Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, PR China; Taian City Central Hospital, Taian, 271000, PR China.
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, PR China.
J Ethnopharmacol. 2021 Feb 10;266:113421. doi: 10.1016/j.jep.2020.113421. Epub 2020 Oct 3.
Irinotecan (CPT-11) is a valuable chemotherapeutic compound, but its use is associated with severe diarrhea in some patients. The CPT-11 prodrug is converted into the active 7-ethyl-10-hydroxycamptothecin (SN-38) metabolite, which can then be retained for extended periods in the intestine, leading to the onset of diarrhea and related symptoms. Banxia Xiexin Decoction (BXD) is commonly employed for the treatment of gastroenteritis in traditional Chinese medicine (TCM), and in clinical settings, it is used to prevent diarrhea in patients undergoing CPT-11 treatment. To date, however, there have been no studies specifically examining which components of BXD can alleviate the gastrointestinal symptoms associated with CPT-11 administration.
This study aimed to identify the main herbal components of BXD associated with protection against CPT-11-induced intestinal toxicity in a murine model system.
SN-38 levels were measured by UPLC-ESI-MS/MS in samples collected from mice subjected to CPT-11-induced diarrhea that had been administered BXD or different components thereof. Pearson correlation and Grey relational analyses were then used to explore spectrum-effect relationships between reductions in intestinal SN-38 levels and specific chemical fingerprints in samples from mice administered particular combinations of BXD component herbs.
We found that different herbal combinations were associated with significant differences in intestinal SN-38 reductions in treated mice. Our spectrum-effect analysis revealed that BXD components including chrysin 6-C-arabinoside-8-C-glucoside, coptisine, hydroxyl oroxylin A 7-O-glucuronide (hydroxyl wogonoside), baicalin, an isomer of 5,6,7-trihydroxyl-flavanone-7-O-glucuronide, berberine, palmatine, and chrysin-7-O-glucuronide were all directly linked with reductions in intestinal SN-38 levels. We therefore speculate that these compounds are the primary bioactive components of BXD, suggesting that they offer protection against CPT-11-induced diarrhea.
By utilizing UPLC to analyze SN-38 levels in mice treated with a variety of herbal combinations, we were able to effectively explore BXD spectrum-effect relationships and to thereby establish the components of this medicinal preparation that were bioactive and capable of preventing CPT-11-induced diarrhea in mice. This and similar spectrum-effect studies represent a robust means of exploring the mechanistic basis for the pharmacological activity of TCM preparations.
伊立替康（CPT-11）是一种有价值的化疗化合物，但它的使用与一些患者的严重腹泻有关。CPT-11 前药转化为活性 7-乙基-10-羟基喜树碱（SN-38）代谢物，然后可以在肠道中保留延长时间，导致腹泻和相关症状的发生。半夏泻心汤（BXD）常用于中医治疗胃肠炎，在临床环境中，它用于预防接受 CPT-11 治疗的患者发生腹泻。然而，迄今为止，尚无研究专门研究 BXD 的哪些成分可以缓解 CPT-11 给药引起的胃肠道症状。
本研究旨在鉴定 BXD 的主要草药成分，以在小鼠模型系统中对抗 CPT-11 诱导的肠道毒性。
通过 UPLC-ESI-MS/MS 测量 SN-38 水平在接受 CPT-11 诱导腹泻的小鼠中采集的样本中，给予 BXD 或其不同成分。然后，使用 Pearson 相关和灰色关联分析探索在给予特定 BXD 成分草药组合的小鼠样本中，肠道 SN-38 水平降低与特定化学指纹图谱之间的谱效关系。
我们发现不同的草药组合与接受治疗的小鼠肠道 SN-38 降低有显著差异。我们的谱效分析表明，BXD 成分包括白杨素 6-C-阿拉伯糖苷-8-C-葡萄糖苷、小檗碱、羟基氧化苦参素 7-O-葡萄糖醛酸苷（羟基甘草苷）、黄芩苷、5,6,7-三羟基黄酮-7-O-葡萄糖醛酸苷的异构体、盐酸巴马汀、黄连碱和白杨素-7-O-葡萄糖醛酸苷，均与肠道 SN-38 水平降低直接相关。因此，我们推测这些化合物是 BXD 的主要生物活性成分，表明它们对 CPT-11 诱导的腹泻具有保护作用。
通过利用 UPLC 分析接受各种草药组合治疗的小鼠中的 SN-38 水平，我们能够有效地探索 BXD 的谱效关系，并由此确定该药物制剂的活性成分，这些成分能够预防 CPT-11 诱导的小鼠腹泻。这种和类似的谱效研究代表了探索中药制剂药理学活性的机制基础的有力手段。
