Metabolomics of voriconazole-induced hepatotoxicity in mice and patients: using different dose groups to find biomarkers

Abstract: Voriconazole is a triazole antifungal agent with broad-spectrum activity against several common yeast and mold species. However, hepatotoxicity is a major adverse effect of voriconazole, and the lack of specific biomarkers for the detection and prediction of voriconazole-induced hepatotoxicity remains an urgent issue. In this study, ultra-high-performance liquid chromatography was coupled with mass spectrometry to analyze plasma and liver metabolites and determine possible plasma biomarkers for hepatotoxicity. Firstly, male C57BL/6J mice were randomly divided into four groups (each n = 7): control (0 mg/kg voriconazole), and 20, 40, and 80 mg/kg voriconazole. Voriconazole was intraperitoneally injected, and the resulting differential plasma and liver metabolites were identified to determine which differential metabolites were released from the liver into the periphery. Additionally, 133 plasma samples obtained from patients with (n = 45) and without (n = 88) hepatotoxicity were collected to further validate the differential metabolites found in the animal experiment. Alpha-ketoglutarate (AKG), 5-hydroxyindole, 7-ketolithocholic acid, 3-methylglutarylcarnitine, uracil, phosphatidylcholine (20:3/20:4), and lysophosphatidylcholine (22:6) were associated with voriconazole hepatotoxicity in a dose-dependent manner. Uracil (area under the curve (AUC): 0.979, 95% confidence interval (CI): 0.958-0.999), and AKG (AUC: 0.877, 95% CI: 0.812-0.941) were biomarkers of voriconazole-induced hepatotoxicity and showed great potential for clinical diagnosis. The combined biomarker composed of uracil, AKG, and alkaline phosphatase reached an AUC of 0.997 (95% CI: 0.993-0.999), showing that the combination of the three is a good choice to judge voriconazole-induced hepatotoxicity.