Abstract：
Evodiamine (EVO), the main active alkaloid in Evodia rutaecarpa, was shown to exert various pharmacological activities, especially anti-tumor. Currently, it is considered a potential anti-cancer drug due to its excellent anti-tumor activity, which unfortunately has adverse reactions, such as the risk of liver and kidney injury, when Evodia rutaecarpa containing EVO is used clinically. In the present study, we aim to clarify the potential toxic target organs and toxicity mechanism of EVO, an active monomer in Evodia rutaecarpa, and to develop mitigation strategies for its toxicity mechanism. Transcriptome analysis and related experiments showed that the PI3K/Akt pathway induced by calcium overload was an important step in EVO-induced apoptosis of renal cells. Specifically, intracellular calcium ions were increased, and mitochondrial calcium ions were decreased. In addition, EVO-induced calcium overload was associated with TRPV1 receptor activation. In vivo TRPV1 antagonist and calcium chelator effects were observed to significantly reduce body weight loss and renal damage in mice due to EVO toxicity. The potential nephrotoxicity of EVO was further confirmed by an in vivo test. In conclusion, TRPV1-mediated calcium overload-induced apoptosis is one of the mechanisms contributing to the nephrotoxicity of EVO due to its toxicity, whereas maintaining body calcium homeostasis is an effective measure to reduce toxicity. These studies suggest that the clinical use of EVO-containing herbal medicines should pay due attention to the changes in renal function of patients as well as the off-target effects of the drugs.
摘要：
乙二胺(EVO),吴茱萸中的主要活性生物碱，被证明发挥各种药理活性，尤其是抗肿瘤。目前,由于其优异的抗肿瘤活性，被认为是一种潜在的抗癌药物，不幸的是有不良反应，比如肝肾损伤的风险，当含有EVO的吴茱萸在临床上使用时。在本研究中,我们旨在阐明EVO的潜在毒性靶器官和毒性机制，吴茱萸中的一种活性单体，并针对其毒性机制制定缓解策略。转录组分析和相关实验表明，钙超载诱导的PI3K/Akt通路是EVO诱导肾细胞凋亡的重要步骤。具体来说,细胞内钙离子增加，线粒体钙离子减少。此外,EVO诱导的钙超载与TRPV1受体激活有关。观察到体内TRPV1拮抗剂和钙螯合剂作用显着减少由于EVO毒性引起的小鼠体重减轻和肾损伤。通过体内试验进一步证实了EVO的潜在肾毒性。总之,TRPV1介导的钙超载诱导的细胞凋亡是EVO肾毒性的机制之一。而维持体内钙稳态是降低毒性的有效措施。这些研究表明，临床使用含EVO的中草药应适当注意患者肾功能的变化以及药物的脱靶作用。
