School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China.
School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China.
J Ethnopharmacol. 2024 Jan 30;319(Pt 2):117233. doi: 10.1016/j.jep.2023.117233. Epub 2023 Oct 2.
Euodiae Fructus (EF), the dried, unripe, scented fruit of Tetradium ruticarpum (A. Juss, T.G.Hartley), is a traditional food and herb with mild toxicity. In Asia, it is processed with licorice (EFP), which has been used for centuries to alleviate pain and suppress cough. Pharmacological studies have reported that this herb could cause liver injury by activating the P450 3A enzyme, thus carrying the risk of clinical application. Processing with licorice is an effective method to reduce EF toxicity. It is urgent to explore the toxic components of EF and the attenuation mechanism of licorice.
This study aimed to indicate the specific pathway of EF-induced damage and identify the mechanism of action of licorice in reducing P450 activation and resulting in reduced liver damage.
Male C57BL-6 mice were used to investigate the toxicity of EF to the liver and determine the attenuation effect on P450 from licorice ingestion. Glutathione (GSH) was used to capture the metabolic activation intermediates of EF. The key component reducing the EF toxicity of licorice was investigated by comparing the differences in chemical components and inhibition on the EF metabolism of licorice from different habitats.
The intermediate product of evodiamine (EVO) in EF was found to be activated by the P450 enzyme during metabolism, causing liver injury and inflammation. Isoliquiritigenin and liquiritigenin in licorice produced by intestinal bacterial metabolism and glycyrrhizin inhibited the metabolic activation of EF. Glycosides in licorice are metabolized into aglycones by intestinal bacteria, inhibiting the metabolic activation of EF and alleviating hepatotoxicity.
By combining with GSH, the electrophilic intermediates produced by the P450 enzyme's metabolic activation of the indole ring of EVO might cause hepatotoxicity. Glycyrrhizin from licorice and the liquiritigenin and isoliquiritigenin generated by intestinal bacterial metabolism play an attenuated function by inhibiting the P450 enzyme and preventing the metabolic activation of EF.
吴茱萸果实（EF），为芸香科吴茱萸属植物石虎 Tetradium ruticarpum（A. Juss，T.G.Hartley）未成熟干燥果实，是一种具有轻微毒性的传统食物和草药。在亚洲，它与甘草（EFP）一起加工，甘草已经使用了几个世纪来缓解疼痛和抑制咳嗽。药理学研究报告称，这种草药可能通过激活 P450 3A 酶引起肝损伤，从而带来临床应用的风险。用甘草加工是降低 EF 毒性的有效方法。迫切需要探索 EF 的毒性成分和甘草的减毒机制。
本研究旨在指出 EF 诱导损伤的具体途径，并确定甘草降低 P450 激活和减轻肝损伤的作用机制。
雄性 C57BL-6 小鼠用于研究 EF 对肝脏的毒性，并确定甘草摄入对 P450 激活的衰减作用。使用谷胱甘肽（GSH）捕获 EF 代谢的代谢激活中间产物。通过比较不同产地甘草的化学成分差异和对 EF 代谢的抑制作用，研究降低甘草 EF 毒性的关键成分。
EF 中的中间产物吴茱萸碱（EVO）在代谢过程中被 P450 酶激活，导致肝损伤和炎症。甘草中的异甘草素和甘草素通过肠道细菌代谢产生，以及甘草酸抑制 EF 的代谢激活。甘草中的糖苷被肠道细菌代谢为苷元，抑制 EF 的代谢激活，减轻肝毒性。
通过与 GSH 结合，EVO 吲哚环 P450 酶代谢激活产生的亲电中间体可能导致肝毒性。甘草中的甘草酸和肠道细菌代谢产生的异甘草素和甘草素通过抑制 P450 酶和防止 EF 的代谢激活发挥衰减作用。
