当前位置: X-MOL 学术Toxicol. Appl. Pharmacol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
The hepatotoxic fluoroquinolone trovafloxacin disturbs TNF- and LPS-induced p65 nuclear translocation in vivo and in vitro.
Toxicology and Applied Pharmacology ( IF 3.3 ) Pub Date : 2020-02-06 , DOI: 10.1016/j.taap.2020.114915
Giulio Giustarini 1 , Suzanna Huppelschoten 2 , Marco Barra 3 , Angela Oppelt 4 , Laura Wagenaar 1 , Richard J Weaver 5 , Marianne Bol-Schoenmakers 1 , Joost J Smit 1 , Bob van de Water 2 , Ursula Klingmüller 4 , Raymond H H Pieters 1
Affiliation  

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.

中文翻译:

肝毒性氟喹诺酮曲伐沙星在体内和体外干扰TNF和LPS诱导的p65核移位。

特异药物性肝损伤(IDILI)是一种严重的疾病,在药物开发过程中无法检测到。已经显示,当与IDILI相关的某些化合物在体内和体外与LPS或TNF组合时,其肝毒性变得明显。在这些化合物中,Trovafloxacin(TVX)在暴露于LPS / TNF的小鼠中诱导肝脏凋亡,并增加促炎细胞因子。TNF / LPS刺激后,肝细胞存活和细胞因子释放依赖于NF-κB的脉冲激活。我们着手评估在小鼠和人类细胞中响应TVX + TNF或LPS模型的NF-κB的动态激活。值得注意的是,TVX在体内和体外都延长了TNF诱导的NF-κB的首次转运。TVX引起的延长的p65易位与IKK和MAPK的磷酸化增加以及NF-κB抑制剂(例如IκBα和A20)在HepG2中的积累有关。相干地,TVX进一步抑制了TNF诱导的HepG2中的NF-κB易位,从而导致ICAM-1的转录减少和凋亡抑制剂。TVX延长了RAW264.7巨噬细胞中LPS诱导的NF-κB移位,从而增加了TNF的分泌。总而言之,这项研究提供了有关TVX诱发的肝损伤机制的新​​的相关见解,突显了小鼠和人类模型之间的相似性。在这项研究中,我们令人信服地表明,经常使用的毒性模型为IDILI的相关途径提供了一致的观点。
更新日期:2020-02-05
down
wechat
bug