Ran Qiang, Huang Mengjun, Wang Lijuan, Li Yanyan, Wu Wenhui, Liu Xia, Chen Juan, Yang Min, Han Keqing, Guo Xiaohong
Department of Orthopedics, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China.
National-Local Joint Engineering Research Center for Innovative Targeted Drugs, Chongqing University of Arts and Sciences, Chongqing, 402160, China.
J Ethnopharmacol. 2025 Feb 11;341:119308. doi: 10.1016/j.jep.2024.119308. Epub 2024 Dec 31.
Drug-induced liver injury (DILI) is an important and common adverse drug event. Rhododendron molle Flos (RMF), as one of toxic Traditional Chinese medicines (TCMs), holds a prominent position in clinical practice for treating rheumatoid arthritis. However, the toxicity of RMF limits its safe. Most of the concerns are about its rapid neurotoxicity and cardiotoxicity, with less attention paid to its hepatotoxicity, and the mechanism of which is still unclear.
To reveal the mechanism of RMF-induced hepatotoxicity by bioinformatics and multi-omics.
Rats were intragastric administered RMF at doses of 0.8 g/kg, 0.4 g/kg, and 0.2 g/kg once daily for 2 weeks. Initially, hepatotoxicity was then evaluated using liver function enzymes, antioxidant enzymes, and histopathology. Subsequently, network toxicology, transcriptomics, and metabolomics were used to identify the genes and metabolites. In addition, molecular docking and Western blot were employed to verify toxic components and key targets.
RMF caused abnormal levels of ALT, γ-GT, TBIL, and TBA in the serum of rats, as well as abnormal levels of MDA, GSH-Px, and SOD in the liver, leading to inflammatory infiltration of liver cells, with a dose-dependent manner. RMF disordered the steroid hormone biosynthesis, pyruvate metabolism, fatty acid biosynthesis, and arachidonic acid metabolism. Six key targets were identified- UGT1A6, CYP2E1, ACOT1, ACSL5, CTH, and PKLR, along with their corresponding metabolites, namely 17β-estradiol, estriol, arachidonic acid, octadecanoic acid, and pyruvic acid. The hepatotoxicity could be attributed to five diterpenoid components, including grayanotoxin-III, rhodojaponin (RJ)-I, RJ-II, RJ-III, and RJ-V.
This study comprehensively identified the toxic components, upstream targets, and downstream metabolites of RMF-induced liver toxicity, providing a basis for evaluating and monitoring liver function in patients during clinical application.
药物性肝损伤（DILI）是一种重要且常见的药物不良事件。闹羊花（RMF）作为有毒的传统中药之一，在类风湿性关节炎的临床治疗中占据重要地位。然而，RMF的毒性限制了其安全性。大多数关注集中在其快速的神经毒性和心脏毒性上，而对其肝毒性的关注较少，且其机制仍不清楚。
通过生物信息学和多组学揭示RMF诱导肝毒性的机制。
将大鼠按0.8 g/kg、0.4 g/kg和0.2 g/kg的剂量每日一次灌胃给予RMF，持续2周。首先，使用肝功能酶、抗氧化酶和组织病理学评估肝毒性。随后，运用网络毒理学、转录组学和代谢组学来鉴定基因和代谢物。此外，采用分子对接和蛋白质印迹法验证有毒成分和关键靶点。
RMF导致大鼠血清中ALT、γ-GT、TBIL和TBA水平异常，以及肝脏中MDA、GSH-Px和SOD水平异常，导致肝细胞炎症浸润，呈剂量依赖性。RMF扰乱了类固醇激素生物合成、丙酮酸代谢、脂肪酸生物合成和花生四烯酸代谢。鉴定出六个关键靶点——UGT1A6、CYP2E1、ACOT1、ACSL5、CTH和PKLR，以及它们相应的代谢物，即17β-雌二醇、雌三醇、花生四烯酸、十八烷酸和丙酮酸。肝毒性可能归因于五种二萜类成分，包括灰藜毒素-III、闹羊花毒素（RJ）-I、RJ-II、RJ-III和RJ-V。
本研究全面鉴定了RMF诱导肝毒性的有毒成分、上游靶点和下游代谢物，为临床应用中评估和监测患者肝功能提供了依据。
