Pharmacy College, Chengdu University of Traditional Chinese Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, PR China.
Pharmacy College, Chengdu University of Traditional Chinese Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, PR China.
J Pharm Biomed Anal. 2019 Oct 25;175:112760. doi: 10.1016/j.jpba.2019.07.008. Epub 2019 Jul 8.
As a kind of replenishing Chinese medicine, polygoni multiflori radix praeparata (PMP) had high application value in clinic. However, with the increase of clinical applications, more and more hepatotoxicity reports have been reported which had shown has a dose-time-toxicity dependent correlation of PMP hepatotoxicity. Therefore, it was particularly important to investigate the safe and effective dose of PMP in clinical drug administration. At the same time, reliable and sensitive biomarkers were used to characterize phenotypic biochemical disturbances in the body, thereby reflecting the hepatotoxicity mechanism caused by PMP, and providing a basis for clinical drug safety. 10, 20, and 40 g·kg doses PMP were intragastricly administered to rats respectively for consecutive 28 days. serum and liver tissue were collected to measure biochemical markers using blood biochemical analyzers and observe the histopathological examination. Serum metabonomics studies were performed by UPLC-Q-TOF-MS to reveal the dose-dependent biochemical disturbances caused by PMP. Compared with the blank group, the results of biochemical analysis showed that the indicators were significantly changed in the medium dose and high dose groups. however, there was no significant difference in the low dose group. A total of 12 characteristic metabolites were obtained through metabolomic analysis. The topological analysis involved 7 metabolic pathways, resulting in significant disturbance in amino acid metabolism, energy metabolism, and bile acid metabolism. Through comprehensive histopathological examination and biochemical analysis, we concluded that the dose of 20 g·kg and 40 g·kg PMP water extracts lead to liver damage after taking over four weeks, and the toxicity was enhanced as the dose increased. The identification method was used to characterize the disorder of hepatic metabolism induced by PMP in a dose-dependent manner. The experimental results provided the basis for the further study of the different doses of hepatotoxicity of PMP, and also provided a warning to the clinical dosage of PMP for a long time.
制何首乌作为一种补益中药，在临床上具有较高的应用价值。然而，随着临床应用的增加，越来越多的肝毒性报告表明，制何首乌肝毒性与剂量-时间-毒性呈相关性。因此，研究制何首乌在临床用药中的安全有效剂量尤为重要。同时，可靠、敏感的生物标志物可用于表征机体表型生化紊乱，从而反映制何首乌引起的肝毒性机制，为临床药物安全性提供依据。分别给予大鼠 10、20 和 40 g·kg 的制何首乌水提物灌胃，连续 28 天。采集血清和肝脏组织，采用血液生化分析仪测定生化标志物，观察组织病理学检查。采用 UPLC-Q-TOF-MS 进行血清代谢组学研究，揭示制何首乌引起的剂量依赖性生化紊乱。与空白组相比，中、高剂量组生化分析结果显示指标明显改变，而低剂量组无明显差异。通过代谢组学分析共得到 12 个特征代谢物。拓扑分析涉及 7 条代谢途径，导致氨基酸代谢、能量代谢和胆汁酸代谢显著紊乱。通过综合组织病理学检查和生化分析，我们得出结论，20 和 40 g·kg 的制何首乌水提物在连续服用四周后导致肝脏损伤，且随着剂量增加毒性增强。采用鉴定方法对制何首乌在剂量依赖性方式诱导的肝脏代谢紊乱进行了特征描述。实验结果为进一步研究制何首乌不同剂量的肝毒性提供了依据，也对长期临床应用制何首乌的剂量提出了警示。
