Li Jia, Shen Feihai, Guan Cuiwen, Wang Wenwen, Sun Xiaozhe, Fu Xinlu, Huang Min, Jin Jing, Huang Zhiying
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China; Pharmaceutical Department, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
PLoS One. 2014 Jul 2;9(7):e100685. doi: 10.1371/journal.pone.0100685. eCollection 2014.
Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF), has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2) in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN), attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.
雷公藤甲素是雷公藤(Tripterygium wilfordii Hook f.,TWHF)的主要活性成分,具有广泛的药理活性。然而,雷公藤甲素的毒性,尤其是肝毒性,限制了其临床应用。雷公藤甲素的肝毒性尚未得到充分表征。本研究的目的是探讨NF-E2相关因子2(Nrf2)在雷公藤甲素诱导的毒性中的作用,以及Nrf2的激活是否可以预防雷公藤甲素诱导的肝毒性。结果表明,雷公藤甲素在HepG2细胞中引起氧化应激和细胞损伤,这些毒性作用可因Nrf2敲低而加剧,或因Nrf2过表达而抵消。用典型的Nrf2激动剂萝卜硫素(SFN)处理可减轻雷公藤甲素诱导的BALB/C小鼠肝功能障碍、结构损伤、谷胱甘肽耗竭和抗氧化酶减少。此外,SFN对雷公藤甲素诱导的肝损伤的保护作用与Nrf2及其下游靶点的激活有关。总体而言,这些结果表明Nrf2激活可预防雷公藤甲素诱导的肝毒性。