ArticleThe Journal of pharmacology and experimental therapeutics2014
Trovafloxacin enhances lipopolysaccharide-stimulated production of tumor necrosis factor-α by macrophages: role of the DNA damage response.
Article in The Journal of pharmacology and experimental therapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 45 citations in OpenAlex.
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- Novel Naphthyridones Targeting Pannexin 1 for Colitis Management.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The involvement of hepatic cytochrome P450s in the cytotoxicity of lapatinib.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- A novel anticancer quinolone, (R)-WAC-224, has anti-leukemia activities against acute myeloid leukemia.Investigational new drugs · 2023Article
- The development and benefits of metformin in various diseases.Frontiers of medicine · 2023Review
- Tissue Reactions and Mechanism in Cardiovascular Diseases Induced by Radiation.International journal of molecular sciences · 2022Review
- Investigation of the idiosyncratic hepatotoxicity of Polygonum multiflorum Thunb. through metabolomics using GC-MS.BMC complementary medicine and therapies · 2021Article
- Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity.Cell communication and signaling : CCS · 2021Article
- Screening for Susceptibility-Related Biomarkers of Diclofenac-Induced Liver Injury in Rats Using Metabolomics.Frontiers in pharmacology · 2021Article
- Susceptibility-Related Cytokine Panel for Prediction ofJournal of inflammation research · 2021Article
- The role of hepatic cytochrome P450s in the cytotoxicity of sertraline.Archives of toxicology · 2020Article
- Screening for Susceptibility-Related Factors and Biomarkers of Xianling Gubao Capsule-Induced Liver Injury.Frontiers in pharmacology · 2020Article
- Emerging Therapeutic Targets AgainstFrontiers in cellular and infection microbiology · 2020Review
- Hepatotoxicity Induced by Isoniazid-Lipopolysaccharide through Endoplasmic Reticulum Stress, Autophagy, and Apoptosis Pathways in Zebrafish.Antimicrobial agents and chemotherapy · 2019Article
- The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone.Archives of toxicology · 2018Article
- Genome-wide gene expression analysis of amphioxus (Branchiostoma belcheri) following lipopolysaccharide challenge using strand-specific RNA-seq.RNA biology · 2017Article
- Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum.Frontiers of medicine · 2017Article
- A novel antagonist of p75NTR reduces peripheral expansion and CNS trafficking of pro-inflammatory monocytes and spares function after traumatic brain injury.Journal of neuroinflammation · 2016Article
- Metabolomic Study on Idiosyncratic Liver Injury Induced by Different Extracts ofFrontiers in pharmacology · 2016Article
- Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.