title: Acetaminophen cytotoxicity is ameliorated in a human liver organotypic co-culture model.
abstract: Organotypic liver culture models for hepatotoxicity studies that mimic in vivo hepatic functionality could help facilitate improved strategies for early safety risk assessment during drug development. Interspecies differences in drug sensitivity and mechanistic profiles, low predictive capacity, and limitations of conventional monocultures of human hepatocytes, with high attrition rates remain major challenges. Herein, we show stable, cell-type specific phenotype/cellular polarity with differentiated functionality in human hepatocyte-like C3A cells (enhanced CYP3A4 activity/albumin synthesis) when in co-culture with human vascular endothelial cells (HUVECs), thus demonstrating biocompatibility and relevance for evaluating drug metabolism and toxicity. In agreement with in vivo studies, acetaminophen (APAP) toxicity was most profound in HUVEC mono-cultures; whilst in C3A:HUVEC co-culture, cells were less susceptible to the toxic effects of APAP, including parameters of oxidative stress and ATP depletion, altered redox homeostasis, and impaired respiration. This resistance to APAP is also observed in a primary human hepatocyte (PHH) based co-culture model, suggesting bidirectional communication/stabilization between different cell types. This simple and easy-to-implement human co-culture model may represent a sustainable and physiologically-relevant alternative cell system to PHHs, complementary to animal testing, for initial hepatotoxicity screening or mechanistic studies of candidate compounds differentially targeting hepatocytes and endothelial cells.
authors.affiliation: Department of Hepatology, Hepatology Laboratory, University of Edinburgh, Edinburgh, UK.
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Nelson
authors.affiliation: Department of Hepatology, Hepatology Laboratory, University of Edinburgh, Edinburgh, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Department of Hepatology, Hepatology Laboratory, University of Edinburgh, Edinburgh, UK.
authors.forename: Philipp
authors.initials: P
authors.lastname: Treskes
authors.affiliation: Scottish National Blood Transfusion Service (SNBTS); Cell Therapy Research Group, Scottish Centre for Regenerative Medicine, University of Edinburgh, UK.
authors.forename: Kay
authors.initials: K
authors.lastname: Samuel
authors.affiliation: Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); University of Barcelona. Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Tura-Ceide
authors.affiliation: Department of Hepatology, Hepatology Laboratory, University of Edinburgh, Edinburgh, UK.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Morley
authors.affiliation: Department of Hepatology, Hepatology Laboratory, University of Edinburgh, Edinburgh, UK.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hayes
authors.affiliation: Department of Hepatology, Hepatology Laboratory, University of Edinburgh, Edinburgh, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Plevris
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects; D019289:Pyruvic Acid / Q000378:metabolism; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D007773:Lactates; D000082:Acetaminophen; D019289:Pyruvic Acid