Maintaining calcium homeostasis as a strategy to alleviate nephrotoxicity caused by evodiamine.

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.

[Research progress in pharmacology and toxicology of evodiamine].

Evodiamine, a bioactive indole alkaloid from Evodia rutaecarpa, E. rutaecarpa var. officinalis, or E. rutaecarpa var. bodinieri, has been extensively investigated due to its pharmacological activities in recent years. At present, evodiamine is proved to significantly suppress the proliferation of a variety of cancer cells and mediate cell processes such as cell cycle arrest and cell migration. In addition, evodiamine displays significant pharmacological activities against cardiovascular diseases(hyperlipidemia, etc.), and tinea manus and pedis. Recently, evodiamine has been found to have potential toxic effects, such as hepatotoxicity, nephrotoxicity, and cardiotoxicity. However, the pharmacological and toxicological mechanism of evodiamine is not clear, and its toxicity in vitro and in vivo has been rarely reported. Therefore, this study reviewed the pharmacological and toxicological articles of evodiamine in recent years, aiming at providing new ideas and references for future research.