Huang Linyan, Li Yi, Pan Hong, Lu Yuanfu, Zhou Xumei, Shi Fuguo
Key Laboratory of Basic Pharmacology of Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563003, China; Department of Clinical Pharmacy, School of Pharmacy, Zunyi Medical University, Zunyi 563003, China.
Key Laboratory of Basic Pharmacology of Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563003, China.
Toxicol Lett. 2020 May 11;330:41-52. doi: 10.1016/j.toxlet.2020.05.004.
Many furan containing compounds have been reported to be toxic resulted from the metabolic activation of the furan ring to reactive metabolite (RM). Cortex Dictamni (CD), a widely used herbal medicine, has been reported to cause severe even fatal hepatotoxicity. The injurious components and mechanism of CD-induced liver injury remain unclear. Our preliminary study showed that dictamnine, one major furanoid in CD, caused mouse liver injury via its reactive epoxide metabolite. Besides dictamnine, the major components of CD are series of bioactivation-alerting furanoids. Thus, we hypothesize that series of furanoids in CD may undergo metabolic activation and play a key role in CD-induced liver injury. Here, a single oral dose of 60 g/kg ethanol extract of CD (ECD) caused severe hepatocellular necrosis in mice at 24 h post-dose. ECD-induced liver injury showed a dose- and time-dependent manner. The hepatotoxic effects could be completely abolished by P450 nonselective inhibitor 1-aminobenzotriazole (ABT) and strongly modulated by other P450 modulators. The furanoids-concentrated fraction of ECD was responsible for the hepatotoxicity. At least ten furanoids with high abundance in ECD, such as obakunone, dictamnine, fraxinellone, limonin, were found to be metabolized to reactive epoxide or cis-enedione. The RM levels were consistent with the liver injury degree. Multiple furanoids, rather than single one, cooperatively contributed to the hepatotoxicity. ECD-induced liver injury could be reproduced by a mixture of pure furanoids. In summary, this study provides toxic component profiles of CD and demonstrates that P450-mediated bioactivation of multiple furanoids is responsible for CD-induced liver injury.
据报道，许多含呋喃的化合物具有毒性，这是由于呋喃环代谢活化为反应性代谢物（RM）所致。白鲜皮（CD）是一种广泛使用的草药，据报道会导致严重甚至致命的肝毒性。CD诱导肝损伤的有害成分和机制仍不清楚。我们的初步研究表明，CD中的一种主要呋喃类化合物白鲜碱通过其反应性环氧化物代谢物导致小鼠肝损伤。除白鲜碱外，CD的主要成分是一系列具有生物活化警示作用的呋喃类化合物。因此，我们推测CD中的一系列呋喃类化合物可能会发生代谢活化，并在CD诱导的肝损伤中起关键作用。在此，单次口服60 g/kg的CD乙醇提取物（ECD）在给药后24小时可导致小鼠严重的肝细胞坏死。ECD诱导的肝损伤呈现剂量和时间依赖性。P450非选择性抑制剂1-氨基苯并三唑（ABT）可完全消除肝毒性作用，其他P450调节剂可强烈调节该作用。ECD中呋喃类化合物浓缩部分具有肝毒性。在ECD中发现至少十种高丰度的呋喃类化合物，如奥巴昆酮、白鲜碱、吴茱萸次碱、柠檬苦素，可代谢为反应性环氧化物或顺式烯二酮。RM水平与肝损伤程度一致。多种呋喃类化合物而非单一一种化合物共同导致肝毒性。ECD诱导的肝损伤可由纯呋喃类化合物混合物重现。总之，本研究提供了CD的毒性成分概况，并证明P450介导的多种呋喃类化合物的生物活化是CD诱导肝损伤的原因。
