| CYP3A4 catalytic activity is induced in confluent Huh7 hepatoma cells. | |
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MedLine Citation:
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PMID: 20233841 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Drug-induced hepatotoxicity is an important cause for disapproval, limitations of use, or withdrawal of drugs, and there is a high need for reproducible in vitro systems that can predict such toxicity. In this study, we show that confluent growth of the human hepatoma cell line Huh7 up to 5 weeks results in increased gene expression of several cytochromes P450 (P450s), UDP-glucuronosyltransferases, transporters, transcription factors, and several liver-specific genes, as measured by low-density array. The most striking effect was seen for CYP3A4 expression. Western blot analysis revealed increased amounts of CYP3A4 together with increased levels of NADPH-P450 reductase, cytochrome b(5), and albumin with prolonged time of confluence. By using the CYP3A4-specific substrates luciferin 6' benzyl ether, testosterone, and midazolam, we could confirm that the increased CYP3A4 gene expression also was accompanied by a similar increase in catalytic activity, inhibitable by the CYP3A4-selective inhibitor ketoconazole. The CYP3A4 activity in confluent cells was also inducible by rifampicin. Finally, the cell system could support the CYP3A4-dependent hepatotoxic activation of aflatoxin B(1), which was effectively inhibited by ketoconazole. Our results show that Huh7 cells grown confluent differentiate into a more metabolically competent cell line, especially with regard to CYP3A4. |
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Authors:
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Louise Sivertsson; Monica Ek; Malin Darnell; Irene Edebert; Magnus Ingelman-Sundberg; Etienne P A Neve |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-16 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 38 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-14 Completed Date: 2010-08-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 995-1002 Citation Subset: IM |
Affiliation:
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Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Nanna Svartz väg 2, SE-171 77 Stockholm, Sweden. Louise.Sivertsson@ki.se |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aflatoxin B1 Catalysis Cell Line Cell Line, Tumor Cytochrome P-450 CYP3A / biosynthesis, metabolism* Cytochrome P-450 Enzyme System / isolation & purification, metabolism Drug Interactions Gene Expression Humans Ketoconazole / metabolism Microsomes, Liver / metabolism* Midazolam Rifampin Testosterone Transcription Factors |
| Chemical | |
Reg. No./Substance:
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0/Transcription Factors; 1162-65-8/Aflatoxin B1; 13292-46-1/Rifampin; 58-22-0/Testosterone; 59467-70-8/Midazolam; 65277-42-1/Ketoconazole; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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