As a potent antifungal drug, fluconazole clinically used to eradicate both systemic and superficial mycoses resulting in hepatotoxicity. The objective of the current study was to evaluate hepatotoxicity and genotoxicity in newborn male mice. Mice were treated orally with 0.5 ml fluconazole doses of (0, 25, 50, and 100 mg/kgbw) per day for five consecutive weeks. Micronucleus test, chromosomal aberrations in bone marrow cells, histopathological investigation and DNA fragmentation in the liver tissue was done. Micronuclei are significantly noticed in bone marrow cells of mice given 50 and 100 mg/kgbw fluconazole however, there is no effect on the genotoxicity induced by 25 mg/kgbw dose of fluconazole. A dose-dependent and significant increase in structural and numerical chromosomal aberrations were detected in the 50 and 100 mg/kgbw fluconazole-treated group but a 100 mg/kg was highly significant. The chromosomal aberrations were manifested in hypoploidy, deletion, centric fusion and stickiness. Besides, hepatocellular massive infiltration, cytoplasmic vacuolation, congestion and dilatation in the central veins were seen in 50 and 100 mg/kgbw fluconazole. Interestingly, 25mg/kgbw fluconazole-treated mice showed mild hepatocellular degeneration. Consequently, these findings confirmed that fluconazole to a greater extent was a potent hepatotoxic drug in vivo in newborn mice.
| Published in | Biomedical Sciences (Volume 7, Issue 1) |
| DOI | 10.11648/j.bs.20210701.11 |
| Page(s) | 1-9 |
| Creative Commons |
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Copyright © The Author(s), 2021. Published by Science Publishing Group |
Fluconazole, Genotoxicity, Micronucleus, Chromosomal Aberration, Hepatotoxicity
| [1] | Talaro KP. Foundations in microbiology. 6th ed. McGraw-Hill Company. American, New York, NY. 2008. |
| [2] | Vanhoutte I, Audenaert K, De Gelder L. Biodegradation of Mycotoxins: Tales from Known and Unexplored Worlds. Front Microbiol. (2016) 7: 561-569. |
| [3] | Almirante B, Rodriguez D. Antifungal Agents in Neonates, Issues and Recommendations. Pediatr. Drugs. (2007) 9 (5): 311–321. |
| [4] | Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results is obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother. (2005) 49: 3640–3645. |
| [5] | Francois I E, Cammue B P A, Borgers M, Ausma J, Dispersyn GD, Thevissen K. Azoles: Mode of antifungal action and resistance development. Med. Chem. (2006) 5: 3–13. |
| [6] | Somchit N, Norshahida AR, Hasiah AH, Zuraini A, Sulaiman MR, Noordin MM. Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats: a comparative in vivo study. Human & Experimental Toxicology. (2004) 23: 519–525. |
| [7] | Abdel-Mottaleb MM, Mortada ND, Elshamy AA, Awad GA. Preparation and evaluation of fluconazole gels. Egypt. J. Biomed. Sci. (2007) 3: 266-286. |
| [8] | Girish, M. B. and Patil, P. A. 2005. The influence of some azoles on wound healing in albino rats. Indian J. Pharmacol., 37 (4): 247-250. |
| [9] | Leonart LP, Tonin FS, Ferreira VL, Suelem TSi, Fábio de Araújo M, Roberto P. Safety and efficacy of different doses of fluconazole used for invasive prophylaxis of fungal infection in neonates. J. Pediatric. (2017) 185: 129-135. |
| [10] | Lollis TR, Bradshaw WT. Fungal prophylaxis in neonates: a review article. Adv. Neonatal Care, 2014; 14 (1): 17-23. |
| [11] | Tully DB, Bao W, Goetz AK, Blystone CR, Ren H, Schmid JE, Strader LF, Wood CR, Best DS, Narotsky MG, Wolf DC, Rockett JC, Dix DJ. Gene expression profiling in liver and testis of rats to characterize the toxicity of triazole fungicides. Toxicol. Applied Pharmacol. (2006) 215: 260–273. |
| [12] | Peffer RC, Moggs JG, Pastoor T, Currie RA, Wright J, Milburn G, Waechter F, Rusyn I. Mouse liver effects of cyproconazole, a triazole fungicide: role of the constitutive androstane receptor. Toxicol. Sci. (2007) 99: 315-325. |
| [13] | Vincent AE, Ng YS, White K, Davey T, Mannella C, Falkous G, Feeney C, Schaefer AM, McFarlan, R, Gorman GS, Taylor RW, Turnbull DM, Picard M. The spectrum of mitochondrial ultrastructural defects in mitochondrial myopathy. Sci Rep. (2016) 6: 30610. |
| [14] | Fenech M. The in vitro micronucleus technique. Mutation Research (2000) 455: 81-95. |
| [15] | Prenkumar K., Bowlus CL. Ascorbic acid reduces the frequency of iron-induced micronuclei in bone marrow cells of mice. Mutat. Res. (2003) 542: 99–103. |
| [16] | Schmid W. The Micronucleus test. Mut. Res. (1975) 31: 9–15. |
| [17] | Yuzbasioglu D, Unal F, Yılmaz S, Aksoy H, Celik M. Genotoxicity testing of fluconazole in vivo and in vitro. Mut. Res. (2008) 649: 155–160. |
| [18] | Gisselsson D, Bjork J, Hoglund JM, Mertens F, Dal Cin P, Akerman M, Mandahl N. Abnormal nuclear shape in soild tumors reflects mitotic instability. Am. J. Pathol. (2001) 158: 199-206. |
| [19] | Holeckova B, Dianovsky J, Sivikova K, Mesarc M. Detection of chromosomal aberrations in cattle cells after conazole fungicide treatment. Toxicology. (2010) 196S: S37–S351. |
| [20] | Preston RJ, Kean BJ, Galloway S. Mammalian in vivo cytogenetic assays: Analysis of chromosome aberrations in bone-marrow cells. Mutat. Res. (1987) 198: 157-165. |
| [21] | Saad HG, Dalvai F, Tanguy-le-Gac, M, Lane, N, Bystricky, K. DNA Dynamics during Early Double-Strand Break Processing Revealed by Non-Intrusive Imaging of Living Cells. PLoS Genet. (2014) 10 (3): e1004187. |
| [22] | Bancroft JD. Theory and practice of histological techniques. 4th ed. Churchill Li veinstone, 1996. |
| [23] | Bozzola, JJ, Russell, LD. Electron microscopy, 2nd ed. Jones and Bartlett publishers, 1998. |
| [24] | Sun G, Thai SF, Lambert GR, Wolf DC, Tully DB, Goetz AK, George MH, Grindstaff RD, Dix DJ, Nesnow S. Fluconazole-induced hepatic cytochrome P450 gene expression and enzymatic activities in rats and mice. Toxicol. Lett. (2006) 164: 44–53. |
| [25] | Potapova T, Gorbsky GJ. The consequences of chromosome segregation errors in mitosis and meiosis. Biology (2017) 6: 12-22. |
| [26] | Biswas SJ, Pathak S, Khuda-Bukhsh AR. Assessment of the genotoxic and cytotoxic potential of an anti-epileptic drug, Phenobarbital, in mice: a time course study. Mut. Res. (2004) 563: 1–11. |
| [27] | Badr A. Cytogenetic activities of 3 sulphonamides. Mut. Res. (1982) 104: 95-100. |
| [28] | Michailova P, Petrova N, Bovera S, Cavicchioh O, Ramella L Sella G. Effect of environmental pollution on the chromosomal variability of chironomus riparius meigen, 1804 (Diptera, chironmidae) Larvae From two Predmont Stations. Genetica. (2000) 108: 171–180. |
| [29] | Oller AR, Erexson G. Lack of micronuclei formation in bone marrow of rats after repeated oral exposure to nickel sulfate hexahydrate. Mutat. Res. (2007) 626 (1–2): 102–110. |
| [30] | Harrison BD, Hashemi J, Bibi M, Pulver R, Bavli D, Nahmias Y, Wellington M, Sapiro G, Berman JA. Tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. PLoS Biol., 2014; 12: e1001815. |
| [31] | Correa RM, Mota TC, Guimarães AC, Bonfim LT, Burbano RR, Bahia MO. Cytotoxic and Genotoxic Effects of Fluconazole on African Green Monkey Kidney (Vero) Cell Line. Biomed. Res. Int. (2018) 6271547. |
| [32] | Jain CK, Majumder HK, Roychoudhury S. Natural compounds as anticancer agents targeting DNA topoisomerases. Curr Genomics. (2017). 18: 75-92. |
| [33] | Dbouk ND, Covington MB, Nguyen K, Chandrasekaran S. Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans. Microbiology. (2019) 19: 243-253. |
| [34] | Peng CA, Gaertner AAE, Henriquez SA, Fang D. Colon-Reyes, R. J. Brumaghim J. L. and Kozubowski, L. Fluconazole induces ROS in Cryptococcus neoformans and contributes to DNA damage in vitro, PLoS One. (2018) 13: e0208471. |
| [35] | Khoza S, Ishmael M, Denver N. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats. J. Toxicol. (2017) 9–18. |
| [36] | Shubin AV, Demidyuk AA, Komissarov et al. Cytoplasmic vacuolization in cell death and survival. Oncotarget. (2016) 7: 55863–55889. |
| [37] | Emam H, Ahmed E, Abdel-Daim M. Antioxidant capacity of omega-3-fatty acids and vitamin E against imidacloprid-induced hepatotoxicity in Japanese quails. Environ Sci Pollut Res. (2018) 25: 11694–11702. |
| [38] | Vohra P, Khera KS. Alterations in key enzymes and micromorphology of vital organs during exposure of imidacloprid in albino rats. Int J. (2015) 3: 134–144. |
| [39] | Jensen HK. et al. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J. Clin. Oncol. (2009) 27: 4709–4717. |
| [40] | Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. (2018) 9: 7204–7218. |
| [41] | Ozkorkmaz EG, Gul N, Ozluk A, Ozay Y. Ultrastructural Alterations of Liver Tissue Cells in Methotrexate-Treated Balb/c Mice. J Microsc Ultrastruct. (2018) 6 (4): 192-196. |
| [42] | Łotowska JM, Sobaniec-Łotowska1 ME, Sobaniec P, Lebensztej DM, Liver sinusoidal endothelial cells in morphogenesis of pediatric autoimmune hepatitis. Ultrastructural characteristics–a novel report. Pol. J. Pathol. (2018) 69 (4): 327-334. |
| [43] | Somchit N, Ngee CS, Yaakob A, Zuraini AZ, Zakaria ZA. Effects of cytochrome P450 inhibitors on itraconazole and fluconazole induced cytotoxicity in hepatocytes. J. Toxicol. (2009) 912320: 30-37. |
| [44] | Picard M, McManus MJ, Csordás G, Várnai P, Dorn GW, Williams D, Hajnóczky G, Wallace DC. Trans-mitochondrial coordination of cristae at regulated membrane junctions. Nat Commun. (2015) 17 (6): 6259. |
| [45] | Fucic A, Markovic D, Herceg Z, Gamulin M, Katic J, Stojkovic R, Ferencic Z, Mildner B, Jazbec AM, Dobranic T. Developmental and transplacental genotoxicology: Fluconazole. Mut. Res. (2008) 657: 43–47. |
APA Style
Azza Attia, Cecil Matta, Reda Elmazoudy, Zeinab Elhenshery. (2021). Cytogenetic and Ultrastructural Studies of Effects of Antifungal Drug, Fluconazole on Liver of New-born Mice. Biomedical Sciences, 7(1), 1-9. https://doi.org/10.11648/j.bs.20210701.11
ACS Style
Azza Attia; Cecil Matta; Reda Elmazoudy; Zeinab Elhenshery. Cytogenetic and Ultrastructural Studies of Effects of Antifungal Drug, Fluconazole on Liver of New-born Mice. Biomed. Sci. 2021, 7(1), 1-9. doi: 10.11648/j.bs.20210701.11
AMA Style
Azza Attia, Cecil Matta, Reda Elmazoudy, Zeinab Elhenshery. Cytogenetic and Ultrastructural Studies of Effects of Antifungal Drug, Fluconazole on Liver of New-born Mice. Biomed Sci. 2021;7(1):1-9. doi: 10.11648/j.bs.20210701.11
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Download@article{10.11648/j.bs.20210701.11,
author = {Azza Attia and Cecil Matta and Reda Elmazoudy and Zeinab Elhenshery},
title = {Cytogenetic and Ultrastructural Studies of Effects of Antifungal Drug, Fluconazole on Liver of New-born Mice},
journal = {Biomedical Sciences},
volume = {7},
number = {1},
pages = {1-9},
doi = {10.11648/j.bs.20210701.11},
url = {https://doi.org/10.11648/j.bs.20210701.11},
eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bs.20210701.11},
abstract = {As a potent antifungal drug, fluconazole clinically used to eradicate both systemic and superficial mycoses resulting in hepatotoxicity. The objective of the current study was to evaluate hepatotoxicity and genotoxicity in newborn male mice. Mice were treated orally with 0.5 ml fluconazole doses of (0, 25, 50, and 100 mg/kgbw) per day for five consecutive weeks. Micronucleus test, chromosomal aberrations in bone marrow cells, histopathological investigation and DNA fragmentation in the liver tissue was done. Micronuclei are significantly noticed in bone marrow cells of mice given 50 and 100 mg/kgbw fluconazole however, there is no effect on the genotoxicity induced by 25 mg/kgbw dose of fluconazole. A dose-dependent and significant increase in structural and numerical chromosomal aberrations were detected in the 50 and 100 mg/kgbw fluconazole-treated group but a 100 mg/kg was highly significant. The chromosomal aberrations were manifested in hypoploidy, deletion, centric fusion and stickiness. Besides, hepatocellular massive infiltration, cytoplasmic vacuolation, congestion and dilatation in the central veins were seen in 50 and 100 mg/kgbw fluconazole. Interestingly, 25mg/kgbw fluconazole-treated mice showed mild hepatocellular degeneration. Consequently, these findings confirmed that fluconazole to a greater extent was a potent hepatotoxic drug in vivo in newborn mice.},
year = {2021}
}
TY - JOUR T1 - Cytogenetic and Ultrastructural Studies of Effects of Antifungal Drug, Fluconazole on Liver of New-born Mice AU - Azza Attia AU - Cecil Matta AU - Reda Elmazoudy AU - Zeinab Elhenshery Y1 - 2021/01/12 PY - 2021 N1 - https://doi.org/10.11648/j.bs.20210701.11 DO - 10.11648/j.bs.20210701.11 T2 - Biomedical Sciences JF - Biomedical Sciences JO - Biomedical Sciences SP - 1 EP - 9 PB - Science Publishing Group SN - 2575-3932 UR - https://doi.org/10.11648/j.bs.20210701.11 AB - As a potent antifungal drug, fluconazole clinically used to eradicate both systemic and superficial mycoses resulting in hepatotoxicity. The objective of the current study was to evaluate hepatotoxicity and genotoxicity in newborn male mice. Mice were treated orally with 0.5 ml fluconazole doses of (0, 25, 50, and 100 mg/kgbw) per day for five consecutive weeks. Micronucleus test, chromosomal aberrations in bone marrow cells, histopathological investigation and DNA fragmentation in the liver tissue was done. Micronuclei are significantly noticed in bone marrow cells of mice given 50 and 100 mg/kgbw fluconazole however, there is no effect on the genotoxicity induced by 25 mg/kgbw dose of fluconazole. A dose-dependent and significant increase in structural and numerical chromosomal aberrations were detected in the 50 and 100 mg/kgbw fluconazole-treated group but a 100 mg/kg was highly significant. The chromosomal aberrations were manifested in hypoploidy, deletion, centric fusion and stickiness. Besides, hepatocellular massive infiltration, cytoplasmic vacuolation, congestion and dilatation in the central veins were seen in 50 and 100 mg/kgbw fluconazole. Interestingly, 25mg/kgbw fluconazole-treated mice showed mild hepatocellular degeneration. Consequently, these findings confirmed that fluconazole to a greater extent was a potent hepatotoxic drug in vivo in newborn mice. VL - 7 IS - 1 ER -
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