秋水仙碱（COL）是一种著名的植物源性有丝分裂毒素，已广泛应用于治疗免疫系统疾病和各种癌症。然而，由于中毒事故频繁发生，其临床应用受到严重限制，且COL中毒的机制尚不清楚。本研究旨在基于动物模型和临床人体病例的非靶向代谢组学分析，揭示COL作为毒素的作用机制。 .KM小鼠口服COL建立中毒模型，采集血浆样本进行非靶向代谢组学分析。进行数据挖掘是为了筛选剂量依赖性差异和扰乱的代谢途径。对临床COL中毒病例在治疗期间不同时间点采集的血液样本进行进一步分析，以研究COL体内代谢处置的时间变化，并验证小鼠的研究结果。最后，通过ELISA和Western blotting分析评估关键通路的表达。组织学检查显示COL中毒小鼠的全身毒性。对模型小鼠血浆样本和临床病例的代谢谱分析均表明，COL中毒可通过FXR/AMPK信号通路显着干扰体内氨基酸代谢和脂质代谢。对COL代谢过程的定量监测进一步表明，随着COL在体内的快速代谢转化，可以大大改善病情，这可能是COL中毒的有效解毒途径。本研究的结果为分子机制提供了新的见解。了解COL中毒的机制，有助于指导该植物毒素的合理使用。版权所有©2023。Elsevier GmbH出版。

Colchicine (COL) is a well-known plant-derived mitogenic toxin that has been widely applied for the treatment of immune system diseases and various cancers. However, its clinical use is severely limited by frequent occurrence of poisoning accidents, and the mechanism of COL poisoning is not clear yet.The present study aimed to unveil how COL works as a toxin based on untargeted metabolomics analysis of animal models and clinical human case.KM mice orally administered COL were used to establish poisoning models, and plasma samples were collected for untargeted metabolomics analysis. The data mining was performed to screen dose-dependent differences and disturbed metabolic pathways. The blood samples collected from clinical COL poisoning human case at various time points during treatment period were further analyzed to investigate the temporal changes in the metabolic disposition of COL in vivo and also verify the findings from mice. Finally, the expression of key pathways was evaluated by ELISA and Western blotting analysis.Histological examination demonstrated systemic toxicity of COL poisoning in mice. Metabolite profiling analysis of plasma samples from model mice and clinical case both revealed that COL poisoning could significantly disturb in vivo metabolism of amino acid and lipid metabolism by the FXR/AMPK signal pathway. Quantitative monitoring of the metabolic process of COL further demonstrated that it could be greatly ameliorated with the rapid metabolic transformation of COL in vivo, which thus may be an effective detoxification pathway for COL poisoning.The findings of the present study provided new insight into the molecular mechanism of COL poisoning, thus helpful for guiding reasonable application of this phytotoxin.Copyright © 2023. Published by Elsevier GmbH.