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Research ArticleArticle

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

Ihab Al Khansa, Olivier Blanck, André Guillouzo and Rémi Bars
Drug Metabolism and Disposition September 2010, 38 (9) 1598-1604; DOI: https://doi.org/10.1124/dmd.110.033753
Ihab Al Khansa
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Olivier Blanck
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André Guillouzo
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Rémi Bars
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Abstract

Cryopreserved rat hepatocytes entrapped within an alginate matrix, commercially available as Liverbeads, were evaluated for their relevance as a screening tool for gene induction in vitro, using quantitative real-time reverse transcriptase-polymerase chain reaction. They were treated with the reference compounds β-naphthoflavone (BNF), phenobarbital (PB), pregnenolone 16α-carbonitrile (PCN), and clofibric acid (CLO) and analyzed for mRNA levels of Cyp1a1, Cyp2b1, Cyp3a1, Cyp4a1, Ugt1a6, and Ugt2b1. In addition, for PB and PCN, the results were compared with those obtained in rat liver in vivo. For each inducer, the gene induction profiles obtained with the Liverbeads in vitro model were time- and dose-dependent. The in vitro gene expression profiles confirmed the corresponding known P450 and UGT induction by each reference compound. In particular, the most strongly induced genes were Cyp1a1 by BNF, Cyp2b1 by PB, Cyp3a1 and Ugt2b1 by PCN, and Cyp4a1 and Cyp2b1 by CLO. Other genes investigated were also induced by the reference compounds, but the expression levels were lower, and increases were seen only after prolonged treatment. In particular, Ugt1a6 and Cyp2b1 were increased by BNF, Cyp1a1, Cyp3a1, and Ugt2b1 by PB, and Cyp3a1 and Ugt2b1 by CLO. All of these results correlated well with published in vitro data and our in vivo data. In conclusion, our results suggest that Liverbeads is a relevant and useful in vitro screening tool for determining gene induction profiles of new molecules. In addition, because Liverbeads from different species are available, this tool offers the possibility to conduct interspecies comparisons.

Footnotes

  • This work was supported in part by Association Nationale de la Recherche et de la Technologie through a Ph.D. scholarship to I.A.K.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.033753.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    PB
    phenobarbital
    BNF
    β-naphthoflavone
    CLO
    clofibric acid
    PCN
    pregnenolone 16α-carbonitrile
    UGT/Ugt
    UDP-glucuronosyltransferase
    qRT-PCR
    quantitative real-time reverse transcriptase-polymerase chain reaction
    CAR
    constitutive androstane receptor
    PXR
    pregnane X receptor
    CTM
    clotrimazole
    PHE
    phenytoin
    DMSO
    dimethyl sulfoxide
    RQ
    relative quantity
    Ct
    cycle threshold.

  • Received April 2, 2010.
  • Accepted June 15, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (9)
Drug Metabolism and Disposition
Vol. 38, Issue 9
1 Sep 2010
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Research ArticleArticle

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

Ihab Al Khansa, Olivier Blanck, André Guillouzo and Rémi Bars
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1598-1604; DOI: https://doi.org/10.1124/dmd.110.033753

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Research ArticleArticle

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

Ihab Al Khansa, Olivier Blanck, André Guillouzo and Rémi Bars
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1598-1604; DOI: https://doi.org/10.1124/dmd.110.033753
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