Relationship of cellular topoisomerase IIα inhibition to cytotoxicity and published genotoxicity of fluoroquinolone antibiotics in V79 cells

Williams, Gary M.; Brunnemann, Klaus D.; Smart, Daniel J.; Molina, David A. Castillo; Jeffrey, Alan M.; Duan, Jian-Dong; Krebsfaenger, Niels; Kampkoetter, Andreas; Schmuck, Gabriele

doi:10.1016/j.cbi.2013.01.003

Cited by 12 publications

(5 citation statements)

References 26 publications

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“…Each value represents the mean ± SEM (n ≥ 3) after 24 h of treatment. Significant differences were observed between controls and matched groups (*p ≤ 0.05; **p ≤ 0.01) 1 3 through a clastogen topoisomerase inhibition MoA (Perrone et al 2002;Williams et al 2013). In vivo, its clastogenic properties were also reported (Singh et al 2003;Attia 2009).…”

Section: Discussionmentioning

confidence: 95%

Complementarity of phosphorylated histones H2AX and H3 quantification in different cell lines for genotoxicity screening

2015

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The in vitro micronucleus assay is broadly used, but is not per se able to discriminate aneugenic from clastogenic compounds, and cytotoxicity can be a confounding factor. In vitro genotoxicity assays generally rely on cell lines with limited metabolic capabilities. Recently, the use of histone H2AX and H3 phosphorylation markers (γH2AX and p-H3) was proposed to discriminate aneugenic from clastogenic chemicals. The aim of the present study was to develop a new genotoxic screening strategy based on the use of the γH2AX and p-H3 biomarkers in combination with cell lines with distinct biotransformation properties. First, we tested a training set of 20 model chemicals comprised of 10 aneugens, five clastogens and five cytotoxics on three human cell lines (HepG2, LS-174T and ACHN). Our data confirm the robustness of these two biomarkers to discriminate efficiently clastogens, aneugens and misleading cytotoxic chemicals in HepG2 cells. Aneugenic compounds induced either an increase or a decrease in p-H3 depending on their mode of action. Clastogens induced γH2AX, and cytotoxic compounds generated a marked decrease in these two biomarkers. Moreover, the use of different cell lines permits to discriminate direct from bioactivated genotoxins without the need of an exogenous metabolic activation system. Finally, we further evaluated this strategy using a test set of 13 chemicals with controversial genotoxic potential. The resulting data demonstrate that the combined analysis of γH2AX and p-H3 is an efficient strategy. Notably, we demonstrated that three compounds (fisetin, hydroquinone and okadaic acid) display both aneugenic and clastogenic properties.

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Section: Discussionmentioning

confidence: 95%

Complementarity of phosphorylated histones H2AX and H3 quantification in different cell lines for genotoxicity screening

2015

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“…Besides anthracylines, a second group of Topoisomerase 2 poisons are known to impair mitochondria. Fluoroquinolones, originally thought to exclusively inhibit bacterial TopIV and gyrase and therefore used in antibacterial therapy, are known to also affect eukaryotic Top2s [85,86,87]. While fluoroquinolone antibiotics are prescribed and consumed frequently without problems, in rare cases, they can lead to adverse effects.…”

Section: Inhibition Of Topoisomerase Function In Mitochondriamentioning

confidence: 99%

Twist and Turn—Topoisomerase Functions in Mitochondrial DNA Maintenance

Goffart

Hangas

Pohjoismäki

2019

IJMS

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Like any genome, mitochondrial DNA (mtDNA) also requires the action of topoisomerases to resolve topological problems in its maintenance, but for a long time, little was known about mitochondrial topoisomerases. The last years have brought a closer insight into the function of these fascinating enzymes in mtDNA topology regulation, replication, transcription, and segregation. Here, we summarize the current knowledge about mitochondrial topoisomerases, paying special attention to mammalian mitochondrial genome maintenance. We also discuss the open gaps in the existing knowledge of mtDNA topology control and the potential involvement of mitochondrial topoisomerases in human pathologies. While Top1mt, the only exclusively mitochondrial topoisomerase in mammals, has been studied intensively for nearly a decade, only recent studies have shed some light onto the mitochondrial function of Top2β and Top3α, enzymes that are shared between nucleus and mitochondria. Top3α mediates the segregation of freshly replicated mtDNA molecules, and its dysfunction leads to mtDNA aggregation and copy number depletion in patients. Top2β, in contrast, regulates mitochondrial DNA replication and transcription through the alteration of mtDNA topology, a fact that should be acknowledged due to the frequent use of Topoisomerase 2 inhibitors in medical therapy.

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“…However, similar effect could be produced on eukaryotic cells. Recently, it has been reported that fluoroquinolones are genotoxic in mammalian cells in culture [47]. Correlation between a particular compound and the observed genotoxicity is a difficult task.…”

Section: Resultsmentioning

confidence: 99%

Ecotoxicological and Genotoxic Evaluation of Buenos Aires City (Argentina) Hospital Wastewater

Magdaleno

Juárez

Dragani

et al. 2014

Journal of Toxicology

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Hospital wastewater (HWW) constitutes a potential risk to the ecosystems and human health due to the presence of toxic and genotoxic chemical compounds. In the present work we investigated toxicity and genotoxicity of wastewaters from the public hospital of Buenos Aires (Argentina). The effluent from the sewage treatment plant (STP) serving around 10 million inhabitants was also evaluated. The study was carried out between April and September 2012. Toxicity and genotoxicity assessment was performed using the green algae Pseudokirchneriella subcapitata and the Allium cepa test, respectively. Toxicity assay showed that 55% of the samples were toxic to the algae (%I of growth between 23.9 and 54.8). The A. cepa test showed that 40% of the samples were genotoxic. The analysis of chromosome aberrations (CA) and micronucleus (MN) showed no significant differences between days and significant differences between months. The sample from the STP was not genotoxic to A. cepa but toxic to the algae (%I = 41%), showing that sewage treatment was not totally effective. This study highlights the need for environmental control programs and the establishment of advanced and effective effluent treatment plants in the hospitals, which are merely dumping the wastewaters in the municipal sewerage system.

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Relationship of cellular topoisomerase IIα inhibition to cytotoxicity and published genotoxicity of fluoroquinolone antibiotics in V79 cells

Cited by 12 publications

References 26 publications

Complementarity of phosphorylated histones H2AX and H3 quantification in different cell lines for genotoxicity screening

Complementarity of phosphorylated histones H2AX and H3 quantification in different cell lines for genotoxicity screening

Twist and Turn—Topoisomerase Functions in Mitochondrial DNA Maintenance

Ecotoxicological and Genotoxic Evaluation of Buenos Aires City (Argentina) Hospital Wastewater

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