Chen Liang, Li Jiaxin, Li Qian, Sun Qingwen
School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China.
Curr Issues Mol Biol. 2024 Oct 11;46(10):11314-11325. doi: 10.3390/cimb46100673.
Due to continuous application as a flavoring agent in the pesticide, pharmaceutical, and food industries, methyl eugenol (ME) persists in the environment and causes deleterious impacts including cytotoxicity, genotoxicity, and liver damage. This study utilized a comprehensive approach, integrating toxicokinetics, metabolomics, and gut microbiota analysis, to explore the mechanisms behind ME-induced hepatotoxicity in mice. The study observed significant rises in ALT and AST levels, along with significant weight loss, indicating severe liver damage. Toxicokinetic data showed delayed Tmax and plasma accumulation after 28 days of repeated ME exposure at doses of 20 mg/kg, 40 mg/kg, and 60 mg/kg. The metabolomic analysis pinpointed four critical pathways-TCA cycle; alanine, aspartate, and glutamate metabolism; arginine biosynthesis; and tyrosine metabolism-linked to 20 potential biomarkers. Gut microbiota analysis revealed that extended ME exposure led to microbial imbalance, particularly altering the populations of Akkermansia, Prevotella, and Ruminococcus, which are key to amino acid metabolism and the TCA cycle, thus contributing to hepatotoxicity. However, the causal relationship between changes in gut microbiota and liver metabolite levels still requires further in-depth research. This study underscores the significant role of liver metabolites and gut microbiota in ME-induced liver damage.
由于甲基丁香酚（ME）在农药、制药和食品工业中持续用作调味剂，它在环境中持续存在，并会造成包括细胞毒性、基因毒性和肝损伤在内的有害影响。本研究采用了一种综合方法，整合了毒代动力学、代谢组学和肠道微生物群分析，以探究ME诱导小鼠肝毒性背后的机制。研究观察到谷丙转氨酶（ALT）和谷草转氨酶（AST）水平显著升高，同时体重显著下降，表明存在严重的肝损伤。毒代动力学数据显示，在以20毫克/千克、40毫克/千克和60毫克/千克的剂量重复暴露于ME 28天后，达峰时间（Tmax）延迟且血浆中出现蓄积。代谢组学分析确定了四个关键途径——三羧酸（TCA）循环；丙氨酸、天冬氨酸和谷氨酸代谢；精氨酸生物合成；以及酪氨酸代谢——与20种潜在生物标志物相关。肠道微生物群分析显示，长期暴露于ME会导致微生物失衡，特别是改变了阿克曼氏菌属、普氏菌属和瘤胃球菌属的种群数量，这些菌属对氨基酸代谢和TCA循环至关重要，从而导致肝毒性。然而，肠道微生物群变化与肝脏代谢物水平之间的因果关系仍需要进一步深入研究。本研究强调了肝脏代谢物和肠道微生物群在ME诱导的肝损伤中的重要作用。
