Psoralen Ameliorates Acetaminophen-Induced Acute Liver Injury by Inhibiting the Enzymatic Activity of CYP2E1

Excessive administration of the antipyretic and analgesic drug acetaminophen can cause acute liver injury. The mechanism is that a large amount of N -acetyl- p -benzoquinone-imine is generated through the metabolism of cytochrome P450 (CYP450), which leads to cell necrosis, oxidative stress, and inflammation. The purpose of this study was to investigate the protective effect of psoralen on acetaminophen-induced acute liver injury, and to clarify the isoform CYP2E1 of human cytochrome P450 in the efficacy of it. The results showed that psoralen ameliorated hepatocyte necrosis by decreasing serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, oxidative stress index malondialdehyde and inflammatory cytokines, such as interleukins (Il6 and Il1β) and tumor necrosis factor (Tnfα) in mice. Molecular docking suggested that psoralen could bind to active sites of CYP2E1, CYP1A2 and CYP3A11. A single dose of psoralen could significantly inhibit the enzymatic activity of CYP2E1 in rats, while administration of psoralen for 5 days had no significant effect on CYP2E1. In conclusion, psoralen can ameliorate acetaminophen-induced acute liver injury, specifically by reducing hepatocyte necrosis, inflammation and oxidative stress. Psoralen could be the substrate of CYP2E1 which can competitively bind to its active site, thereby competing with acetaminophen, thus inhibiting the enzymatic activity of CYP2E1 to have an impact on rates of drug metabolism in the liver. Graphical Abstract