title: Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes.
abstract: Human pluripotent stem cells (hPSC) have the potential to become important tools for the establishment of new models for in vitro drug testing of, for example, toxicity and pharmacological effects. Late-stage attrition in the pharmaceutical industry is to a large extent caused by selection of drug candidates using nonpredictive preclinical models that are not clinically relevant. The current hepatic in vivo and in vitro models show clear limitations, especially for studies of chronic hepatotoxicity. For these reasons, we evaluated the potential of using hPSC-derived hepatocytes for long-term exposure to toxic drugs. The differentiated hepatocytes were incubated with hepatotoxic compounds for up to 14 days, using a repeated-dose approach. The hPSC-derived hepatocytes became more sensitive to the toxic compounds after extended exposures and, in addition to conventional cytotoxicity, evidence of phospholipidosis and steatosis was also observed in the cells. This is, to the best of our knowledge, the first report of a long-term toxicity study using hPSC-derived hepatocytes, and the observations support further development and validation of hPSC-based toxicity models for evaluating novel drugs, chemicals, and cosmetics.
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.) Gustav.holmgren@his.se.
authors: Gustav
authors: G
authors: Holmgren
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
authors: Anna-Karin
authors: AK
authors: Sjögren
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
authors: Isabel
authors: I
authors: Barragan
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
authors: Alan
authors: A
authors: Sabirsh
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
authors: Peter
authors: P
authors: Sartipy
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
authors: Jane
authors: J
authors: Synnergren
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
authors: Petter
authors: P
authors: Björquist
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
authors: Magnus
authors: M
authors: Ingelman-Sundberg
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
authors: Tommy B
authors: TB
authors: Andersson
authors: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
authors: Josefina
authors: J
authors: Edsbagge
mesh_terms: D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology*; D005234:Fatty Liver / Q000139:chemically induced; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D008064:Lipidoses / Q000139:chemically induced; D008099:Liver / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D039904:Pluripotent Stem Cells / Q000187:drug effects*
chemical_list: D004364:Pharmaceutical Preparations