Zhou Wang, Chen Xi, Zhao Guolin, Xu Dengqiu, Jiang Zhenzhou, Zhang Luyong, Wang Tao
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.
Front Pharmacol. 2018 Oct 22;9:1179. doi: 10.3389/fphar.2018.01179. eCollection 2018.
Psoralen is a major component of the common traditional Chinese medicine (FP). In this study, we focused on psoralen to explore FP-induced hepatotoxicity and the underlying mechanisms. The acute oral median lethal dose of psoralen in ICR mice was determined to be 1,673 mg/kg. C57BL/6 mice were administered psoralen intragastrically at doses of 400 mg/kg or 800 mg/kg, and were sacrificed 24 h after treatment. Changes in various hepatotoxicity indicators demonstrated that psoralen can cause mild liver injury in mice. Psoralen inhibited the viability of normal human liver L02 cells by inducing S-phase arrest. In addition, psoralen in both the mouse livers and L02 cells upregulated cyclin E1 and p27 protein levels. The 2/3 partial hepatectomy mouse model was used to further explore the effects of psoralen on the liver regeneration and hepatocellular cycle arrest . The results showed that the decrease of liver regenerative and self-healing capabilities induced by hepatocellular cycle arrest may play an important role in the hepatotoxicity of psoralen. The further mechanism researches indicated that psoralen-induced hepatotoxicity was associated with inhibition of mTOR signalling pathway and mitochondrial injury; furthermore, MHY, an mTOR activator, partly alleviated the inhibition of mTOR and S-phase cycle arrest induced by psoralen in L02 cells. In conclusion, in this study we showed for the first time, that psoralen significantly induced liver injury in mice; the decrease of liver regenerative and compensatory capabilities induced by hepatocellular cycle arrest may play an important role in the progression of hepatotoxicity associated with the upregulation of cyclin E1 and p27, as well as the inhibition of mTOR signalling and mitochondrial injury. Our findings may contribute to the reduction of hepatotoxicity risk induced by
补骨脂素是常见中药补骨脂的主要成分。在本研究中，我们聚焦于补骨脂素，以探究补骨脂所致的肝毒性及其潜在机制。经测定，补骨脂素对ICR小鼠的急性经口半数致死剂量为1673 mg/kg。将C57BL/6小鼠以400 mg/kg或800 mg/kg的剂量灌胃给予补骨脂素，并在治疗24小时后处死。各种肝毒性指标的变化表明，补骨脂素可导致小鼠轻度肝损伤。补骨脂素通过诱导S期阻滞抑制正常人肝L02细胞的活力。此外，补骨脂素在小鼠肝脏和L02细胞中均上调了细胞周期蛋白E1和p27蛋白水平。采用2/3部分肝切除小鼠模型进一步探究补骨脂素对肝脏再生和肝细胞周期阻滞的影响。结果表明，肝细胞周期阻滞所致的肝脏再生和自我修复能力下降可能在补骨脂素的肝毒性中起重要作用。进一步的机制研究表明，补骨脂素诱导的肝毒性与mTOR信号通路的抑制和线粒体损伤有关；此外，mTOR激活剂MHY部分缓解了补骨脂素在L02细胞中诱导的mTOR抑制和S期周期阻滞。总之，在本研究中我们首次表明，补骨脂素可显著诱导小鼠肝损伤；肝细胞周期阻滞所致的肝脏再生和代偿能力下降可能在与细胞周期蛋白E1和p27上调、mTOR信号抑制及线粒体损伤相关的肝毒性进展中起重要作用。我们的研究结果可能有助于降低由……诱导的肝毒性风险
