Metabolic characteristics of voriconazole – Induced liver injury in rats

Abstract

Voriconazole (VOR) – induced liver injury is a common adverse reaction, and can lead to serious clinical outcomes. It is of great significance to describe the metabolic characteristics of VOR – induced liver injury and to elucidate the potential mechanisms. This study investigated the changes of plasma metabolic profiles in a rat model of VOR – induced liver injury by non – targeted metabolomics. Correlation analysis was performed between differentially expressed metabolites and plasma liver function indexes. The metabolites with strong correlation were determined for their predictive performance for liver injury using receiver operating characteristic (ROC) curve analysis. Potential biomarkers were then screened combined with liver pathological scores. Finally, the expression level of genes that involved in lipid metabolism were determined in rat liver to verify the mechanism of VOR – induced liver injury we proposed. VOR – induced liver injury in rats was characterized by plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, the lipid droplets accumulation in liver, as well as inflammation and fibrosis. Significant changes of plasma metabolites were observed, with a decrease in lipid metabolites accounting for over 50% of all changed metabolites, and alterations of cholesterol and bile acids metabolites. The decrease of 3 phosphatidylcholine (PC) in plasma could indicate the occurrence of VOR – induced liver injury. Decreased fatty acids (FA) oxidation and bile acid excretion might be the potential mechanisms of VOR – induced liver injury. This study provided new insights into the molecular characterization of VOR – induced liver injury.