CYP3A4 inducer aggravates big flower Evodiae Fructus-induced hepatotoxicity whereas limonin attenuates its hepatotoxicity
CYP3A4 inducer aggravates big flower Evodiae Fructus-induced hepatotoxicity whereas limonin attenuates its hepatotoxicity
复制标题
CYP3A4诱导剂加重大花吴茱萸引起的肝毒性，柠檬苦素减弱其肝毒性
DOI：
10.1016/j.jep.2020.113277
复制
发表时间：
2021
影响因子：
5.4
通讯作者：
Liu Xiaoqiu
中科院分区：
文献类型：
--
作者：
Zhang Wei;Wang Mengjiao;Song Huijie;Gao Chengfeng;Wang Dongmei;Hua Huiming;Pan Yingni;Liu Xiaoqiu
Ethnopharmacological relevance: Evodiae Fructus (EF), the traditional Chinese medicine, has been typically used to treat headache, abdominal pain, hernias, and menorrhagia for thousands of years. It is a mild toxicity herbmedicine listed in Sheng Nong’s Herbal Classic. Recently, EF was reported to have toxicity or no toxicity in some investigations. Toxicity and approaches to reducing toxicity of EF are of great interest. Limonin (LIM), a major triterpenoid component of EF, also had various pharmacological activities such as anti-inflammatory, anticancer, and antioxidant effects. However, little attention was paid to the role of LIM in EF-induced hepatotoxicity..Aim of study: The study aimed to address the problem of controversial hepatotoxicity of EF, evaluate the role of CYP3A4 inducer/inhibitor in EF-induced hepatotoxicity and disclose the effect of LIM in EF-induced hepatotoxicity..Materials and methods: The chemical compositions and hepatotoxicity of small flower EF (SEF), medium flower EF (MEF), big flower EF (BEF) and the “organ knock-out” samples (the shell and seed part of BEF) were investigated. Simultaneously, C57BL-6 mice were randomly divided into four groups, which were given orally administered BEF, BEF in combination with dexamethasone (DEX), BEF in combination with ketoconazole (KTC), and BEF in combination with LIM, respectively..Results: In this study, more alkaloids and less LIM were detected in BEF compared with the compounds in SEF and MEF. Furthermore, we found that BEF group induced hepatotoxicity whereas no hepatotoxicity was observed in SEF and MEF groups. In addition, no LIM was detected in the shell part of BEF and five alkaloids were not detected in the seed part of BEF. Correspondingly, the shell part of BEF group induced hepatotoxicity whereas no hepatotoxicity was observed in the seed part of BEF group. It was also found that the BEF-induced hepatotoxicity was remarkably exacerbated when the mice were pretreated with DEX whereas the BEF-induced hepatotoxicity could be reversed by pretreatment with KTC or LIM..Conclusions: Based on the results in this study, the misuse of BEF but not SEF and MEF could produce hepatotoxicity. The hepatotoxicity difference of different categories of EF might be associated with the relative contents of alkaloids and LIM. In addition, the results demonstrated that CYP3A4 inducer aggravated BEF-induced hepatotoxicity and LIM attenuated its hepatotoxicity.
