School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing 100029, China.
Molecules. 2022 Dec 21;28(1):25. doi: 10.3390/molecules28010025.
. (PMT), a commonly used Chinese herbal medicine for treating diseases such as poisoning and white hair, has attracted constant attention due to the frequent occurrence of liver injury incidents. To date, its hepatotoxic equivalent markers (HEMs) and potential hepatotoxic mechanisms are still unclear. In order to clarify the HEMs of PMT and further explore the potential mechanisms of hepatotoxicity, firstly, the chemical constituents in PMT extract were globally characterized, and the fingerprints of PMT extracts were established along with the detection of their hepatotoxicity in vivo. Then, the correlations between hepatotoxic features and component contents were modeled by chemometrics to screen HEMs of PMT, which were then further evaluated. Finally, the hepatotoxic mechanisms of PMT were investigated using liver metabolomics and molecular docking. The results show that the chemical combination of 2,3,5,4-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) and emodin-8-O-glucoside (EG) was discovered as the HEMs of PMT through pre-screening and verifying process. Liver metabolomics revealed that PMT caused liver injury by interfering with purine metabolism, which might be related to mitochondrial function disorder and oxidative injury via the up-regulations of xanthosine and xanthine, and the down-regulation of 5' nucleotidase (NT5E) and adenylate kinase 2 (AK2). This study not only found that the HEMs of PMT were TSG and EG, but also clarified that PMT might affect purine metabolism to induce liver injury, which contributed to our understanding of the underlying mechanisms of PMT hepatotoxicity.
白头翁为治疗中毒和白发等疾病的常用中草药，因肝损伤事件频发而备受关注。目前，其肝毒性等效标志物（HEMs）及其潜在肝毒性机制尚不清楚。为明确白头翁的 HEMs，并进一步探讨其潜在的肝毒性机制，首先对白头翁提取物中的化学成分进行了全面表征，并建立了白头翁提取物的指纹图谱，同时检测了其体内的肝毒性。然后，通过化学计量学对肝毒性特征与成分含量之间的相关性进行建模，以筛选白头翁的 HEMs，并进一步进行评估。最后，采用肝代谢组学和分子对接技术研究了白头翁的肝毒性机制。结果表明，通过预筛选和验证过程，发现 2,3,5,4-四羟基二苯乙烯-2-O-β-D-葡萄糖苷（TSG）和大黄素-8-O-葡萄糖苷（EG）的化学组合是白头翁的 HEMs。肝代谢组学研究表明，白头翁通过干扰嘌呤代谢引起肝损伤，这可能与线粒体功能障碍和氧化损伤有关，其机制可能是通过上调次黄嘌呤和黄嘌呤，下调 5'核苷酸酶（NT5E）和腺苷酸激酶 2（AK2）。本研究不仅发现白头翁的 HEMs 是 TSG 和 EG，还阐明了白头翁可能通过影响嘌呤代谢引起肝损伤，这有助于我们理解白头翁肝毒性的潜在机制。
