Comparison of Inducibility of Multidrug Resistance (MDR)1, Multidrug Resistance-Associated Protein (MRP)1, and MRP2 mRNAs by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Cynomolgus Monkey Hepatocytes(Pharmacology)
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概要
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This study investigated the changes in the mRNA levels of the ATP binding cassette (ABC) transporters multidrug resistance 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and multidrug resistance-as-sociated protein 2 (MRP2) following exposure to the prototypical microsomal enzyme inducers rifampicin (Rif), dexamethasone (Dex), and omeprazole (Ome) in primary cultures of cryopreserved human and cynomolgus monkey hepatocytes. Analysis was performed by real-time reverse transcription-polymerase chain reaction using primers and TaqMan probes. First, the time course of the mRNA expression of these transporters in primary cultures of human and cynomolgus monkey hepatocytes was examined in detail. The ratio of MDR1 and MRP2 mRNA to β-actin mRNA in both human and cynomolgus monkey hepatocytes remained constant from 48 to 72h and from 24 to 72h of culture, respectively. Second, the hepatocytes were exposed to the inducers and the changes in the levels of the transporter mRNAs were examined. Rif increased MDR1 and MRP1 mRNA levels in both human and cynomolgus monkey hepatocytes, while Ome slightly increased MDR1 and MRP1 mRNA levels in cynomolgus monkey hepatocytes. Rif and Ome increased MRP2 mRNA levels in both human and cynomolgus monkey hepatocytes. In contrast, Dex tended to decrease the mRNA levels of MDR1, MRP1, and MRP2 in both human and cynomolgus monkey hepatocytes. Cynomolgus monkey hepatocytes appeared to be more responsive than human hepatocytes to the inducers. These results indicate that primary cultures of cynomolgus monkey hepatocytes are as useful as primary cultures of human hepatocytes for evaluating the induction of MDR1, MRP1, and MRP2 mRNAs in preclinical studies.
- 公益社団法人日本薬学会の論文
- 2008-11-01
著者
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NARIMATSU Shizuo
Laboratories of Health Chemistry,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
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NISHIMURA Masuhiro
Research and Development Center, Otsuka Pharmaceutical Factory, Inc.
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NAITO Shinsaku
Research and Development Center, Otsuka Pharmaceutical Factory, Inc.
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Nishimura M
Research And Development Center Otsuka Pharmaceutical Factory Inc.
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Nishimura Masuhiro
Div. Of Pharmacology Drug Safety And Metabolism Otsuka Pharmaceutical Factory Inc.
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Nishimura Masuhiro
Department Of Drug Metabolism Division Of Pharmacology Drug Safety And Metabolism Otsuka Pharmaceuti
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Nishimura Masuhiro
Research And Development Center Otsuka Pharmaceutical Factory Inc.
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KOEDA Akiko
Ina Research Inc.
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MORIKAWA Hiroshi
Ina Research Inc.
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SATOH Tetsuo
Ina Research Inc.
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Naito Shinsaku
Research And Development Center Otsuka Pharmaceutical Factory Inc.
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Naito Shinsaku
Res. And Dev. Center Otsuka Pharmaceutical Factory Inc.
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Narimatsu Shizuo
Laboratories Health Chemistry Faculty Of Pharmaceutical Sciences Okayama University
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Nishimura Masuhiro
Res. And Dev. Center Otsuka Pharmaceutical Factory Inc.
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Satoh Tetsuo
Non-profit Organization Human & Animal Bridging Research Institute Ichikawa General Hospital
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Naito S
Otsuka Pharmaceutical Factory Inc. Tokushima Jpn
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Motoyama Harumi
Ina Research Inc.
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