School of Pharmacy, Second Military Medical University, Shanghai, 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
Department of Health Toxicology, Faculty of Naval Medicine, Second Military Medical University, Shanghai, 200433, China.
Food Chem Toxicol. 2021 Jul;153:112250. doi: 10.1016/j.fct.2021.112250. Epub 2021 May 5.
Gardeniae Fructus (Zhizi in Chinese, ZZ in brief), a commonly used herbal medicine, has aroused wide concern for hepatotoxicity, but the mechanism remains to be investigated. This study was aimed at investigating the mechanism of ZZ-induced liver injury in vivo and in vitro based on metabolomics and evaluating the hepatotoxicity prediction ability of the in vitro model. SD rats were administered with extracted ZZ and HepG2 cells were treated with genipin, the major hepatotoxic metabolite of ZZ. Liver, plasma, intracellular and extracellular samples were obtained for metabolomics analysis. As a result, ZZ caused plasma biochemical and liver histopathological alterations in rats, and induced purine and amino acid metabolism disorder in the liver and pyrimidine, primary bile acids, amino acid metabolism and pantothenate and CoA biosynthesis disorder in the plasma. Pyrimidine, purine, amino acid metabolism and pantothenate and CoA biosynthesis were also found to be disturbed in the genipin-treated HepG2 cells, which exhibited similarity with the result in vivo. This study comprehensively illustrates the underlying mechanism involved in ZZ-related hepatotoxicity from the aspect of metabolome, and provides evidence that identifying hepatotoxicity can be achieved in cells, representing a non-animal alternative for systemic toxicology.
栀子（Zhizi，ZZ）为常用中药，其肝毒性已引起广泛关注，但具体机制仍需深入研究。本研究基于代谢组学方法，从体内和体外两方面探讨 ZZ 诱导肝损伤的机制，并评估体外模型的肝毒性预测能力。SD 大鼠给予栀子提取物，HepG2 细胞给予栀子苷的主要肝毒性代谢产物京尼平处理，分别收集肝、血浆、细胞内和细胞外样本进行代谢组学分析。结果显示，ZZ 导致大鼠血浆生化和肝脏组织病理学改变，并引起肝脏嘌呤和氨基酸代谢紊乱以及血浆嘧啶、初级胆汁酸、氨基酸代谢和泛酸及辅酶 A 生物合成紊乱。京尼平处理的 HepG2 细胞也出现嘧啶、嘌呤、氨基酸代谢和泛酸及辅酶 A 生物合成紊乱，与体内结果相似。本研究从代谢组学角度全面阐明了 ZZ 相关性肝毒性的潜在机制，为在细胞中识别肝毒性提供了证据，代表了一种替代整体毒性的非动物方法。
