Title | Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Gamal 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 |
Journal | Sci Rep |
Volume | 7 |
Pagination | 37541 |
Date Published | 2017 Jan 30 |
ISSN | 2045-2322 |
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. |
DOI | 10.1038/srep37541 |
Alternate Journal | Sci Rep |
PubMed ID | 28134251 |
PubMed Central ID | PMC5278402 |