The inhibitory effect of licorice on the hepatotoxicity induced by the metabolic activation of Euodiae Fructus

Euodiae Fructus (EF), the dried, unripe, scented fruit of Tetradium ruticarpum (A. Juss, T.G.Hartley), is a traditional food and herb with mild toxicity. In Asia, it is processed with licorice (EFP), which has been used for centuries to alleviate pain and suppress cough. Pharmacological studies have reported that this herb could cause liver injury by activating the P450 3A enzyme, thus carrying the risk of clinical application. Processing with licorice is an effective method to reduce EF toxicity. It is urgent to explore the toxic components of EF and the attenuation mechanism of licorice. This study aimed to indicate the specific pathway of EF-induced damage and identify the mechanism of action of licorice in reducing P450 activation and resulting in reduced liver damage. Male C57BL-6 mice were used to investigate the toxicity of EF to the liver and determine the attenuation effect on P450 from licorice ingestion. Glutathione (GSH) was used to capture the metabolic activation intermediates of EF. The key component reducing the EF toxicity of licorice was investigated by comparing the differences in chemical components and inhibition on the EF metabolism of licorice from different habitats. The intermediate product of evodiamine (EVO) in EF was found to be activated by the P450 enzyme during metabolism, causing liver injury and inflammation. Isoliquiritigenin and liquiritigenin in licorice produced by intestinal bacterial metabolism and glycyrrhizin inhibited the metabolic activation of EF. Glycosides in licorice are metabolized into aglycones by intestinal bacteria, inhibiting the metabolic activation of EF and alleviating hepatotoxicity. By combining with GSH, the electrophilic intermediates produced by the P450 enzyme's metabolic activation of the indole ring of EVO might cause hepatotoxicity. Glycyrrhizin from licorice and the liquiritigenin and isoliquiritigenin generated by intestinal bacterial metabolism play an attenuated function by inhibiting the P450 enzyme and preventing the metabolic activation of EF.