Leading science, pioneering therapies
CRM Publications

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

TitleLow-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.
Publication TypeJournal Article
Year of Publication2017
AuthorsGamal W, Treskes P, Samuel K, Sullivan GJ, Siller R, Srsen V, Morgan K, Bryans A, Kozlowska A, Koulovasilopoulos A, Underwood I, Smith S, Del-Pozo J, Moss S, Thompson AInés, Henderson NC, Hayes PC, Plevris JN, Bagnaninchi PO, Nelson LJ
JournalSci Rep
Volume7
Pagination37541
Date Published2017 Jan 30
ISSN2045-2322
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.

DOI10.1038/srep37541
Alternate JournalSci Rep
PubMed ID28134251
PubMed Central IDPMC5278402
Publication institute
CRM