗癌,免疫抑制和抗病毒应用.
- 布雷奎纳的毒性概况仍然不完全理解,需要进一步研究细胞反应.
研究的目的:
- 为了研究原发性人类肝细胞 (PHH) 和脏近位管状上皮细胞 (RPTEC/TERT1) 对素暴露的差异性细胞反应.
- 为了评估单次与重复的布雷奎纳暴露对细胞毒性和压力路径的影响.
主要方法:
- 暴露PHH和RPTEC/TERT1细胞于brequinar (一次24小时暴露高达100μM;重复5天暴露在0.3,3和20μM).
- 转录组分析以评估细胞反应,包括药物代谢和压力路径.
- 评估RPTEC/TERT1细胞中的线粒体呼吸.
主要成果:
- 与RPTEC/TERT1细胞相比,PHH对布雷奎纳的敏感性较低,有诱导药物代谢酶 (CYP1A,CYP3A) 的证据表明解毒.
- 这两种细胞类型在暴露于布雷奎纳时都显示出应激反应途径 (未折叠的蛋白质反应,Nrf2,p53,炎症) 的调节.
- RPTEC/TERT1细胞表现出对重复暴露布雷基纳的敏感性增加,即使在低度 (0.3μM) 中,并且在暴露24小时后线粒体呼吸受损.
结论:
- 布雷奎纳在人类肝脏和细胞中诱导差异性毒性,细胞更容易受到影响.
- 重复暴露方案对于准确评估布雷奎纳的体外毒性至关重要,特别是在细胞中.
- 布雷奎纳对线粒体呼吸和压力通路的影响需要进一步调查其制药开发.
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