Investigation of the active components in Tripterygium wilfordii leading to its acute hepatotoxicty and nephrotoxicity
Investigation of the active components in Tripterygium wilfordii leading to its acute hepatotoxicty and nephrotoxicity
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雷公藤急性肝、肾毒性活性成分的研究
DOI：
10.1016/j.jep.2015.01.004
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发表时间：
2015-03-13
影响因子：
5.4
通讯作者：
Xing, Jie
中科院分区：
文献类型：
--
作者：
Li, Xin-Xiu;Du, Fu-Ying;Xing, Jie
民族药理学相关性：传统草药雷公藤。F. (TW)在临床上广泛用于治疗类风湿性关节炎和自身免疫性疾病。然而，TW的不良反应包括肝毒性和肾毒性已被频繁报道。萜类和生物碱是雷公藤中最重要的活性成分之一。雷公藤内酯醇（TP）是雷公藤中的主要萜类化合物，具有毒性作用，其代谢途径可能导致TP的解毒作用。在这项研究中，是否其他主要萜烯或生物碱的TW有助于其毒性进行了调查。代谢消除在其潜在的解毒过程中的作用也evaluated.Materials和方法：TW及其五个主要活性成分（一个萜烯和四个生物碱）在小鼠中的毒性进行了评估，在死亡率和血液生化水平（ALT，AST，BUN和CREA）。TP用作阳性对照。导致TW或其两种代表性组分潜在解毒的代谢途径（雷公藤内酯酮和雷公藤红素）在谷胱甘肽（GSH）耗尽的（用L-丁噻二唑-S，R-亚砜，BSO处理）和氨基苯并三唑（ABT; P450的非特异性抑制剂）处理的小鼠。在正常小鼠中，萜类化合物TP和雷公藤内酯酮（TN）的主要代谢途径是羟基化和半胱氨酸结合，生物碱雷公藤甲素（WG）主要经历氧化代谢和水解。在ABT/BSO处理的小鼠中，TP、TN和WG的羟基化代谢产物的水平低于正常小鼠，TN的半胱氨酸结合物的水平升高可能是由于应激反应。TW（或TP）1.2mg·kg ~（-1）处理组小鼠死亡率和ALT（但BUN无显著性差异）均显著高于正常小鼠（P < 0.01），提示TW及其活性成分TP具有急性毒性（可能无肾毒性）。ABT和/或BSO预处理可增加TW或TP的急性毒性（包括肝毒性和肾毒性）。在正常小鼠和ABT/BSO处理的小鼠中，TN或四种生物碱均未发现明显的毒性。结论：TP可能是TW毒性的主要贡献者，TW中的萜烯TN和生物碱在治疗剂量的20倍以下的剂量水平可能没有毒理学问题。代谢消除为反应性较低的代谢物意味着TW的解毒潜力很高，在与其他β-内酰胺酶抑制剂或GSH消耗剂联合给药期间，应谨慎使用TW临床。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Ethnopharmacological relevance: The traditional herbal medicine Triptetygium wilfordii Hook. f. (TW) has been widely used for the treatment of rheumatoid arthritis and autoimmune disease in the clinic. However, adverse reactions of TW including hepatotoxicity and nephrotoxicity have been frequently reported. Terpenes and alkaloids are among the most important active components in TW. Triptolide (TP), a major terpene in TW, has been found to induce toxicity, and metabolic pathways could lead to detoxification of TP. In this study, whether other major terpenes or alkaloids in TW contribute to its toxicity was investigated. The role of metabolic eliminations in their potential detoxification process was also evaluated.Materials and methods: The toxicity of TW and its five major active components (one terpene and four alkaloids) in mice was evaluated in terms of mortality and blood biochemical levels (ALT, AST, BUN and CREA). TP was used as a positive control. Metabolic pathways leading to potential detoxification of TW or its two representative components (triptonide and wilforgine) were evaluated in glutathione (GSH)-depleted (treated with L-buthionine-S,R-sulfoxinine, BSO) and aminobenzotriazole (ABT; a nonspecific inhibitor for P450s)-treated mice.Results: In normal mice, the major metabolic pathways for the terpene compounds TP and triptonide (TN) were hydroxylation and cysteine conjugation, and the alkaloid wilforgine (WG) mainly underwent oxidative metabolism and hydrolysis. In ABT/BSO-treated mice, the hydroxylated metabolites of TP, TN and WG were found at a lower level than normal mice, and the level of cysteine conjugates of TN increased probably due to the stress response. Compared with normal mice, mortality and levels of ALT (but not BUN) were significantly higher (P < 0.01) in TW (or TP)-treated mice (1.2 mg kg(-1)), indicating the acute toxicity (may not nephrotoxicity) of TW and its active component TP. Pretreatment with ABT and/or BSO increased the acute toxicity (including hepatotoxicity and nephrotoxicity) caused by TW or TP. No significant toxicity was found for TN or four alkaloids in normal mice or ABT/BSO-treated mice.Conclusions: TP was probably the main contributor to the toxicity of TW, and the terpene TN and alkaloids in TW may be of no toxicological concern at dosage levels up to 20-fold of the therapeutic dose. Metabolic eliminations to less reactive metabolites implied a high potential for detoxification of TW, and caution should be taken for TW clinical use during co-administration with other CYP inhibitors or GSH-depleting agents. (C) 2015 Elsevier Ireland Ltd. All rights reserved.