Rentschler Simone, Doss Sandra, Kaiser Lars, Weinschrott Helga, Kohl Matthias, Deigner Hans-Peter, Sauer Martin
Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Straße 17, 78054 VS-Schwenningen, Germany.
Fraunhofer Institute IZI (Leipzig), Department Rostock, Schillingallee 68, 18057 Rostock, Germany.
Int J Mol Sci. 2024 Dec 23;25(24):13739. doi: 10.3390/ijms252413739.
Recent research has concentrated on the development of suitable in vitro cell models for the early identification of hepatotoxicity during drug development in order to reduce the number of animal models and to obtain a better predictability for hepatotoxic reactions in humans. The aim of the presented study was to identify translational biomarkers for acute liver injury in human patients that can serve as biomarkers for hepatocellular injury in vivo and in vitro in simple cell models. Therefore, 188 different metabolites from patients with acute-on-chronic liver failure before and after liver transplantation were analyzed with mass spectrometry. The identified potential metabolic biomarker set, including acylcarnitines, phosphatidylcholines and sphingomyelins, was used to screen primary and permanent hepatocyte culture models for their ability to model hepatotoxic responses caused by different drugs with known and unknown hepatotoxic potential. The results obtained suggest that simple in vitro cell models have the capability to display metabolic responses in biomarkers for liver cell damage in course of the treatment with different drugs and therefore can serve as a basis for in vitro models for metabolic analysis in drug toxicity testing. The identified metabolites should further be evaluated for their potential to serve as a metabolic biomarker set indicating hepatocellular injury in vitro as well as in vivo.
最近的研究集中在开发合适的体外细胞模型，以便在药物研发过程中早期识别肝毒性，从而减少动物模型的使用数量，并提高对人类肝毒性反应的预测能力。本研究的目的是确定人类急性肝损伤的转化生物标志物，这些标志物可在简单细胞模型中作为体内和体外肝细胞损伤的生物标志物。因此，对188例慢性肝衰竭急性发作患者在肝移植前后的不同代谢物进行了质谱分析。所确定的潜在代谢生物标志物集，包括酰基肉碱、磷脂酰胆碱和鞘磷脂，用于筛选原代和永生化肝细胞培养模型模拟由具有已知和未知肝毒性潜力的不同药物引起的肝毒性反应的能力。所得结果表明，简单的体外细胞模型有能力在不同药物治疗过程中展示肝细胞损伤生物标志物的代谢反应，因此可作为药物毒性测试中代谢分析体外模型的基础。所确定的代谢物应进一步评估其作为代谢生物标志物集在体外和体内指示肝细胞损伤的潜力。
