Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
Toxicol Lett. 2022 Jul 15;365:1-10. doi: 10.1016/j.toxlet.2022.05.008. Epub 2022 Jun 6.
Dioscorea bulbifera L. (DBL) is one of traditional Chinese medicines and has been used for the treatment of goiter, tumor and carbuncles. However, clinic application of the herbal medicine has been limited, due to reported severe hepatotoxicity. 8-Epidiosbulbin E acetate (EEA), one of the major components of DBL, can cause severe liver damage. The furan ring of EEA is metabolized by CYP3A4 to a cis-enedial reactive intermediate prone to react amino and/or thiol groups of amino acid residues. In this study, we investigated the interaction of the reactive intermediate with biologic amines. EEA-derived biologic amine adducts, including spermidine, spermine, putrescine, ornithine, lysine and glutamine were detected in cultured mouse primary hepatocytes treated with EEA. Only spermidine adduct was observed in bile of mice given EEA. The detection of the adducts was established by labeling with bromobenzyl mercaptan and LC-MS/MS analysis. Exposure of EEA resulted in concentration dependent cytotoxicity in hepatocytes. Pretreatment with spermidine attenuated the susceptibility of cells to the cytotoxicity of EEA, because of the compensation of the depleted spermidine.
盾叶薯蓣（DBL）是一种传统中药，已用于治疗甲状腺肿、肿瘤和痈疽。然而，由于报道的严重肝毒性，该草药的临床应用受到限制。8-表薯蓣皂素 E 乙酸酯（EEA）是 DBL 的主要成分之一，可导致严重的肝损伤。EEA 的呋喃环由 CYP3A4 代谢为顺式烯二醛反应性中间产物，容易与氨基酸残基的氨基和/或巯基反应。在这项研究中，我们研究了反应性中间产物与生物胺的相互作用。在用 EEA 处理的培养的小鼠原代肝细胞中检测到 EEA 衍生的生物胺加合物，包括精脒、精胺、腐胺、鸟氨酸、赖氨酸和谷氨酰胺。仅在给予 EEA 的小鼠胆汁中观察到精脒加合物。通过溴苄基巯基标记和 LC-MS/MS 分析建立了加合物的检测。EEA 的暴露导致肝细胞中浓度依赖性的细胞毒性。由于精脒的耗竭得到补偿，精脒预处理可减轻细胞对 EEA 细胞毒性的敏感性。
