Toll-like receptor 4 activation potentiates voriconazole-induced hepatotoxicity via transcriptional repression of the farnesoid X receptor in murine hepatocytes

Objectives: Voriconazole (VRC)-induced hepatotoxicity is an important consideration in the clinical application of voriconazole. This study explores the potential role of Toll-like Receptor (TLR) 4 activation on voriconazole-induced hepatotoxicity and its underlying mechanisms.

Methods: A model of VRC- and lipopolysaccharide (LPS)-induced hepatotoxicity was constructed using C57BL/6 mice. Parallel experiments were carried out on wild-type mice (WT-LPS + VRC) and TLR4 knockout mice (KO-LPS + VRC) to examine the relationship between TLR4 activation and regulation of the farnesoid X receptor (FXR). Biochemical parameters and liver histopathology were observed. Quantitative Real-Time PCR and western blotting were used to assess gene and protein expression levels.

Key findings: Administering voriconazole twice within a 24-h period induces hepatotoxicity in mice under LPS-induced inflammatory conditions. VRC treatment caused darkening of the bile compared to normal mice. Conversely, KO-LPS + VRC mice maintained normal hepatocyte morphology and displayed light-coloured bile. The expression of p65 in the hepatocytes of KO-LPS + VRC was less than that of the WT-LPS + VRC. Additionally, the expression of nuclear FXR in the KO-LPS + VRC group was significantly higher than in the hepatocytes of WT-LPS + VRC.

Conclusions: Activation of the TLR4 signalling pathway suppresses the activity of nuclear receptor FXR, impairs hepatic bile acid metabolism, impairs VRC excretion, and contributes to VRC hepatotoxicity.