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      Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]

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      Embargo Lift Date: 2022-06-24
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      Author(s)
      Fernandez-Checa, J. C.
      Bagnaninchi, P.
      Ye, H.
      Sancho-Bru, P.
      Falcon-Perez, J. M.
      Royo, F.
      Garcia-Ruiz, C.
      Konu, Özlen
      Miranda, J.
      Lunov, O.
      Dejneka, A.
      Elfick, A.
      McDonald, A.
      Sullivan, G. J.
      Aithal, G. P.
      Lucena, M. I.
      Andrade, R. J.
      Fromenty, B.
      Kranendonk, M.
      Cubero, F. J.
      Nelson, L. J.
      Date
      2021-06-24
      Source Title
      Journal of Hepatology
      Print ISSN
      0168-8278
      Publisher
      Elsevier
      Volume
      75
      Issue
      4
      Pages
      935 - 959
      Language
      English
      Type
      Article
      Item Usage Stats
      53
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      11
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      Abstract
      Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF) and one of the leading indications for liver transplantation in Western societies. Given the wide use of both prescribed and over the counter drugs, DILI has become a major health issue for which there is a pressing need to find novel and effective therapies. Although significant progress has been made in understanding the molecular mechanisms underlying DILI, our incomplete knowledge of its pathogenesis and inability to predict DILI is largely due to both discordance between human and animal DILI in preclinical drug development and a lack of models that faithfully recapitulate complex pathophysiological features of human DILI. This is exemplified by the hepatotoxicity of acetaminophen (APAP) overdose, a major cause of ALF because of its extensive worldwide use as an analgesic. Despite intensive efforts utilising current animal and in vitro models, the mechanisms involved in the hepatotoxicity of APAP are still not fully understood. In this expert Consensus Statement, which is endorsed by the European Drug-Induced Liver Injury Network, we aim to facilitate and outline clinically impactful discoveries by detailing the requirements for more realistic human-based systems to assess hepatotoxicity and guide future drug safety testing. We present novel insights and discuss major players in APAP pathophysiology, and describe emerging in vitro and in vivo pre-clinical models, as well as advanced imaging and in silico technologies, which may improve prediction of clinical outcomes of DILI.
      Keywords
      Acetaminophen
      iPSCs
      Liver-on-a-chip
      Humanized models
      Permalink
      http://hdl.handle.net/11693/77611
      Published Version (Please cite this version)
      https://doi.org/10.1016/j.jhep.2021.06.021
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      • Aysel Sabuncu Brain Research Center (BAM) 228
      • Department of Molecular Biology and Genetics 512
      • Institute of Materials Science and Nanotechnology (UNAM) 2098
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