The potential mechanism and chemical compounds contributed to Psoraleae Fructus-induced hepatotoxicity from the aspect of mitochondrial dysfunction

Abstract

Background Psoraleae Fructus (PF) is a widely-used traditional Chinese medicine in Asia for osteoporosis and vitiligo. The cases of PF-induced hepatotoxicity were frequently reported, which restricted its clinical application. However, the potential hepatotoxic components and the underlying mechanisms remain to be fully elucidated. Methods Kunming mice were intragastrically administrated with salt-processed Psoraleae Fructus (SPF) water extracts for 4 weeks. The pathohistological changes and biochemical assays were performed to evaluate the level of hepatic injuries. Transcriptomic analysis, western blots and qPCR were applied to investigate the potential mechanism. Further high content screening was conducted to identify the potential mitotoxic chemicals in PF. Results SPF promoted hepatic steatosis by inhibiting the expressions of ACOX1, ACADM, CPT1 and CYP7A1. SPF led to mitochondrial structure damage and the decrease of mtDNA copy number. Transcriptomic analysis and western blots validated the impairment of mitochondrial oxidative phosphorylation (OXPHOS) contributed to SPF-induced liver injuries. Considering the high relevance of mitochondrial function with SPF-induced hepatotoxicity, high content screening was conducted to identify the mitotoxic chemicals in SPF. At the same concentration, bavachin, isobavachalcone, psoralidin and bakuchiol showed the most potent mitochondrial toxicity by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide level and the opening of mitochondrial permeability transition pore. Conclusions Our study unveiled SPF promoted hepatic injury by inducing mitochondrial dysfunction and the potential mitotoxic chemical constituents in SPF.