Comparison of the inducibility of CYP mRNA exposed to typical inducers in fresh and cryopreserved cynomolgus monkey hepatocytes |
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| Institution: | 1. Ina Research Inc., Ina, Japan;2. Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan;3. Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan;4. Department of Pharmacy, Ryukyu University Hospital, Okinawa, Japan;1. Auckland Bioengineering Institute, The University of Auckland, Auckland, 1010, New Zealand;2. Chongqing Institute for Food and Drug Control, Chongqing City, China;1. Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan;2. Food Safety Commission, Cabinet Office, Government of Japan, Akasaka Park Bldg. 22F 5-2-20 Akasaka, Minato-ku, Tokyo, 107-6122, Japan;3. Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kanagawa, 210-9501, Japan;4. Essential Medicines and Health Products, Access to Medicines, Vaccines and Pharmaceuticals, World Health Organization, Avenue Appia 20, 1211, Geneva 27, Switzerland;5. Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan;1. Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine, Japan;2. Division of Research Planning and Development, Medical Research Support Center, Nihon University School of Medicine, Japan;3. Division of Companion Diagnostics, Department of Pathology of Microbiology, Nihon University School of Medicine, Japan;4. Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Japan;1. Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan;2. Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan;3. Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan;4. PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan;5. Global Center for Medical Engineering and Informatics, Osaka University, Osaka, 565-0871, Japan;6. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan;1. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;2. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Japan;3. Shin Nippon Biomedical Laboratories, Ltd, Kainan, Wakayama, Japan |
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| Abstract: | Herein, we evaluated CYPs and their nuclear receptor mRNA induction by exposure to typical inducers, omeprazole, rifampicin, and phenobarbital in cynomolgus monkey hepatocytes. Six freshly-isolated hepatocytes and 6 cryopreserved hepatocytes from cynomolgus monkey liver were prepared for a 14-day monolayer culture, 28-day co-culture with feeder cells, and 28-day 3D spheroid culture with feeder cells. Omeprazole and rifampicin respectively induced CYP1A1 and CYP3A8 mRNAs, while phenobarbital induced CYP2C43, CYP2C75, and CYP3A8, and slightly induced CYP2B6. The nuclear receptors AHR, PXR, and CAR mRNA levels, which were activated by omeprazole, rifampicin, and phenobarbital, respectively, tended to decrease via exposure to inducers despite the increase in CYP mRNA levels. These trends were similar for all three culture methods. No evident difference was observed in CYP mRNA induction between fresh and cryopreserved hepatocytes. Based on mRNA levels, the co-culture and 3D spheroid culture methods are more reasonable than monolayer culture for CYP evaluation, because the use of feeder cells can reduce the number of hepatocytes, improve the cell adhesion, and maintain the mRNA expression levels. In addition, co-culture method is more cost-effective, as common culture plates can be used. |
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| Keywords: | Cynomolgus monkey hepatocyte Monolayer Co-culture Spheroid Induction Cytochrome P450 Nuclear receptor |
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