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

doi:10.5246/jcps.2017.10.080

Journal of Chinese Pharmaceutical Sciences ›› 2017, Vol. 26 ›› Issue (10): 709-718.DOI: 10.5246/jcps.2017.10.080

• Original articles • Previous Articles Next Articles

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).

Abstract

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

CLC Number:

R916.3

Supporting:

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 signaling protects against oxaliplatin-induced hepatotoxicity in mice

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