以个体为中心的模型揭示曲格列酮介导的特异性药物诱导肝损伤的机制

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-08-06 DOI:10.1007/s00204-024-03833-z
Salomé Roux, Sara Cherradi, Hong Tuan Duong
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摘要

偶发性药物性肝损伤是一种罕见且不可预测的疾病。由于其发生与个体有关,破译其起始机制是一项艰巨的任务。因此,利用非以个体为中心的模型进行的研究可能会得出一般性的机理结论,但这并不一定是正确的。在此,我们使用以个体为中心的球形模型来分析曲格列酮介导的 iDILI 风险的启动机制。以个体为中心的球体模型是利用专有的细胞教育技术生成的。在生理条件下,这些培养球体包含肝细胞、肝星状细胞、活化的单核巨噬细胞和树突状细胞。我们发现,1 期和 2 期药物代谢酶是以个体依赖的方式被诱导的。然而,我们并没有观察到 DEMs 诱导与曲格列酮 (TGZ) 介导的 iDILI 风险有任何关联。我们分析了曲格列酮介导的 iDILI,发现一名 44 岁男性的 iDILI 风险与曲格列酮介导的自体巨噬细胞和树突状细胞抑制 IL-12 表达有关。我们进行了一项拯救实验,结果表明,用 TGZ 和重组 IL-12 处理这名 44 岁男性的球形细胞可抑制 iDILI 风险。我们在另一名有 iDILI 风险的 31 岁女性身上证实了这一机制。我们在此证明,以个体为中心的球形体是一种多功能模型,可以预测 iDILI 风险,并分析药物对活化巨噬细胞和树突状细胞的直接影响,从而揭示 iDILI 发生的启动机制。该模型为减轻 iDILI 风险的个性化策略开辟了前景。
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Uncovering the mechanism of troglitazone-mediated idiosyncratic drug-induced liver injury with individual-centric models

Idiosyncratic drug-induced liver injury is a rare and unpredictable event. Deciphering its initiating-mechanism is a hard task as its occurrence is individual dependent. Thus, studies that utilize models that are not individual-centric might drive to a general mechanistic conclusion that is not necessarily true. Here, we use the individual-centric spheroid model to analyze the initiating-mechanism of troglitazone-mediated iDILI risk. Individual-centric spheroid models were generated using a proprietary cell educating technology. These educated spheroids contain hepatocytes, hepatic stellate cells, activated monocyte-derived macrophages, and dendritic cells under physiological conditions. We show that phases 1 and 2 drug-metabolizing enzymes were induced in an individual-dependent manner. However, we did not observe any association of DEMs induction and troglitazone (TGZ)-mediated iDILI risk. We analyzed TGZ-mediated iDILI and found that a 44-year-old male showed iDILI risk that is associated with TGZ-mediated suppression of IL-12 expression by autologous macrophages and dendritic cells. We performed a rescue experiment and showed that treatment of spheroids from this 44-year-old male with TGZ and recombinant IL-12 suppressed iDILI risk. We confirmed the mechanism in another 31-year-old female with iDILI risk. We demonstrate here that individual-centric spheroid are versatile models that allow to predict iDILI risk and to analyze a direct effect of the drug on activated macrophages and dendritic cells to uncover the initiating-mechanism of iDILI occurrence. This model opens perspectives for a personalized strategy to mitigate iDILI risk.

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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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