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

Wesam Gamal, Philipp Treskes, Kay Samuel, Gareth J. Sullivan, Richard Siller, Vlastamil Srsen, Katie Morgan, Anna Bryans, Ada Kozlowska, Andreas Koulovasilopoulos, Ian Underwood, Stewart Smith, Jorge del-Pozo, Sharon Moss, Alexandra Inés Thompson, Neil C. Henderson, Peter C. Hayes, John N. Plevris, Pierre-Olivier Bagnaninchi, Leonard J. Nelson

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Article number37541
Number of pages16
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 30 Jan 2017

Fingerprint

Dive into the research topics of 'Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver'. Together they form a unique fingerprint.

Cite this