Second exposure to acetaminophen overdose is associated with liver fibrosis in mice

Authors

  • Mohammad AlWahsh Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan; Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany, Tel: +49 231 1392 192, E-mail: mohammad.al-wahsh@isas.de
  • Amnah Othman Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany
  • Lama Hamadneh Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
  • Ahmad Telfah Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany
  • Jörg Lambert Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany
  • Suhair Hikmat Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
  • Amin Alassi Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
  • Fatma El Zahraa Mohamed Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167-Mannheim, Germany; Department of Pathology, Faculty of Medicine, Minia University, 11432-Minia, Egypt
  • Roland Hergenröder Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany
  • Tariq Al-Qirim Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
  • Steven Dooley Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167-Mannheim, Germany
  • Seddik Hammad Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167-Mannheim, Germany; Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany, Tel: +49 621 383 5603, E-mail: seddik.hammad@medma.uni-heidelberg.de; Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523-Qena, Egypt

DOI:

https://doi.org/10.17179/excli2018-1920

Keywords:

APAP, metabolic profiling, adaptation

Abstract

Repeated administration of hepatotoxicants is usually accompanied by liver fibrosis. However, the difference in response as a result of repeated exposures of acetaminophen (APAP) compared to a single dose is not well-studied. Therefore, in the current study, the liver response after a second dose of APAP was investigated. Adult fasted Balb/C mice were exposed to two toxic doses of 300 mg/kg APAP, which were administered 72 h apart from each other. Subsequently, blood and liver from the treated mice were collected 24 h and 72 h after both APAP administrations. Liver transaminase, i.e. alanine amino transferase (ALT) and aspartate amino transferase (AST) levels revealed that the fulminant liver damage was reduced after the second APAP administration compared to that observed at the same time point after the first treatment. These results correlated with the necrotic areas as indicated by histological analyses. Surprisingly, Picro Sirius Red (PSR) staining showed that the accumulation of extracellular matrix after the second dose coincides with the upregulation of some fibrogenic signatures, e.g., alpha smooth muscle actin. Non-targeted liver tissue metabolic profiling indicates that most alterations occur 24 h after the first dose of APAP. However, the levels of most metabolites recover to basal values over time. This organ adaptation process is also confirmed by the upregulation of antioxidative systems like e.g. superoxide dismutase and catalase. From the results, it can be concluded that there is a different response of the liver to APAP toxic doses, if the liver has already been exposed to APAP. A necroinflammatory process followed by a liver regeneration was observed after the first APAP exposure. However, fibrogenesis through the accumulation of extracellular matrix is observed after a second challenge. Therefore, further studies are required to mechanistically understand the so called “liver memory”.

Published

2019-02-06

How to Cite

AlWahsh, M., Othman, A., Hamadneh, L., Telfah, A., Lambert, J., Hikmat, S., Alassi, A., Mohamed, F. E. Z., Hergenröder, R., Al-Qirim, T., Dooley, S., & Hammad, S. (2019). Second exposure to acetaminophen overdose is associated with liver fibrosis in mice. EXCLI Journal, 18, 51–62. https://doi.org/10.17179/excli2018-1920

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Section

Original articles