Metabolism of Acetaminophen by Enteric Epithelial Cells Mitigates Hepatocellular Toxicity In Vitro

Author:

Morgan Katie1ORCID,Morley Steven D.1ORCID,Raja Arslan K.1ORCID,Vandeputte Martin1ORCID,Samuel Kay2ORCID,Waterfall Martin3ORCID,Homer Natalie Z. M.4ORCID,Hayes Peter C.1ORCID,Fallowfield Jonathan A.15ORCID,Plevris John N.1ORCID

Affiliation:

1. Hepatology Laboratory, The University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK

2. Scottish Blood Transfusion Service, Jack Copland Centre, 52 Research Avenue North, Edinburgh EH14 4BE, UK

3. Flow Cytometry Facility, Ashworth Laboratories, Institute of Immunology & Infection Research, The University of Edinburgh, The Kings Buildings, Edinburgh EH9 3FL, UK

4. Mass Spectrometry Facility, Centre for Cardiovascular Science, Queen’s Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

5. Institute for Regeneration and Repair, Edinburgh BioQuarter, The University of Edinburgh, 4-5 Little France Drive, Edinburgh EH16 4UU, UK

Abstract

The gut–liver axis is defined by dietary and environmental communication between the gut, microbiome and the liver with its redox and immune systems, the overactivation of which can lead to hepatic injury. We used media preconditioning to mimic some aspects of the enterohepatic circulation by treating the human Caco-2 intestinal epithelial cell line with 5, 10 and 20 mM paracetamol (N-acetyl-para-aminophenol; APAP) for 24 h, after which cell culture supernatants were transferred to differentiated human hepatic HepaRG cells for a further 24 h. Cell viability was assessed by mitochondrial function and ATP production, while membrane integrity was monitored by cellular-based impedance. Metabolism by Caco-2 cells was determined by liquid chromatography with tandem mass spectrometry. Caco-2 cell viability was not affected by APAP, while cell membrane integrity and tight junctions were maintained and became tighter with increasing APAP concentrations, suggesting a reduction in the permeability of the intestinal epithelium. During 24 h incubation, Caco-2 cells metabolised 64–68% of APAP, leaving 32–36% of intact starting compound to be transferred to HepaRG cells. When cultured with Caco-2-preconditioned medium, HepaRG cells also showed no loss of cell viability or membrane integrity, completely in contrast to direct treatment with APAP, which resulted in a rapid loss of cell viability and membrane integrity and, ultimately, cell death. Thus, the pre-metabolism of APAP could mitigate previously observed hepatotoxicity to hepatic tight junctions caused by direct exposure to APAP. These observations could have important implications for the direct exposure of hepatic parenchyma to APAP, administered via the intravenous route.

Funder

University of Edinburgh Hepatology Laboratory endowment funds

NHS Lothian R&D fund

Publisher

MDPI AG

Subject

General Medicine

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