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Research ArticleArticle

CYP3A4 Induction by Drugs: Correlation between a Pregnane X Receptor Reporter Gene Assay and CYP3A4 Expression in Human Hepatocytes

Gang Luo, Mark Cunningham, Sean Kim, Tim Burn, Jianrong Lin, Michael Sinz, Geraldine Hamilton, Christopher Rizzo, Summer Jolley, Darryl Gilbert, April Downey, Daniel Mudra, Richard Graham, Kathy Carroll, Jindong Xie, Ajay Madan, Andrew Parkinson, Dave Christ, Bernard Selling, Edward LeCluyse and Liang-Shang Gan
Drug Metabolism and Disposition July 2002, 30 (7) 795-804; DOI: https://doi.org/10.1124/dmd.30.7.795
Gang Luo
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Mark Cunningham
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Sean Kim
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Tim Burn
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Jianrong Lin
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Michael Sinz
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Geraldine Hamilton
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Christopher Rizzo
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Summer Jolley
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Darryl Gilbert
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April Downey
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Daniel Mudra
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Richard Graham
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Kathy Carroll
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Jindong Xie
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Ajay Madan
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Andrew Parkinson
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Dave Christ
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Bernard Selling
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Edward LeCluyse
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Liang-Shang Gan
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Abstract

Induction of cytochrome P450 3A4 (CYP3A4) is determined typically by employing primary culture of human hepatocytes and measuring CYP3A4 mRNA, protein and microsomal activity. Recently a pregnane X receptor (PXR) reporter gene assay was established to screen CYP3A4 inducers. To evaluate results from the PXR reporter gene assay with those from the aforementioned conventional assays, 14 drugs were evaluated for their ability to induce CYP3A4 and activate PXR. Sandwiched primary cultures of human hepatocytes from six donors were used and CYP3A4 activity was assessed by measuring microsomal testosterone 6β-hydroxylase activity. Hepatic CYP3A4 mRNA and protein levels were also analyzed using branched DNA technology/Northern blotting and Western blotting, respectively. In general, PXR activation correlated with the induction potential observed in human hepatocyte cultures. Clotrimazole, phenobarbital, rifampin, and sulfinpyrazone highly activated PXR and increased CYP3A4 activity; carbamazepine, dexamethasone, dexamethasone-t-butylacetate, phenytoin, sulfadimidine, and taxol weakly activated PXR and induced CYP3A4 activity, and methotrexate and probenecid showed no marked activation in either system. Ritonavir and troleandomycin showed marked PXR activation but no increase (in the case of troleandomycin) or a significant decrease (in the case of ritonavir) in microsomal CYP3A4 activity. It is concluded that the PXR reporter gene assay is a reliable and complementary method to assess the CYP3A4 induction potential of drugs and other xenobiotics.

Footnotes

  • Abbreviations used are::
    PXR
    pregnane X receptor
    DMSO
    dimethylsulfoxide
    bDNA
    branched DNA
    CAR
    constitutive androstane receptor
    ABT-378
    lopinavir
    • Received November 7, 2001.
    • Accepted March 22, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (7)
Drug Metabolism and Disposition
Vol. 30, Issue 7
1 Jul 2002
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Research ArticleArticle

CYP3A4 Induction by Drugs: Correlation between a Pregnane X Receptor Reporter Gene Assay and CYP3A4 Expression in Human Hepatocytes

Gang Luo, Mark Cunningham, Sean Kim, Tim Burn, Jianrong Lin, Michael Sinz, Geraldine Hamilton, Christopher Rizzo, Summer Jolley, Darryl Gilbert, April Downey, Daniel Mudra, Richard Graham, Kathy Carroll, Jindong Xie, Ajay Madan, Andrew Parkinson, Dave Christ, Bernard Selling, Edward LeCluyse and Liang-Shang Gan
Drug Metabolism and Disposition July 1, 2002, 30 (7) 795-804; DOI: https://doi.org/10.1124/dmd.30.7.795

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Research ArticleArticle

CYP3A4 Induction by Drugs: Correlation between a Pregnane X Receptor Reporter Gene Assay and CYP3A4 Expression in Human Hepatocytes

Gang Luo, Mark Cunningham, Sean Kim, Tim Burn, Jianrong Lin, Michael Sinz, Geraldine Hamilton, Christopher Rizzo, Summer Jolley, Darryl Gilbert, April Downey, Daniel Mudra, Richard Graham, Kathy Carroll, Jindong Xie, Ajay Madan, Andrew Parkinson, Dave Christ, Bernard Selling, Edward LeCluyse and Liang-Shang Gan
Drug Metabolism and Disposition July 1, 2002, 30 (7) 795-804; DOI: https://doi.org/10.1124/dmd.30.7.795
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