Please use this identifier to cite or link to this item: https://doi.org/10.1124/dmd.106.009837
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dc.titleSmall interfering RNA-mediated silencing of cytochrome P450 3A4 gene
dc.contributor.authorChen, J.
dc.contributor.authorYang, X.-X.
dc.contributor.authorHuang, M.
dc.contributor.authorHu, Z.-P.
dc.contributor.authorHe, M.
dc.contributor.authorDuan, W.
dc.contributor.authorChan, E.
dc.contributor.authorSheu, F.-S.
dc.contributor.authorChen, X.
dc.contributor.authorZhou, S.-F.
dc.date.accessioned2014-10-27T08:39:49Z
dc.date.available2014-10-27T08:39:49Z
dc.date.issued2006
dc.identifier.citationChen, J., Yang, X.-X., Huang, M., Hu, Z.-P., He, M., Duan, W., Chan, E., Sheu, F.-S., Chen, X., Zhou, S.-F. (2006). Small interfering RNA-mediated silencing of cytochrome P450 3A4 gene. Drug Metabolism and Disposition 34 (9) : 1650-1657. ScholarBank@NUS Repository. https://doi.org/10.1124/dmd.106.009837
dc.identifier.issn00909556
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/101681
dc.description.abstractRNA 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 μM to >1000 μM. Nifedipine at 5.78, 14.44, and 28.88 μM 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. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1124/dmd.106.009837
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentPHARMACY
dc.contributor.departmentBIOLOGICAL SCIENCES
dc.description.doi10.1124/dmd.106.009837
dc.description.sourcetitleDrug Metabolism and Disposition
dc.description.volume34
dc.description.issue9
dc.description.page1650-1657
dc.description.codenDMDSA
dc.identifier.isiut000239938500028
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