Cytokine-associated drug toxicity in human hepatocytes is associated with signaling network dysregulation.
Cytokine-associated drug toxicity in human hepatocytes is associated with signaling network dysregulation.
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人肝细胞中与细胞因子相关的药物毒性与信号网络失调有关。
DOI：
10.1039/b926287c
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发表时间：
2010-07
影响因子：
--
通讯作者：
Lauffenburger, Douglas A.
中科院分区：
文献类型：
--
作者：
Cosgrove, Benjamin D.;Alexopoulos, Leonidas G.;Hang, Ta-chun;Hendriks, Bart S.;Sorger, Peter K.;Griffith, Linda G.;Lauffenburger, Douglas A.
特异质药物肝毒性是药物开发中的一个主要问题，这是由于标准临床前毒性评估的预测能力差以及对其潜在机制的了解有限。在动物模型中的发现表明，在同时存在炎性细胞因子信号传导的情况下，许多具有特异质肝毒性的药物在人体中的不良反应可以重现。根据这些观察结果，我们最近开发了一种体外药物/炎性细胞因子联合治疗方法，该方法可以在培养的原代人肝细胞中重现临床药物肝毒性特征-特别是特异质药物。这些观察结果表明，药物诱导的应激可能与细胞因子信号转导相互作用，诱导肝细胞毒性，但肝细胞信号转导机制，这些相互作用的了解甚少。在这里，我们收集了来自多个人类供体的培养肝细胞中的高通量磷蛋白信号传导和细胞毒性测量值，这些肝细胞用肝毒性药物（例如曲伐他汀、克拉霉素）和细胞因子（肿瘤坏死因子-α、干扰素-γ、白细胞介素-1 α和白细胞介素-6）联合治疗。我们证明，通过正交偏最小二乘回归（OPLSR）建模这些信号响应数据，药物/细胞因子肝细胞毒性是综合控制的四个关键信号通路：Akt，p70 S6激酶，MEK-ERK，和p38-HSP 27。该模型预测，并且实验研究证实，MEK-ERK和p38-HSP 27通路在药物/细胞因子肝细胞毒性协同作用中贡献促死亡信号传导影响。此外，我们的四途径OPLSR模型成功预测了不同人类供体的药物/细胞因子肝细胞毒性，即使信号传导和细胞毒性反应都是高度供体特异性的。我们的研究结果强调了激酶信号在药物/细胞因子肝细胞毒性协同作用中的关键作用，并揭示了肝细胞毒性反应受多途径信号网络平衡的控制。
Idiosyncratic drug hepatotoxicity is a major problem in pharmaceutical development due to poor prediction capability of standard preclinical toxicity assessments and limited knowledge of its underlying mechanisms. Findings in animal models have shown that adverse effects of numerous drugs with idiosyncratic hepatotoxicity in humans can be reproduced in the presence of coincident inflammatory cytokine signaling. Following these observations, we have recently developed an in vitro drug/inflammatory cytokine co-treatment approach that can reproduce clinical drug hepatotoxicity signatures -- particularly for idiosyncratic drugs -- in cultured primary human hepatocytes. These observations have suggested that drug-induced stresses may interact with cytokine signaling to induce hepatic cytotoxicity, but the hepatocyte signaling mechanisms governing these interactions are poorly understood. Here, we collect high-throughput phosphoprotein signaling and cytotoxicity measurements in cultured hepatocytes, from multiple human donors, treated with combinations of hepatotoxic drugs (e.g. trovafloxacin, clarithromycin) and cytokines (tumor necrosis factor-α, interferon-γ, interleukin-1α, and interleukin-6). We demonstrate, through orthogonal partial least-squares regression (OPLSR) modeling of these signal-response data, that drug/cytokine hepatic cytotoxicity is integratively controlled by four key signaling pathways: Akt, p70 S6 kinase, MEK–ERK, and p38–HSP27. This modeling predicted, and experimental studies confirmed, that the MEK–ERK and p38–HSP27 pathways contribute pro-death signaling influences in drug/cytokine hepatic cytotoxicity synergy. Further, our four-pathway OPLSR model produced successful prediction of drug/cytokine hepatic cytotoxicities across different human donors, even though signaling and cytotoxicity responses were both highly donor-specific. Our findings highlight the critical role of kinase signaling in drug/cytokine hepatic cytotoxicity synergies and reveal that hepatic cytotoxicity responses are governed by multi-pathway signaling network balance.
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DOI：
10.1124/jpet.107.122069
发表时间：
2007-08
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Deng X;Luyendyk JP;Zou W;Lu J;Malle E;Ganey PE;Roth RA
通讯作者：
Roth RA
影响因子：
4.4
作者：
Kemp, Melissa L.;Wille, Lucia;Lauffenburger, Douglas A.
通讯作者：
Lauffenburger, Douglas A.
影响因子：
2.4
作者：
Bylesjo, Max;Rantalainen, Mattias;Trygg, Johan
通讯作者：
Trygg, Johan
影响因子：
3.8
作者：
Cosgrove, Benjamin D.;King, Bracken M.;Lauffenburger, Douglas A.
通讯作者：
Lauffenburger, Douglas A.
影响因子：
2.8
作者：
Cosgrove, Benjamin D.;Griffith, Linda G.;Lauffenburger, Douglas A.
通讯作者：
Lauffenburger, Douglas A.