Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay

摘要

Psoralen and isopsoralen are secondary plant metabolites found in many fruits, vegetables, and medicinal herbs. Psoralen-containing plants ( Psoralea corylifolia L.) have been reported to cause hepatotoxicity. Herein, we found that psoralen and isopsoralen were oxidized by CYP450s to reactive furanoepoxide or γ-ketoenal intermediates, causing a mechanism-based inhibition of CYP3A4. Furthermore, in GSH-depleted mice, the hepatotoxicity of these reactive metabolites has been demonstrated by pre-treatment with a well-known GSH synthesis inhibitor, L-buthionine-S, Rsulfoxinine (BSO). Moreover, a molecular docking simulation of the present study was undertaken to understand the coordination reaction that plays a significant role in the combination of unstable intermediates and CYP3A4. These results suggested that psoralen and isopsoralen are modest hepatotoxic agents, as their reactive metabolites could be deactivated by H 2 O and GSH in the liver, which partly contributes to the ingestion of psoralen-containing fruits and vegetables being safe.