High-content imaging of human hepatic spheroids for researching the mechanism of duloxetine-induced hepatotoxicity.
High-content imaging of human hepatic spheroids for researching the mechanism of duloxetine-induced hepatotoxicity.
复制标题
人肝球高内涵成像研究度洛西汀肝毒性机制
DOI：
10.1038/s41419-022-05042-x
复制
发表时间：
2022-08-01
影响因子：
9
通讯作者：
Wang, Yunfang
中科院分区：
文献类型：
--
作者：
Liu, Juan;Li, Ruihong;Zhang, Tingting;Xue, Rui;Li, Tingting;Li, Zheng;Zhuang, Xiaomei;Wang, Qi;Chen, Yu Ann;Dong, Jiahong;Zhang, Youzhi;Wang, Yunfang
度洛西汀（DLX）已被批准用于成功治疗精神疾病，包括重度抑郁症、糖尿病神经病变、纤维肌痛和广泛性焦虑症。然而，由于 DLX 的使用带有制造商的肝毒性警告，考虑到它在许多药物性肝损伤 (DILI) 病例中的影响，因此不建议慢性肝病患者使用。在我们之前的研究中，我们开发了一种增强的人体模拟肝球体（EHS）成像模型系统，用于使用人肝癌细胞系HepaRG和粉碎的肝脏生物基质支架的支持来进行药物肝毒性评估，该系统证明了肝脏特异性功能的显着改善。在当前的研究中，我们能够使用这个稳健的模型来证明DLX-DILI是人类CYP450特异性的、代谢依赖性的、氧化应激触发的复杂肝损伤。对暴露于DLX的类器官的高内涵成像分析（HCA）表明，DLX中潜在的毒基团萘基环引发氧化应激，最终导致肝类器官中的线粒体功能障碍，反之亦然。此外，在暴露的 EHS 中还检测到 DLX 诱导的肝脂肪变性和胆汁淤积。我们还发现，一种新型化合物 S-071031B 用苯并间二氧杂环戊烯取代了 DLX 的萘环，通过减少氧化应激，显着降低了肝毒性。因此，我们最终提出与人类相关的 EHS 模型作为一个理想的、高度有效的系统，用于评估 DLX 诱导的肝毒性并探索体外相关机制。此外，HCA在功能性肝类器官上的应用在指导化合物结构修饰和优化以通过降低肝毒性来改善药物开发方面具有广阔的应用前景。
Duloxetine (DLX) has been approved for the successful treatment of psychiatric diseases, including major depressive disorder, diabetic neuropathy, fibromyalgia and generalized anxiety disorder. However, since the usage of DLX carries a manufacturer warning of hepatotoxicity given its implication in numerous cases of drug-induced liver injuries (DILI), it is not recommended for patients with chronic liver diseases. In our previous study, we developed an enhanced human-simulated hepatic spheroid (EHS) imaging model system for performing drug hepatotoxicity evaluation using the human hepatoma cell line HepaRG and the support of a pulverized liver biomatrix scaffold, which demonstrated much improved hepatic-specific functions. In the current study, we were able to use this robust model to demonstrate that the DLX-DILI is a human CYP450 specific, metabolism-dependent, oxidative stress triggered complex hepatic injury. High-content imaging analysis (HCA) of organoids exposed to DLX showed that the potential toxicophore, naphthyl ring in DLX initiated oxidative stress which ultimately led to mitochondrial dysfunction in the hepatic organoids, and vice versa. Furthermore, DLX-induced hepatic steatosis and cholestasis was also detected in the exposed EHSs. We also discovered that a novel compound S-071031B, which replaced DLX’s naphthyl ring with benzodioxole, showed dramatically lower hepatotoxicities through reducing oxidative stress. Thus, we conclusively present the human-relevant EHS model as an ideal, highly competent system for evaluating DLX induced hepatotoxicity and exploring related mechanisms in vitro. Moreover, HCA use on functional hepatic organoids has promising application prospects for guiding compound structural modifications and optimization in order to improve drug development by reducing hepatotoxicity.
登录
查看更多内容
影响因子：
25.7
作者：
Leung, Tung-Ming;Nieto, Natalia
通讯作者：
Nieto, Natalia
影响因子：
2.4
作者：
Lin ND;Norman H;Regev A;Perahia DG;Li H;Chang CL;Dore DD
通讯作者：
Dore DD
影响因子：
11.4
作者：
Gille A;Turkistani A;Tsitsipatis D;Hou X;Tauber S;Hamann I;Urban N;Erler K;Steinbrenner H;Klotz LO
通讯作者：
Klotz LO
影响因子：
22.8
作者：
Carvalho, Andre F.;Sharma, Manu S.;Fava, Giovanni A.
通讯作者：
Fava, Giovanni A.
影响因子：
6.1
作者：
Rebelo, Sofia P.;Costa, Rita;Alves, Paula M.
通讯作者：
Alves, Paula M.