Department of Pharmaceutical Analysis, School of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
School of Basic Medical Sciences, Zunyi Medical University, Zunyi, 563000, China; School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550025, China.
Food Chem Toxicol. 2023 Aug;178:113913. doi: 10.1016/j.fct.2023.113913. Epub 2023 Jun 20.
Endemic arsenic (As) poisoning is a severe biogeochemical disease that endangers human health. Epidemiological investigations and animal experiments have confirmed the damaging effects of As on the liver, but there is an urgent need to investigate the underlying mechanisms. This study adopted a metabolomic approach using UHPLC-QE/MS to identify the different metabolites and metabolic mechanisms associated with As-induced hepatotoxicity in mice. A network pharmacology approach was applied to predict the potential target of As-induced hepatotoxicity. The predicted targets of differential metabolites were subjected to a deep matching for elucidating the integration mechanisms. The results demonstrate that the levels of ALT and AST in plasma significantly increased in mice after As exposure. In addition, the liver tissue showed disorganized liver lobules, lax cytoplasm and inflammatory cell infiltration. Metabolomic analysis revealed that As exposure caused disturbance to 40 and 75 potential differential metabolites in plasma and liver, respectively. Further investigation led to discovering five vital metabolic pathways, including phenylalanine, tyrosine, and tryptophan biosynthesis and nicotinate and nicotinamide metabolism pathways. These pathways may responded to As-induced hepatotoxicity primarily through lipid metabolism, apoptosis, and deoxyribonucleic acid damage. The network pharmacology suggested that As could induce hepatotoxicity in mice by acting on targets including Hsp90aa1, Akt2, Egfr, and Tnf, which regulate PI3K Akt, HIF-1, MAPK, and TNF signaling pathways. Finally, the integrated metabolomics and network pharmacology revealed eight key targets associated with As-induced hepatoxicity, namely DNMT1, MAOB, PARP1, MAOA, EPHX2, ANPEP, XDH, and ADA. The results also suggest that nicotinic acid and nicotinamide metabolisms may be involved in As-induced hepatotoxicity. This research identified the metabolites, targets, and mechanisms of As-induced hepatotoxicity, offering meaningful insights and establishing the groundwork for developing antidotes for widespread As poisoning.
地方性砷中毒是一种严重的生物地球化学疾病，危害人类健康。流行病学调查和动物实验证实了砷对肝脏的损害作用，但仍迫切需要研究其潜在机制。本研究采用 UHPLC-QE/MS 代谢组学方法，鉴定了与小鼠砷诱导肝毒性相关的不同代谢物和代谢机制。应用网络药理学方法预测砷诱导肝毒性的潜在靶标。对差异代谢物的预测靶标进行深入匹配，以阐明整合机制。结果表明，砷暴露后小鼠血浆中 ALT 和 AST 水平显著升高。此外，肝组织显示肝小叶排列紊乱，细胞质疏松，炎性细胞浸润。代谢组学分析显示，砷暴露分别导致血浆和肝组织中 40 和 75 个潜在差异代谢物发生紊乱。进一步研究发现，有五个重要的代谢途径受到影响，包括苯丙氨酸、酪氨酸和色氨酸生物合成以及烟酸和烟酰胺代谢途径。这些途径可能主要通过脂质代谢、细胞凋亡和脱氧核糖核酸损伤来应对砷诱导的肝毒性。网络药理学提示，砷可能通过作用于包括 Hsp90aa1、Akt2、Egfr 和 Tnf 在内的靶点诱导小鼠肝毒性，这些靶点调节 PI3K Akt、HIF-1、MAPK 和 TNF 信号通路。最后，整合代谢组学和网络药理学揭示了与砷诱导肝毒性相关的八个关键靶标，即 DNMT1、MAOB、PARP1、MAOA、EPHX2、ANPEP、XDH 和 ADA。研究结果还表明，烟酸和烟酰胺代谢可能与砷诱导的肝毒性有关。本研究确定了砷诱导肝毒性的代谢物、靶标和机制，为开发广泛存在的砷中毒解毒剂提供了有意义的见解和基础。
