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Sci Rep. 2017 Jan 30;7:37541. doi: 10.1038/srep37541.

Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.

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MRC Centre for Regenerative Medicine, SCRM Building, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, UK.
Hepatology Laboratory, University of Edinburgh, Royal Infirmary of Edinburgh, 49 Little France Crescent EH16 4SB, UK.
Scottish National Blood Transfusion Service, Research, Development and Innovation Directorate, Cell Therapy Group, Ellens Glen Road, Edinburgh, EH17 7QT, UK.
Department of Biochemistry, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway, UK.
Norwegian Center for Stem Cell Research, PO Box 1112 Blindern, 0317 Oslo, Norway.
Institute of Immunology, Oslo University Hospital-Rikshospitalet, PO Box 4950 Nydalen, Oslo 0424, Norway.
Institute for Bioengineering, University of Edinburgh, King's Buildings, Colin MacLaurin Road, EH9 3DW, UK.
Institute for Integrated Micro and Nano systems, University of Edinburgh, Scottish Micro Electronic Centre, Alexander Crum Brown Road, EH9 3FF, UK.
Easter Bush Pathology, The Royal (Dick) School of Veterinary Studies and The Roslin Institute, Easter Bush Campus, Midlothian, EH25 9RG, UK.
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.


Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization.

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