Preliminary Evaluation of Three-Dimensional Primary Human Hepatocyte Culture System for Assay of Drug-Metabolizing Enzyme-Inducing Potential

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  • Arakawa Hiroshi
    Laboratory of Biopharmaceutics, Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
  • Kamioka Hiroki
    Laboratory of Biopharmaceutics, Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare
  • Jomura Tomoko
    Biotech Application Group Research and Development, Toyo Gosei Co., Ltd.
  • Koyama Satoshi
    Laboratory of Biopharmaceutics, Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare
  • Idota Yoko
    Laboratory of Biopharmaceutics, Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare
  • Yano Kentaro
    Laboratory of Biopharmaceutics, Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare
  • Kojima Hajime
    Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences
  • Ogihara Takuo
    Laboratory of Biopharmaceutics, Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare

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<p>Drug-induced liver injury (DILI) is a common reason for withdrawal of candidate drugs from clinical trials, or of approved drugs from the market. DILI may be induced not only by intact parental drugs, but also by metabolites or intermediates, and therefore should be evaluated in the enzyme-induced state. Here, we present a protocol for assay of drug-metabolizing enzyme-inducing potential using three-dimensional (3D) primary cultures of human hepatocytes (hepatocyte spheroids). Hepatocyte spheroids could be used up to 21 d after seeding (pre-culture for 7 d and exposure to inducer for up to 14 d), based on preliminary evaluation of basal activities of CYP subtypes and mRNA expression of the corresponding transcription factor and xenobiotic receptors (aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR)). After 2 d exposure of hepatocyte spheroids to omeprazole, phenobarbital and rifampicin (typical inducers of CYP1A2, 2B6 and 3A4, respectively), CYP1A2, 2B6 and 3A4 mRNA expression levels were significantly increased. The mRNA induction of CYP2B6 remained reasonably stable between days 2 and 14 of exposure to inducers, while induction of both CYP1A2 and 3A4 continued to increase up to day 14. These enzyme activities were all significantly increased compared with the control until day 14. Our findings indicate that our 3D hepatocyte spheroids system would be especially suitable for long-term testing of enzyme activity induction by drugs, either to predict or to verify clinical events.</p>

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