Source:http://linkedlifedata.com/resource/pubmed/id/16760227
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
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| pubmed:dateCreated |
2006-8-23
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| pubmed:abstractText |
RNA interference (RNAi) is a specific and powerful tool used to manipulate gene expression and study gene function. The cytochrome P450 3A4 (CYP3A4) can metabolize more than 50% of drugs. In the present study, we investigated whether vector-expressed small interfering RNAs (siRNAs) altered the CYP3A4 expression and function using the Chinese hamster cell line (V79) overexpressing CYP3A4 (CHL-3A4). Three different siRNA oligonucleotides (3A4I, 3A4II, and 3A4III) were designed and tested for their ability to interfere with CYP3A4 gene expression. Our study demonstrated that transient transfection of CHL-3A4 cells with the 3A4III siRNAs, but not 3A4I and II, significantly reduced CYP3A4 mRNA levels by 65% and protein expression levels by 75%. All these siRNAs did not affect the expression of CYP3A5 at both mRNA and protein levels in V79 cells overexpressing CYP3A5. Transfection of CHL-3A4 cells with 3A4III siRNAs significantly diminished the cytotoxicity of two CYP3A4 substrate drugs, cyclophosphamide and ifosfamide, in CHL-3A4 cells, with the IC50 increased from 55 to 210 microM to >1000 microM. Nifedipine at 5.78, 14.44, and 28.88 microM was significantly (P < 0.01) depleted by approximately 100, 40, and 22%, respectively, in S9 fractions from CHL-3A4 cells compared with parental CHL-pIC19h cells. In addition, transfection of the CHL-3A4 cells with vectors expressing the 3A4III siRNAs almost completely inhibited CYP3A4-mediated nifedipine metabolism. This study demonstrated, for the first time, the specific suppression of CYP3A4 expression and function using vector-based RNAi technique. The use of RNAi is a promising tool for the study of cytochrome P450 family function.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Alkylating,
http://linkedlifedata.com/resource/pubmed/chemical/CYP3A4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CYP3A5 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channel Blockers,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclophosphamide,
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/Ifosfamide,
http://linkedlifedata.com/resource/pubmed/chemical/Nifedipine,
http://linkedlifedata.com/resource/pubmed/chemical/Oligonucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering
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| pubmed:status |
MEDLINE
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| pubmed:month |
Sep
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| pubmed:issn |
0090-9556
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
34
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| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1650-7
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| pubmed:dateRevised |
2008-11-21
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| pubmed:meshHeading |
pubmed-meshheading:16760227-Animals,
pubmed-meshheading:16760227-Antineoplastic Agents, Alkylating,
pubmed-meshheading:16760227-Calcium Channel Blockers,
pubmed-meshheading:16760227-Cell Line,
pubmed-meshheading:16760227-Cell Survival,
pubmed-meshheading:16760227-Cricetinae,
pubmed-meshheading:16760227-Cyclophosphamide,
pubmed-meshheading:16760227-Cytochrome P-450 CYP3A,
pubmed-meshheading:16760227-Cytochrome P-450 Enzyme System,
pubmed-meshheading:16760227-Genetic Vectors,
pubmed-meshheading:16760227-Ifosfamide,
pubmed-meshheading:16760227-Inhibitory Concentration 50,
pubmed-meshheading:16760227-Nifedipine,
pubmed-meshheading:16760227-Oligonucleotides,
pubmed-meshheading:16760227-RNA, Messenger,
pubmed-meshheading:16760227-RNA, Small Interfering,
pubmed-meshheading:16760227-RNA Interference,
pubmed-meshheading:16760227-Transfection
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| pubmed:year |
2006
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| pubmed:articleTitle |
Small interfering RNA-mediated silencing of cytochrome P450 3A4 gene.
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| pubmed:affiliation |
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, China.
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| pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't
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