Schisandrol A mitigated voriconazole-induced liver injury in mice through regulation of farnesoid X receptor-mediated bile acid metabolism.

Abstract

Schisandrol A has been previously used to mitigate hepatotoxicity. However, the effects of schisandrol A on voriconazole-induced hepatic injury have not been investigated. In this study, we aimed to explore the effects of schisandrol A on voriconazole-induced hepatic injury in mice, as well as to elucidate the underlying mechanism. Mice were continuously treated with voriconazole with or without schisandrol A administration. Acetaminophen was used as a positive control to induce liver damage. Hematological, histological, and gene analyses were conducted, and the therapeutic target of schisandrol A was verified. Our results showed that voriconazole-induced hepatic injury was similar to that induced by acetaminophen. Importantly, schisandrol A alleviated voriconazole-induced hepatic steatosis, cell death, inflammation, and fibrosis. Schisandrol A reduced oxidative damage and inflammation in the liver. Furthermore, schisandrol A reduced total bile acid, cholesterol, and triglyceride levels in the liver and serum. The expression of farnesoid X receptor (FXR), small heterodimer partner, cytochrome P450 (CYP) 7A1, and CYP8B1 in the liver was altered by schisandrol A treatment. The binding of schisandrol A to FXR was verified by the cellular thermal shift assay and molecular docking. In conclusion, these findings suggested the favorable effects of schisandrol A against voriconazole-induced hepatotoxicity.