Regulation of mRNA Expression of MDR1, MRP1, MRP2 and MRP3 by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Rat Hepatocytes
The mRNA induction of various transporters by rifampicin (Rif), dexamethasone (Dex) and omeprazole (Ome) was investigated in primary cultures of cryopreserved human and rat hepatocytes. Analysis was performed by quantitative realtime RTPCR using primers and TaqMan probes. In primary cultures of hu...
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Published in | DRUG METABOLISM AND PHARMACOKINETICS Vol. 21; no. 4; pp. 297 - 307 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Elsevier Ltd
01.01.2006
Japanese Society for the Study of Xenobiotics |
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Abstract | The mRNA induction of various transporters by rifampicin (Rif), dexamethasone (Dex) and omeprazole (Ome) was investigated in primary cultures of cryopreserved human and rat hepatocytes. Analysis was performed by quantitative realtime RTPCR using primers and TaqMan probes. In primary cultures of human hepatocytes, mRNA levels of MDR and MRP1 were increased by about 1.5 fold and 1.3 fold, respectively, by exposure to Rif at 2 to 50μM as compared with 0.1% DMSOtreated controls. MRP2 mRNA levels in the same human hepatocytes were significantly increased by 1.2 to 1.8 fold by exposure to Rif at 50μM as compared with controls. In primary cultures of rat hepatocytes, Mdr1a and Mdr1b mRNA levels were not increased or only slightly increased at 24hr by exposure to any of the inducers at 2, 10 or 50μM. Mrp2 mRNA levels in the same rat hepatocytes were significantly increased by 7 to 45 fold by exposure to Dex at 2μM as compared with controls. Based on the species differences observed in the present study, primary cultures of cryopreserved hepatocytes from both the human and rat should be useful in preclinical drug development for evaluating candidate drugs for transporter induction. |
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AbstractList | The mRNA induction of various transporters by rifampicin (Rif), dexamethasone (Dex) and omeprazole (Ome) was investigated in primary cultures of cryopreserved human and rat hepatocytes. Analysis was performed by quantitative real-time RT-PCR using primers and TaqMan probes. In primary cultures of human hepatocytes, mRNA levels of MDR and MRP1 were increased by about 1.5 fold and 1.3 fold, respectively, by exposure to Rif at 2 to 50 microM as compared with 0.1% DMSO-treated controls. MRP2 mRNA levels in the same human hepatocytes were significantly increased by 1.2 to 1.8 fold by exposure to Rif at 50 microM as compared with controls. In primary cultures of rat hepatocytes, Mdr1a and Mdr1b mRNA levels were not increased or only slightly increased at 24 hr by exposure to any of the inducers at 2, 10 or 50 microM. Mrp2 mRNA levels in the same rat hepatocytes were significantly increased by 7 to 45 fold by exposure to Dex at 2 microM as compared with controls. Based on the species differences observed in the present study, primary cultures of cryopreserved hepatocytes from both the human and rat should be useful in preclinical drug development for evaluating candidate drugs for transporter induction. The mRNA induction of various transporters by rifampicin (Rif), dexamethasone (Dex) and omeprazole (Ome) was investigated in primary cultures of cryopreserved human and rat hepatocytes. Analysis was performed by quantitative realtime RTPCR using primers and TaqMan probes. In primary cultures of human hepatocytes, mRNA levels of MDR and MRP1 were increased by about 1.5 fold and 1.3 fold, respectively, by exposure to Rif at 2 to 50μM as compared with 0.1% DMSOtreated controls. MRP2 mRNA levels in the same human hepatocytes were significantly increased by 1.2 to 1.8 fold by exposure to Rif at 50μM as compared with controls. In primary cultures of rat hepatocytes, Mdr1a and Mdr1b mRNA levels were not increased or only slightly increased at 24hr by exposure to any of the inducers at 2, 10 or 50μM. Mrp2 mRNA levels in the same rat hepatocytes were significantly increased by 7 to 45 fold by exposure to Dex at 2μM as compared with controls. Based on the species differences observed in the present study, primary cultures of cryopreserved hepatocytes from both the human and rat should be useful in preclinical drug development for evaluating candidate drugs for transporter induction. The mRNA induction of various transporters by rifampicin (Rif), dexamethasone (Dex) and omeprazole (Ome) was investigated in primary cultures of cryopreserved human and rat hepatocytes. Analysis was performed by quantitative real-time RT-PCR using primers and TaqMan probes. In primary cultures of human hepatocytes, mRNA levels of MDR and MRP1 were increased by about 1.5 fold and 1.3 fold, respectively, by exposure to Rif at 2 to 50 μM as compared with 0.1% DMSO-treated controls. MRP2 mRNA levels in the same human hepatocytes were significantly increased by 1.2 to 1.8 fold by exposure to Rif at 50μM as compared with controls. In primary cultures of rat hepatocytes, Mdr1a and Mdr1b mRNA levels were not increased or only slightly increased at 24 hr by exposure to any of the inducers at 2, 10 or 50μM. Mrp2 mRNA levels in the same rat hepatocytes were significantly increased by 7 to 45 fold by exposure to Dex at 2μM as compared with controls. Based on the species differences observed in the present study, primary cultures of cryopreserved hepatocytes from both the human and rat should be useful in preclinical drug development for evaluating candidate drugs for transporter induction. |
Author | Nakayama, Mitsuo Suzuki, Emako Satoh, Tetsuo Naito, Shinsaku Narimatsu, Shizuo Nishimura, Masuhiro Koeda, Akiko Kawano, Yuichi |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/16946557$$D View this record in MEDLINE/PubMed |
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Snippet | The mRNA induction of various transporters by rifampicin (Rif), dexamethasone (Dex) and omeprazole (Ome) was investigated in primary cultures of cryopreserved... |
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SubjectTerms | Animals ATP-Binding Cassette, Sub-Family B, Member 1 - genetics Cells, Cultured Dexamethasone - pharmacology Enzyme Induction - drug effects Enzyme Inhibitors Female Gene Expression Regulation - drug effects hepatocytes Hepatocytes - drug effects Hepatocytes - metabolism human Humans induction Membrane Transport Proteins - genetics Microsomes - drug effects Microsomes - enzymology Multidrug Resistance-Associated Proteins - genetics Omeprazole - pharmacology rat Rats Rats, Sprague-Dawley Rifampin - pharmacology RNA, Messenger - genetics RNA, Messenger - metabolism Transcription, Genetic - drug effects Transcription, Genetic - genetics transporter |
Title | Regulation of mRNA Expression of MDR1, MRP1, MRP2 and MRP3 by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Rat Hepatocytes |
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