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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2003-2-25
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pubmed:abstractText |
CYP3A is responsible for approximately 50% of the therapeutic drug-metabolizing activity in the liver. The present study was undertaken to establish the CYP3A4 inducible model for analysis of human drug metabolism using a bioartificial liver composed of the functional hepatocellular carcinoma cell (HCC) line FLC-5. A radial-flow bioreactor (RFB), which is a carrier-filled type bioreactor, was used for 3-dimensional perfusion culture of FLC-5 cells. The CYP3A4 messenger RNA (mRNA) expression level 48 hours after rifampicin treatment in the RBF was approximately 100 times higher than that in a monolayer culture. Western blot analysis also demonstrated an increase in expression of the CYP3A protein. When testosterone, a substrate for CYP3A4, was added to the rifampicin-treated cell culture, 6 beta-hydroxy testosterone as a metabolite was formed. Electrophoretic mobility shift assay (EMSA) with a CYP3A4 ER6 probe demonstrated that relatively high molecular weight complex containing pregnane X receptor (PXR)/retinoid X receptor alpha(RXR alpha), compared with that in the monolayer culture, is possibly generated in the RFB culture of FLC-5 treated with rifampicin. Similarly, the assay with a probe of HNF-4 alpha-binding motif indicated the formation of a large protein complex in the RFB culture. Because it is known that PXR transactivates CYP3A4 gene via its response element and expression of PXR is regulated by HNF-4 alpha, the large complexes binding to response elements of PXR or HNF-4 alpha in the RFB culture may contribute to up-regulation of CYP3A4 mRNA. In conclusion, the bioartificial liver composed of human functional HCC cell line was useful in studying drug interactions during induction of human CYP3A4.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Basic Helix-Loop-Helix Leucine...,
http://linkedlifedata.com/resource/pubmed/chemical/CYP3A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CYP3A4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 CYP3A,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Hepatocyte Nuclear Factor 4,
http://linkedlifedata.com/resource/pubmed/chemical/MLX protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Pharmaceutical Preparations,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Steroid,
http://linkedlifedata.com/resource/pubmed/chemical/Rifampin,
http://linkedlifedata.com/resource/pubmed/chemical/Testosterone,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/pregnane X receptor
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0270-9139
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pubmed:author |
pubmed-author:AizakiHidekiH,
pubmed-author:ChibaKanK,
pubmed-author:HosokawaMasakiyoM,
pubmed-author:IwahoriTohruT,
pubmed-author:MaehashiHarukaH,
pubmed-author:MasakiTakahiroT,
pubmed-author:MatsuuraTomokazuT,
pubmed-author:OhkawaKiyoshiK,
pubmed-author:SaitoMasayaM,
pubmed-author:SugoKenK,
pubmed-author:SuzukiTetsuroT
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pubmed:issnType |
Print
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pubmed:volume |
37
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
665-73
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:12601364-Basic Helix-Loop-Helix Leucine Zipper Transcription Factors,
pubmed-meshheading:12601364-Bioreactors,
pubmed-meshheading:12601364-Carcinoma, Hepatocellular,
pubmed-meshheading:12601364-Chromatography, High Pressure Liquid,
pubmed-meshheading:12601364-Cytochrome P-450 CYP3A,
pubmed-meshheading:12601364-Cytochrome P-450 Enzyme System,
pubmed-meshheading:12601364-DNA-Binding Proteins,
pubmed-meshheading:12601364-Electrophoretic Mobility Shift Assay,
pubmed-meshheading:12601364-Enzyme Induction,
pubmed-meshheading:12601364-Gene Expression,
pubmed-meshheading:12601364-Gene Expression Regulation,
pubmed-meshheading:12601364-Hepatocyte Nuclear Factor 4,
pubmed-meshheading:12601364-Humans,
pubmed-meshheading:12601364-Liver,
pubmed-meshheading:12601364-Liver Neoplasms,
pubmed-meshheading:12601364-Microscopy, Electron,
pubmed-meshheading:12601364-Microsomes, Liver,
pubmed-meshheading:12601364-Models, Biological,
pubmed-meshheading:12601364-Pharmaceutical Preparations,
pubmed-meshheading:12601364-Phosphoproteins,
pubmed-meshheading:12601364-Polymerase Chain Reaction,
pubmed-meshheading:12601364-RNA, Messenger,
pubmed-meshheading:12601364-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:12601364-Receptors, Steroid,
pubmed-meshheading:12601364-Rifampin,
pubmed-meshheading:12601364-Testosterone,
pubmed-meshheading:12601364-Transcription Factors,
pubmed-meshheading:12601364-Tumor Cells, Cultured
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pubmed:year |
2003
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pubmed:articleTitle |
CYP3A4 inducible model for in vitro analysis of human drug metabolism using a bioartificial liver.
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pubmed:affiliation |
Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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