Idiosyncratic Hepatotoxicity Evaluation And Mechanism Of Cortex Dictamni Based On Immune Stress

Cortex Dictamni is a traditional non-toxic traditional Chinese medicine commonly used in clinic,which has a good effect on psoriasis,vitiligo and other chronic skin diseases.However,in recent years,the national food and drug adverse reaction monitoring center has reported liver injury caused by Zhixue capsule containing Cortex Dictamni,and there are clinical reports of liver injury caused by single Cortex Dictamni.Therefore,the problem of liver injury caused by Cortex Dictamni has been widely concerned.We present a novel and clinic-associated safety assessment strategy,namely as “disease-syndrome-based toxicology”.It is confirmed that the immunity of traditional Chinese medicine,such as Polygonum multiflorum,Epimedium and Psoralea corylifolia,has the characteristic of heterogeneous liver injury.The strategy is able to access the relativity,susceptibility and controllability of the toxicity of TCMs.The new strategy provides a theoretical and methodological guidance to practice and development of the TCM in favor of precision medicine.This present study evaluated the liver injury induced by Cortex Dictamni and investigated the related mechanism by using the LPS model.Liver function indexes and pathological results showed that Cortex Dictamni aqueous extract or Cortex Dictamni ethanol extracts led to liver injury in normal rats.However,AE or EE could lead to liver injury in LPS-treated rats.Furthermore,AE or EE enhanced the LPSstimulated inflammatory cytokine production,implying that TNF-α,IL-1β,IL-6.NLRP3 inflammasome,is a specific indicator of Cortex Dictamni-induced immune idiosyncratic hepatotoxicity.In addition,we used the NLRP3 inflammasome activation model to screen the possible active ingredients in Cortex Dictamni.It was found that Isomaculosidine could promote the activation of NLRP3 inflammasome.We further explored its mechanism and found that Isomaculosidine could synergistically increase the activation of NLRP3 inflammasome.The role of Isomaculosidine in promoting the activation of NLRP3 inflammasome was confirmed by in vitro evaluation models.These results suggest that Isomaculosidine is one of the main active components of Cortex Dictamni-induced idiosyncratic hepatotoxicity.