1. Academic Validation
  2. The hepatotoxic fluoroquinolone trovafloxacin disturbs TNF- and LPS-induced p65 nuclear translocation in vivo and in vitro

The hepatotoxic fluoroquinolone trovafloxacin disturbs TNF- and LPS-induced p65 nuclear translocation in vivo and in vitro

  • Toxicol Appl Pharmacol. 2020 Mar 15;391:114915. doi: 10.1016/j.taap.2020.114915.
Giulio Giustarini 1 Suzanna Huppelschoten 2 Marco Barra 3 Angela Oppelt 4 Laura Wagenaar 5 Richard J Weaver 6 Marianne Bol-Schoenmakers 5 Joost J Smit 5 Bob van de Water 2 Ursula Klingmüller 4 Raymond H H Pieters 7
Affiliations

Affiliations

  • 1 Immunotoxicology, Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands. Electronic address: g.giustarini@uu.nl.
  • 2 Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
  • 3 Immunotoxicology, Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; University of Pisa, Department of Pharmacy, Italy.
  • 4 Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 5 Immunotoxicology, Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
  • 6 Biopharmacy, Institut de Recherches Internationales Servier (I.R.I.S.), Suresnes 92284, France.
  • 7 Immunotoxicology, Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands. Electronic address: r.h.h.pieters@uu.nl.
Abstract

Idiosyncratic drug-induced liver injury (IDILI) is a severe disease that cannot be detected during drug development. It has been shown that hepatotoxicity of some compounds associated with IDILI becomes apparent when these are combined in vivo and in vitro with LPS or TNF. Among these compounds trovafloxacin (TVX) induced Apoptosis in the liver and increased pro-inflammatory cytokines in mice exposed to LPS/TNF. The hepatocyte survival and the cytokine release after TNF/LPS stimulation relies on a pulsatile activation of NF-κB. We set out to evaluate the dynamic activation of NF-κB in response to TVX + TNF or LPS models, both in mouse and human cells. Remarkably, TVX prolonged the first translocation of NF-κB induced by TNF both in vivo and in vitro. The prolonged p65 translocation caused by TVX was associated with an increased phosphorylation of IKK and MAPKs and accumulation of inhibitors of NF-κB such as IκBα and A20 in HepG2. Coherently, TVX suppressed further TNF-induced NF-κB translocations in HepG2 leading to decreased transcription of ICAM-1 and inhibitors of Apoptosis. TVX prolonged LPS-induced NF-κB translocation in RAW264.7 macrophages increasing the secretion of TNF. In summary, this study presents new, relevant insights into the mechanism of TVX-induced liver injury underlining the resemblance between mouse and human models. In this study we convincingly show that regularly used toxicity models provide a coherent view of relevant pathways for IDILI. We propose that assessment of the kinetics of activation of NF-κB and MAPKs is an appropriate tool for the identification of hepatotoxic compounds during drug development.

Keywords

Drug-induced liver injury; Inflammation; LPS; NF-κB; TNF; Trovafloxacin.

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