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