State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Department of Pharmacy, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, China.
Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410011, China.
Toxicol Lett. 2023 Apr 15;379:67-75. doi: 10.1016/j.toxlet.2023.03.011. Epub 2023 Mar 28.
This study was to investigate the potential mechanism of triptolide-induced hepatotoxicity. We found a novel and variable role of p53/Nrf2 crosstalk in triptolide-induced hepatotoxic process. Low doses of triptolide led to adaptive stress response without obvious toxicity, while high levels of triptolide caused severe adversity. Correspondingly, at the lower levels of triptolide treatment, nuclear translocation of Nrf2 as well as its downstream efflux transporters multidrug resistance proteins and bile salt export pump expressions were significantly enhanced, so did p53 pathways that also increased; at a toxic concentration, total and nuclear accumulations of Nrf2 decreased, while p53 showed an obvious nuclear translocation. Further studies showed the cross-regulation between p53 and Nrf2 after different concentrations of triptolide treatment. Under mild stress conditions, Nrf2 induced p53 highly expression to maintain the pro-survival outcome, while p53 showed no obvious effect on Nrf2 expression and transcriptional activity. Under high stress conditions, the remaining Nrf2 as well as the largely induced p53 mutually inhibited each other, leading to a hepatotoxic result. Nrf2 and p53 could physically and dynamically interact. Low levels of triptolide enhanced the interaction between Nrf2 and p53. Reversely, p53/Nrf2 complex dissociated at high levels of triptolide treatment. Altogether, variable p53/Nrf2 crosstalk contributes to triptolide-induced self-protection and hepatotoxicity, modulation of which may be a potential strategy for triptolide-induced hepatotoxicity intervention.
这项研究旨在探讨雷公藤内酯醇诱导肝毒性的潜在机制。我们发现了 p53/Nrf2 相互作用在雷公藤内酯醇诱导的肝毒性过程中的一个新的、可变的作用。低剂量的雷公藤内酯醇导致适应性应激反应，没有明显的毒性，而高水平的雷公藤内酯醇则导致严重的逆境。相应地，在较低水平的雷公藤内酯醇处理时，Nrf2 的核转位以及其下游流出转运蛋白多药耐药蛋白和胆汁盐输出泵的表达明显增强，p53 途径也增加；在毒性浓度下，Nrf2 的总核积累减少，而 p53 则明显核转位。进一步的研究表明，不同浓度的雷公藤内酯醇处理后，p53 和 Nrf2 之间存在交叉调节。在轻度应激条件下，Nrf2 诱导 p53 高度表达以维持生存结果，而 p53 对 Nrf2 表达和转录活性没有明显影响。在高应激条件下，剩余的 Nrf2 以及大量诱导的 p53 相互抑制，导致肝毒性结果。Nrf2 和 p53 可以物理和动态相互作用。低水平的雷公藤内酯醇增强了 Nrf2 和 p53 之间的相互作用。相反，在高水平的雷公藤内酯醇处理时，p53/Nrf2 复合物解离。总之，可变的 p53/Nrf2 相互作用导致雷公藤内酯醇诱导的自我保护和肝毒性，调节这种相互作用可能是雷公藤内酯醇诱导肝毒性干预的潜在策略。
