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Research ArticleArticle

Use of a Reporter Gene Assay to Predict and Rank the Potency and Efficacy of CYP3A4 Inducers

Wafaa El-Sankary, G. Gordon Gibson, Andy Ayrton and Nick Plant
Drug Metabolism and Disposition November 2001, 29 (11) 1499-1504;
Wafaa El-Sankary
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G. Gordon Gibson
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Andy Ayrton
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Nick Plant
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Abstract

Regulation of the CYP3A4 gene has been studied using an in vitro reporter gene assay. The effect of 17 xenobiotics on ∼1 kilobase of the CYP3A4 proximal promoter, upstream of a secretory placental alkaline phosphatase reporter gene was investigated following transfection into the HepG2 cell line. Transfections were carried out either in the basal system or with cotransfection of expression plasmids for the human pregnane X receptor (hPXR) and the human glucocorticoid receptor (hGR), two important receptors in the regulation of CYP3A4 gene expression. Compounds were tested at four concentrations, and the resulting data were used to calculate maximal induction (Imax) and EC50values. An “overall inductive ability” (IA) was derived by dividingImax by EC50. Of the compounds tested seven were established transcriptional inducers, all of which were positive in the in vitro assay. The remaining 10 compounds represented a group with preliminary evidence for CYP3A transcriptional activation. Nine of these compounds produced statistically significant inductions in vitro, with only pravastatin failing to activate the reporter gene. This is of potential interest in light of the high IA values observed with the other structurally and functionally similar statins tested. We conclude that a four-concentration-point, in vitro model is capable of identifying CYP3A4 transcriptional inducers and yields an IA value allowing the ranking of compounds for their overall ability to induce CYP3A4 transcription. In addition, the majority of the compounds tested showed increased IA values in the hPXR/hGR cotransfected system, underpinning the importance of these receptors in CYP3A4 gene transcriptional regulation.

Footnotes

  • Abbreviations used are::
    P450
    cytochrome P450
    kb
    kilobase
    bp
    base pair
    hPXR
    human pregnane X receptor
    hGR
    human glucocorticoid receptor
    SPAP
    secretory placental alkaline phosphatase
    IA
    overall inductive ability
    Dex
    dexamethasone
    Rif
    rifampicin
    PCN
    pregnenolone-16α-carbonitrile
    Cipro
    ciprofibrate
    BNF
    β-naphthoflavone
    Keto
    ketoconazole
    PB
    phenobarbitone
    Clot
    clotrimazole
    CPA
    cyproterone acetate
    Carb
    carbamazepine
    Spir
    spironolactone
    Phen
    phenytoin
    Sulf
    sulfinpyrazone
    Met
    metyrapone
    Lov
    lovastatin
    Sim
    simvastatin
    Prav
    pravastatin
    Trog
    troglitazone
    Piog
    pioglitazone
    Fex
    SCE, specific chemical effect
    • Received May 8, 2001.
    • Accepted August 16, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (11)
Drug Metabolism and Disposition
Vol. 29, Issue 11
1 Nov 2001
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Research ArticleArticle

Use of a Reporter Gene Assay to Predict and Rank the Potency and Efficacy of CYP3A4 Inducers

Wafaa El-Sankary, G. Gordon Gibson, Andy Ayrton and Nick Plant
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1499-1504;

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Research ArticleArticle

Use of a Reporter Gene Assay to Predict and Rank the Potency and Efficacy of CYP3A4 Inducers

Wafaa El-Sankary, G. Gordon Gibson, Andy Ayrton and Nick Plant
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1499-1504;
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