National Institutes for Food and Drug Control, Beijing 100050, China.
Department of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Molecules. 2023 Jan 31;28(3):1341. doi: 10.3390/molecules28031341.
Brucine (BRU) and brucine N-oxide (BNO) are prominent, bioactive, and toxic alkaloids in crude and processed Semen Strychni. Studies have demonstrated that BRU and BNO possess comprehensive pharmacological activities, such as anti-inflammatory and analgesic. In this context, a comparative study of BRU and BNO was performed by combination analysis of in silico ADMET prediction, in vivo toxicity evaluation, and potential action mechanism exploration. ADMET prediction showed that BRU and BNO might induce liver injury, and BRU may have a stronger hepatoxic effect. The prediction was experimentally verified using the zebrafish model. The BRU-induced hepatotoxicity of zebrafish larvae had a dose-response relationship. The mechanism of BRU-induced hepatotoxicity might relate to phosphorylation, kinase activity, and signal transduction. By comparison, signal transduction and gap junctions might involve BNO-induced hepatotoxicity. Our results provided a better understanding of BRU- and BNO-induced hepatotoxicity. We also built a foundation to elucidate the material base of the hepatotoxicity of traditional Chinese medicine Semen Strychni.
马钱子中的士的宁（BRU）和士的宁 N-氧化物（BNO）是重要的、具有生物活性的、有毒的生物碱。研究表明，BRU 和 BNO 具有广泛的药理活性，如抗炎和镇痛。在这种情况下，通过体内毒性评价和潜在作用机制的探索，对 BRU 和 BNO 进行了比较研究。ADMET 预测显示，BRU 和 BNO 可能会引起肝损伤，BRU 可能具有更强的肝毒性作用。该预测通过斑马鱼模型进行了实验验证。BRU 诱导的斑马鱼幼鱼肝毒性呈剂量反应关系。BRU 诱导肝毒性的机制可能与磷酸化、激酶活性和信号转导有关。相比之下，信号转导和间隙连接可能与 BNO 诱导的肝毒性有关。我们的研究结果提供了对 BRU 和 BNO 诱导的肝毒性的更好理解。我们还为阐明中药马钱子的肝毒性的物质基础奠定了基础。
