corylifol-a and Chemical-and-Drug-Induced-Liver-Injury

Psoralea corylifolia L. (P. corylifolia) has attracted increasing attention because of its potential hepatotoxicity. In this study, we used network analysis (toxic component and hepatotoxic target prediction, proteinprotein interaction, GO enrichment analysis, KEGG pathway analysis, and molecular docking) to predict the components and mechanism of P. corylifolia-induced hepatotoxicity and then selected 4-hydroxylonchocarpin and corylifol A for experimental verification. HepG2 cells were treated with low, medium, and high concentrations of 4-hydroxylonchocarpin or corylifol A. The activities of ALT, AST, and LDH in cell culture media and the MDA level, SOD activity, and GSH level in cell extracts were measured. Moreover, apoptosis, ROS levels, and mitochondrial membrane potential were evaluated. The results showed that the activities of ALT, AST, and LDH in the culture medium increased, and hepatocyte apoptosis increased. The level of MDA increased, and the activity of SOD and level of GSH decreased, and the ROS level increased with 4-hydroxylonchocarpin and corylifol A intervention. Furthermore, the mitochondrial membrane potential decreased in the 4-hydroxylonchocarpin and corylifol A groups. This study suggests that 4-hydroxylonchocarpin and corylifol A cause hepatocyte injury and apoptosis by inducing oxidative stress and mitochondrial dysfunction, suggesting that these compounds may be the potential hepatotoxic components of P. corylifolia.

Topics: Chemical and Drug Induced Liver Injury; Molecular Docking Simulation; Psoralea; Reactive Oxygen Species; Superoxide Dismutase

As an edible traditional Chinese herb, Fructus psoraleae (FP) has been widely used in Asia for the treatment of vitiligo, bone fracture and osteoporosis. Several cases on markedly elevated bilirubin and acute liver injury following administration of FP and its related proprietary medicine have been reported, but the mechanism in FP-associated toxicity has not been well investigated yet. This study aimed to investigate the inhibitory effects of FP extract and its major constituents against human UDP-glucuronosyltransferase 1A1 (UGT1A1), the key enzyme responsible for metabolic elimination of bilirubin. To this end, N-(3-carboxy propyl)-4-hydroxy-1,8-naphthalimide (NCHN), a newly developed specific fluorescent probe for UGT1A1, was used to evaluate the inhibitory effects of FP extract or its fractions in human liver microsomes (HLM), while LC-UV fingerprint and UGT1A1 inhibition profile were combined to identity and characterize the naturally occurring inhibitors of UGT1A1 in FP. Our results demonstrated that both the extract of FP and five major components of FP displayed evident inhibitory effects on UGT1A1 in HLM. Among these five identified naturally occurring inhibitors, bavachin and corylifol A were found to be strong inhibitors of UGT1A1 with the inhibition kinetic parameters (Ki) values lower than 1 μM, while neobavaisoflavone, isobavachalcone, and bavachinin displayed moderate inhibitory effects against UGT1A1 in HLM, with the Ki values ranging from 1.61 to 9.86μM. These findings suggested that FP contains natural compounds with potent inhibitory effects against human UGT1A1, which may be one of the important reasons for triggering FP-associated toxicity, including elevated bilirubin levels and liver injury.

Topics: Bilirubin; Chalcones; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Flavones; Flavonoids; Fruit; Glucuronosyltransferase; Humans; Isoflavones; Liver; Microsomes, Liver; Plant Extracts; Psoralea