Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China; Department of Pharmacy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Key Laboratory of Assessment of Clinical Drugs Risk and Individual Application, Beijing 100730, China.
Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China.
Toxicol Lett. 2021 May 15;342:85-94. doi: 10.1016/j.toxlet.2021.02.008. Epub 2021 Feb 16.
Triptolide (TP), an active component of Tripterygium wilfordii Hook. F, has been widely used in China for treating autoimmune and inflammatory diseases, and has also been validated by modern science and developed as a candidate anti-cancer treatment. However, liver toxicity of TP has seriously hindered its use and development, the clinical features and primary toxicological mechanism have been unclear. Considering the major target regulation mechanism of TP is the suppression of global transcription regulated by RNAPII, which is closed related with the detoxification of drugs. This paper tries to verify the synergistic liver injury and its mechanism of TP when co-administered with CYP3A4 substrate drug. The experiments showed that TP dose-dependently blocked transcriptional activation of CYP3A4 in both hPXR and hPXR-CYP3A4 reporter cell lines, lowered the mRNA and protein expression of PXR target genes such as CYP3A1, CYP2B1, and MDR1, and inhibited the functional activity of CYP3A in a time- and concentration-dependent manner in sandwich-cultured rat hepatocytes (SCRH) and female Sprague-Dawley (f-SD) rats. Furthermore, TP combined with atorvastatin (ATR), the substrate of CYP3A4, synergistically enhanced hepatotoxicity in cultured HepG2 and SCRH cells (CI is 0.38 and 0.29, respectively), as well as in f-SD rats, with higher exposure levels of both drugs. These results clearly indicate that TP inhibits PXR-mediated transcriptional activation of CYP3A4, leading to a blockade on the detoxification of itself and ATR, thereby greatly promoting liver injury. This study may implies the key cause of TP related liver injury and provides experimental data for the rational use of TP in a clinical scenario.
雷公藤红素（TP）是雷公藤（Tripterygium wilfordii Hook. F）的一种活性成分，在中国被广泛用于治疗自身免疫和炎症性疾病，也得到了现代科学的验证，并被开发为一种候选的抗癌治疗药物。然而，TP 的肝毒性严重阻碍了其应用和发展，其临床特征和主要毒性机制尚不清楚。鉴于 TP 的主要靶标调控机制是抑制由 RNAPII 调控的全局转录，这与药物解毒密切相关。本文试图验证 TP 与 CYP3A4 底物药物联合使用时的协同肝损伤及其机制。实验表明，TP 剂量依赖性地阻断了 hPXR 和 hPXR-CYP3A4 报告细胞系中 CYP3A4 的转录激活，降低了 PXR 靶基因如 CYP3A1、CYP2B1 和 MDR1 的 mRNA 和蛋白表达，并以时间和浓度依赖的方式抑制了 SCRH 中的 CYP3A 功能活性。在雌性 Sprague-Dawley (f-SD) 大鼠中。此外，TP 与阿托伐他汀（ATR）联合使用，ATR 是 CYP3A4 的底物，协同增强了培养的 HepG2 和 SCRH 细胞（CI 分别为 0.38 和 0.29）以及 f-SD 大鼠的肝毒性，两药的暴露水平均较高。这些结果清楚地表明，TP 抑制了 PXR 介导的 CYP3A4 转录激活，导致自身和 ATR 的解毒作用受阻，从而大大促进了肝损伤。本研究可能提示了 TP 相关肝损伤的关键原因，并为 TP 在临床应用中的合理使用提供了实验数据。
