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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Induction Profile of Rat Organic Anion Transporting Polypeptide 2 (oatp2) by Prototypical Drug-Metabolizing Enzyme Inducers That Activate Gene Expression through Ligand-Activated Transcription Factor Pathways

Grace L. Guo, Supratim Choudhuri and Curtis D. Klaassen
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 206-212; DOI: https://doi.org/10.1124/jpet.300.1.206
Grace L. Guo
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Supratim Choudhuri
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Curtis D. Klaassen
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Abstract

Knowledge of regulation of transporters would aid in predicting pharmacokinetics and drug-drug interactions. Treatment of rats with pregnenolone-16α-carbonitrile (PCN) and phenobarbital increases hepatic uptake of cardiac glycosides. Rat organic anion transporting polypeptide 2 (oatp2; Slc21a5) transports cardiac glycosides with high affinity. Levels of rat hepatic oatp2 protein and mRNA are regulated by PCN and phenobarbital treatment; however, the effects of other microsomal enzyme inducers on oatp2 have not been investigated. Therefore, the purpose of this study was to further determine whether oatp2 is regulated by a broader scale of drug-metabolizing enzyme inducers that are ligands or activators for the aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor (PPAR), and antioxidant/electrophile response element (ARE/EpRE). Oatp2 protein levels determined by Western blot were decreased 56 to 72% by the AhR ligands, increased 84 to 132% by the CAR ligands, and increased 230 to 360% by PXR ligands. The PPAR ligands and ARE/EpRE activators generally had minimal effects on oatp2 protein levels. Oatp2 mRNA levels, determined by the bDNA technique, generally did not show a correlation with the altered oatp2 protein levels, e.g., among PXR ligands, only PCN increased oatp2 mRNA levels, but spironolactone and dexamethasone did not. Furthermore, only PCN, but not spironolactone and dexamethasone, increased the transcription of the oatp2 gene as the amount of hnRNA was increased when determined by reverse transcription-polymerase chain reaction. In conclusion, some drug-metabolizing enzyme inducers regulate oatp2 protein levels, especially the CYP3A inducers. However, there is no correlation between their ability to increase levels of oatp2 protein and mRNA, suggesting that regulation of oatp2 by drug-metabolizing enzyme inducers occurs at both the transcriptional and post-translational levels.

Footnotes

  • This work was supported by Grants ES-09649 and ES-03192 from the National Institute of Environmental Health Sciences.

  • Abbreviations

    oatp
    organic anion transporting polypeptide
    AhR
    aryl hydrocarbon receptor
    CAR
    constitutive androstane receptor
    PXR
    pregnane-X-receptor
    PPAR
    peroxisome proliferator-activated receptor
    ARE/EpRE
    antioxidant/electrophile response element
    bDNA
    branched DNA signal amplification technique
    hnRNA
    heterogeneous nuclear RNA
    CYP
    cytochrome P450
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    PCB
    polychlorinated biphenyl
    SD
    Sprague-Dawley
    BNF
    β-naphthoflavone
    DAS
    diallyl sulfide
    SPIRO
    spironolactone
    DEX
    dexamethasone
    CLOF
    clofibric acid
    DEHP
    diethylhexylphthalate
    PFDA
    perflurodecanoic acid
    BHA
    butylated hydroxyanisole
    EQ
    ethoxyquin
    OLTI
    oltipraz
    TBST
    Tris-buffered saline/Tween 20
    RT-PCR
    reverse transcription-polymerase chain reaction
    I-3-C
    indole-3-carbinol
    • Received August 27, 2001.
    • Accepted October 12, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
    Vol. 300, Issue 1
    1 Jan 2002
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    Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

    Induction Profile of Rat Organic Anion Transporting Polypeptide 2 (oatp2) by Prototypical Drug-Metabolizing Enzyme Inducers That Activate Gene Expression through Ligand-Activated Transcription Factor Pathways

    Grace L. Guo, Supratim Choudhuri and Curtis D. Klaassen
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 206-212; DOI: https://doi.org/10.1124/jpet.300.1.206

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    Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

    Induction Profile of Rat Organic Anion Transporting Polypeptide 2 (oatp2) by Prototypical Drug-Metabolizing Enzyme Inducers That Activate Gene Expression through Ligand-Activated Transcription Factor Pathways

    Grace L. Guo, Supratim Choudhuri and Curtis D. Klaassen
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 206-212; DOI: https://doi.org/10.1124/jpet.300.1.206
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