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Research ArticleToxicology

Trovafloxacin Enhances Lipopolysaccharide-Stimulated Production of Tumor Necrosis Factor-α by Macrophages: Role of the DNA Damage Response

Kyle L. Poulsen, Jesus Olivero-Verbel, Kevin M. Beggs, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics July 2014, 350 (1) 164-170; DOI: https://doi.org/10.1124/jpet.114.214189
Kyle L. Poulsen
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan (K.L.P., K.M.B., P.E.G., and R.A.R.); and Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, Colombia (J.O.-V.)
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Jesus Olivero-Verbel
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan (K.L.P., K.M.B., P.E.G., and R.A.R.); and Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, Colombia (J.O.-V.)
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Kevin M. Beggs
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan (K.L.P., K.M.B., P.E.G., and R.A.R.); and Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, Colombia (J.O.-V.)
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Patricia E. Ganey
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan (K.L.P., K.M.B., P.E.G., and R.A.R.); and Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, Colombia (J.O.-V.)
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Robert A. Roth
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan (K.L.P., K.M.B., P.E.G., and R.A.R.); and Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, Colombia (J.O.-V.)
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Abstract

Trovafloxacin (TVX) is a drug that has caused idiosyncratic, drug-induced liver injury (IDILI) in humans. In a murine model of IDILI, otherwise nontoxic doses of TVX and the inflammagen lipopolysaccharide (LPS) interacted to produce pronounced hepatocellular injury. The liver injury depended on a TVX-induced, small but significant prolongation of tumor necrosis factor-α (TNF) appearance in the plasma. The enhancement of TNF expression by TVX was reproduced in vitro in RAW 264.7 murine macrophages (RAW cells) stimulated with LPS. The current study was designed to identify the molecular target of TVX responsible for this response in RAW cells. An in silico analysis suggested a favorable binding profile of TVX to eukaryotic topoisomerase II-α (TopIIα), and a cell-free assay revealed that TVX inhibited eukaryotic TopIIα activity. Topoisomerase inhibition is known to lead to DNA damage, and TVX increased the DNA damage marker phosphorylated histone 2A.X in RAW cells. Moreover, TVX induced activation of the DNA damage sensor kinases, ataxia telangiectasia mutated (ATM) and Rad3-related (ATR). The ATR inhibitor NU6027 [6-(cyclohexylmethoxy)-5-nitrosopyrimidine-2,4-diamine] prevented the TVX-mediated increases in LPS-induced TNF mRNA and protein release, whereas a selective ATM inhibitor [2-(4-morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one (KU55933)] was without effect. TVX prolonged TNF mRNA stability, and this effect was largely attenuated by NU6027. These results suggest that TVX can inhibit eukaryotic topoisomerase, leading to activation of ATR and potentiation of TNF release by macrophages, at least in part through increased mRNA stability. This off-target effect might contribute to the ability of TVX to precipitate IDILI in humans.

Footnotes

    • Received February 23, 2014.
    • Accepted May 5, 2014.
  • This study was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK061315]. K.L.P. was supported by the National Institutes of Health National Institute of Environmental Health Sciences Training Grant [Grant T32-ES007255].

  • dx.doi.org/10.1124/jpet.114.214189.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 1
1 Jul 2014
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Research ArticleToxicology

Trovafloxacin-Induced TNF Production

Kyle L. Poulsen, Jesus Olivero-Verbel, Kevin M. Beggs, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics July 1, 2014, 350 (1) 164-170; DOI: https://doi.org/10.1124/jpet.114.214189

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Research ArticleToxicology

Trovafloxacin-Induced TNF Production

Kyle L. Poulsen, Jesus Olivero-Verbel, Kevin M. Beggs, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics July 1, 2014, 350 (1) 164-170; DOI: https://doi.org/10.1124/jpet.114.214189
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