Study On The Hepatotoxic Material Basis Of Gardeniae Fructus In Rat

Gardenia jasminoides Ellis is classified as a traditional Chinese medicine with both medicinal and food properties.However,in recent years,there have been reports that Gardenia can cause liver toxicity,which severely hinders its safe use in clinical settings.It is generally believed that geniposide is the basis for the liver toxicity of Gardenia,while some scholars believe that the formation of geniposide metabolite(genipin)leads to liver damage.Currently,the toxic substance basis of Gardenia jasminoides is still unclear,and there is some academic controversy surrounding it.Objective:To elucidate the material basis of the toxicity of Gardenia jasminoides,and to analyze the relationship between drug metabolism and hepatotoxicity of geniposide.Methods:1.Serum pharmacochemistry of Gardenia jasminoides study:Gardenia jasminoides extract was given by gavage in rat,1h and 24h blood after administration was collected,and the absorbed components of Gardenia jasminoides were analyzed by liquid mass spectrometry,and the structure of the absorbed components was determined based on the secondary mass spectrometry fragments and reference standard comparison.2.Comparison of the hepatotoxicity of geniposide and genipin in rats by different routes of administration:comparison of the hepatotoxicity of 300 mg/kg geniposide and genipin by oral and intraperitoneal routes,and the hepatotoxicity was evaluated by blood transaminases ALT and AST.3.Comparison of metabolism and toxicity of geniposide in normal and pseudo-sterile rats:pseudo-sterile rats were established using a combination of antibiotics,and blood transaminases ALT and AST were used to evaluate hepatotoxicity.4.Network toxicology prediction of genipin and experimental validation:The CTD database was used to predict genipin targets,the liver injury related targets was collected from Genecard database,and the intersected targets were obtained between genipin targets and liver injury related targets,and biofunctional enrichment was performed to screen the pathways regulated by genipin and target interactions to find the core targets.The key core targets of network toxicology were validated at the animal level,and dexamethasone anti-inflammatory treatment was performed to verify whether anti-inflammatory treatment could improve the hepatotoxicity of genipin.Results:1.In this study,the serum pharmacochemistry of Gardenia jasminoides was studied,and it was clarified that geniposide,genipin,and Geniposidic acid were the absorbed components in blood,where geniposide was the highest content.By comparing the metabolism and toxicity of geniposide and genipin in drug delivery route,it was found that geniposide can be metabolized to form genipin.2.Comparison of the liver toxicity of geniposide and genipin via different administration routes revealed that geniposide can be metabolized to form genipin.Oral administration of geniposide resulted in greater liver toxicity than intraperitoneal injection,while oral administration of genipin resulted in less liver toxicity than intraperitoneal inj ection.This indicates that geniposide is not the original toxic substance,but rather that it forms a toxic metabolite after metabolism.3.By comparing the hepatotoxicity of geniposide and genipin in normal rats and pseudosterile rats,it was found that geniposide metabolized into genipin in normal rats with high content and obvious hepatotoxicity,while geniposide metabolized into genipin in pseudosterile rats with low content and weak hepatotoxicity,which further showed that geniposide was biotransformed into toxic metabolites of genipin,and intestinal drug metabolism played an important role.The metabolism experiment of enterobacteria and glucosidase in vitro also suggested that geniposide could be metabolized by glucose to form genipin.4.The toxicological prediction network of genipin and experiment confirmed that genipin caused liver injury,especially induced inflammation,through multiple targets and multiple pathways.The experimental verification found that genipin can lead to increased levels of inflammatory factors,and anti-inflammatory dexamethasone treatment can attenuate genipin liver injury.Conclusion:Through the maximum absorption of geniposide into the blood of gardenia,geniposide further removes glucose in the intestinal drug metabolism to form the key toxic metabolite genipin.It is determined that the metabolic pathway of the hepatotoxic substances of gardenia is gardenia→geniposide→genipin.Intestinal drug metabolism can form geniposide into a key metabolite,genipin,which plays a key catalytic role.Genipin can induce inflammation and cause liver injury.Anti-inflammatory treatment may be a potential strategy for treating geniposide liver injury.