Highlight report: hepatotoxicity of triazole fungicides
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Recently, Knebel and colleagues from the German Federal Institute of Risk Assessment in Berlin contributed a study about the mechanisms of action of the triazole fungicides propiconazole and tebuconazole (Knebel et al. 2019). Triazole fungicides act by inhibition of the fungus-specific cytochrome P450 lanosterol-14α-demethylase (Georgopapadakou 1998). The general population is exposed to triazoles via the diet (EFSA 2015). Adverse effects of triazole fungicides include hypertrophy, vacuolization and steatosis of hepatocytes (Schmidt et al. 2016; Heise et al. 2015, 2018). Therefore, the authors studied by which molecular mechanisms triazoles cause hepatotoxicity. For this purpose, they used HepaRG subclones that are deficient in specific nuclear receptors (Knebel et al. 2019). They observed that the knockout of the nuclear receptor PXR but not of CAR ameliorated triglyceride accumulation after incubation with triazoles. However, the studied compounds did not seem to act exclusively by PXR; rather they seem to activate several nuclear receptors, thereby inducing a complex gene expression response, as also observed by Tully et al. (2006) and Hester and Nesnow (2008).
Currently, much effort is invested to improve the possibilities of in vitro systems of hepatotoxicity (Luckert et al. 2017; Grinberg et al. 2014, 2018; Braeuning et al. 2019; Gu et al. 2018). Traditionally, in vitro systems served to identify the molecular mechanisms responsible for adverse effects (Weng et al. 2014; Frey et al. 2014; Arbo et al. 2016) and more recently have also been used to predict doses and blood concentrations causing an increased risk of toxicity in humans (Albrecht et al. 2019; Sachinidis et al. 2019). This is an approach that often is supported by methods of systems modeling (Ghallab et al. 2016; Hoehme et al. 2010). Knebel and colleagues are to be congratulated for their elegant study identifying PXR as a central player in a multi-receptor response induced by triazole fungicides.
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Conflict of interest
The author declares that she has no conflict of interest.