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BioMed Research International
Volume 2016, Article ID 5398730, 9 pages
Research Article

Evaluation of Hepatotoxicity with Treatment Doses of Flucytosine and Amphotericin B for Invasive Fungal Infections

1Department of Pathology, Faculty of Medicine, “Vasile Goldis” Western University of Arad, 86 Rebreanu Street, 310414 Arad, Romania
2Department of Bioethics, Faculty of Medicine, “Vasile Goldis” Western University of Arad, 86 Rebreanu Street, 310414 Arad, Romania
3Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
4Faculty of Veterinary Medicine, Department of Chemistry, Biochemistry and Molecular Biology, Banat University of Agricultural Sciences and Veterinary Medicine “King Mihai I of Romania” Timisoara, 119 Calea Aradului, 300645 Timisoara, Romania
5Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania
6Department of Histology, Faculty of Medicine, “Vasile Goldis” Western University of Arad, 86 Rebreanu Street, 310414 Arad, Romania

Received 16 September 2015; Revised 6 December 2015; Accepted 9 December 2015

Academic Editor: Bo Zuo

Copyright © 2016 Alexandra Folk et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients. In this study we aimed to evaluate the hepatotoxicity induced by combined therapy of flucytosine and amphotericin B, at three different doses administered to mice for 14 days: 50 mg/kg flucytosine and 300 μg/kg amphotericin B; 100 mg/kg flucytosine and 600 μg/kg amphotericin B; 150 mg/kg flucytosine and 900 μg/kg amphotericin B. Liver injuries were evaluated by analysis of optic and electron microscopy samples, changes in TNF-α, IL-6, and NF-κB inflammation markers levels of expression, and evaluation of mRNA profiles. Histological and ultrastructural analysis revealed an increase in parenchymal and portal inflammation in mice and Kupffer cells activation. Combined antifungal treatment stimulated activation of an inflammatory pathway, demonstrated by a significant dose-dependent increase of TNF-α and IL-6 immunoreactivity, together with mRNA upregulation. Also, NF-κB was activated, as suggested by the high levels found in hepatic tissue and upregulation of target genes. Our results suggest that antifungal combined therapy exerts a synergistic inflammatory activation in a dose-dependent manner, through NF-κB pathway, which promotes an inflammatory cascade during inflammation. The use of combined antifungal therapy needs to be dose limiting due to the associated risk of liver injury, especially for those patients with hepatic dysfunction.