Dynamic42 GmbH, Jena, Germany.
Institute of Biochemistry II, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
Sci Rep. 2023 Aug 16;13(1):13338. doi: 10.1038/s41598-023-40004-z.
Drug-induced liver injury induced by already approved substances is a major threat to human patients, potentially resulting in drug withdrawal and substantial loss of financial resources in the pharmaceutical industry. Trovafloxacin, a broad-spectrum fluoroquinolone, was found to have unexpected side effects of severe hepatotoxicity, which was not detected by preclinical testing. To address the limitations of current drug testing strategies mainly involving 2D cell cultures and animal testing, a three-dimensional microphysiological model of the human liver containing expandable human liver sinusoidal endothelial cells, monocyte-derived macrophages and differentiated HepaRG cells was utilized to investigate the toxicity of trovafloxacin and compared it to the structurally-related non-toxic drug levofloxacin. In the model, trovafloxacin elicited vascular and hepatocellular toxicity associated with pro-inflammatory cytokine release already at clinically relevant concentrations, whereas levofloxacin did not provoke tissue injury. Similar to in vivo, cytokine secretion was dependent on a multicellular immune response, highlighting the potential of the complex microphysiological liver model for reliably detecting drug-related cytotoxicity in preclinical testing. Moreover, hepatic glutathione depletion and mitochondrial ROS formation were elucidated as intrinsic toxicity mechanisms contributing to trovafloxacin toxicity.
已经批准的药物引起的肝损伤是人类患者的主要威胁，可能导致药物撤市和制药行业大量资金损失。曲伐沙星是一种广谱氟喹诺酮类药物，被发现具有严重肝毒性的意外副作用，这在临床前测试中并未检测到。为了解决当前药物测试策略的局限性，这些策略主要涉及 2D 细胞培养和动物测试，利用包含可扩展的人肝窦内皮细胞、单核细胞来源的巨噬细胞和分化的 HepaRG 细胞的人肝三维微生理模型来研究曲伐沙星的毒性，并将其与结构相关的无毒药物左氧氟沙星进行比较。在该模型中，曲伐沙星在临床相关浓度下引发与促炎细胞因子释放相关的血管和肝细胞毒性，而左氧氟沙星则不会引起组织损伤。与体内相似，细胞因子的分泌依赖于多细胞免疫反应，突出了复杂的微生理肝模型在临床前测试中可靠检测药物相关细胞毒性的潜力。此外，还阐明了肝谷胱甘肽耗竭和线粒体 ROS 形成是导致曲伐沙星毒性的内在毒性机制。
