Nrf2/ARE信号通路保护奥沙利铂所致小鼠肝毒性

doi:10.5246/jcps.2017.10.080

中国药学(英文版) ›› 2017, Vol. 26 ›› Issue (10): 709-718.DOI: 10.5246/jcps.2017.10.080

Nrf2/ARE信号通路保护奥沙利铂所致小鼠肝毒性

何柳¹, 徐江丽¹, 郭丽梅², 阙琳玲¹, 尹文琤³, 曹宝山³, 余四旺^1*

1. 北京大学医学部药学院化学生物学系, 北京 100191
2. 北京大学医学部第三医院基础医学院病理系, 北京 100191
3. 北京大学第三医院化疗与放射科, 北京 100191

收稿日期:2017-05-19 修回日期:2017-06-24 出版日期:2017-10-31 发布日期:2017-07-15
通讯作者: Tel.: +86-010-82805140, E-mail: swang_yu@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81272468, 81372266, 91429305 and 21001011) and WU JIEPING Medical Foundation (Grant No. 320.6750.12196).

Nrf2/ARE signaling protects against oxaliplatin-induced hepatotoxicity in mice

Liu He¹, Jiangli Xu¹, Limei Guo², Linling Que¹, Wencheng Yin³, Baoshan Cao³, Siwang Yu^1*

1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Department of Pathology, School of Basic Medical Sciences, Third Hospital, Peking University Health Science Center, Beijing 100191, China
3. Department of Chemotherapy and Radiation, Peking University Third Hospital, Beijing 100191, China

Received:2017-05-19 Revised:2017-06-24 Online:2017-10-31 Published:2017-07-15
Contact: Tel.: +86-010-82805140, E-mail: swang_yu@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81272468, 81372266, 91429305 and 21001011) and WU JIEPING Medical Foundation (Grant No. 320.6750.12196).

摘要/Abstract

摘要：

核因子E2相关因子2 (Nrf2)调控一系列由抗氧化反应元件(ARE)驱动的应激和代谢调控相关基因的表达。目前普遍认为癌细胞中的Nrf2/ARE信号通路与放化疗耐药密切相关, 但缺乏Nrf2对化疗毒性如肝毒性影响的相关研究。在本研究中, 首先利用来源于Nrf2敲除和野生小鼠的原代胚胎成纤维细胞(MEFs)及肝细胞检测9种化疗药物的细胞毒活性。结果表明, 奥沙利铂对肝细胞的细胞毒明显高于MEFs, 且在Nrf2缺失的肝细胞中显著加剧。与野生型小鼠比, 奥沙利铂处理导致Nrf2^–/–小鼠出现明显的脂肪性肝炎和严重的肝损伤, 主要表现为血清转氨酶和胆红素显著升高, 脂肪积聚增加, 炎症浸润和淤血。Nrf2缺失导致肝毒性增加可能是由抗氧化基因表达减少和谷胱甘肽消耗引起的。我们的研究结果表明, 奥沙利铂所致肝毒性显著受Nrf2水平影响, 因此Nrf2可作为潜在的生物标志物来预测或靶标来预防奥沙利铂所致的肝毒性。

关键词: Nrf2, 奥沙利铂, 肝毒性, Nrf2-/-小鼠

Abstract:

Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the expression of a wide array of antioxidant response element (ARE)-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts (MEFs) and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2^–/–mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-inducedhepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.

Key words: Nrf2, Oxaliplatin, Hepatotoxicity, Nrf2-/- mice

中图分类号:

R916.3

Supporting:

何柳, 徐江丽, 郭丽梅, 阙琳玲, 尹文琤, 曹宝山, 余四旺. Nrf2/ARE信号通路保护奥沙利铂所致小鼠肝毒性[J]. 中国药学(英文版), 2017, 26(10): 709-718.

Liu He, Jiangli Xu, Limei Guo, Linling Que, Wencheng Yin, Baoshan Cao, Siwang Yu. Nrf2/ARE signaling protects against oxaliplatin-induced hepatotoxicity in mice[J]. Journal of Chinese Pharmaceutical Sciences, 2017, 26(10): 709-718.

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Nrf2/ARE信号通路保护奥沙利铂所致小鼠肝毒性

Nrf2/ARE signaling protects against oxaliplatin-induced hepatotoxicity in mice

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