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Research ArticleArticle

Coordinated Regulation of Hepatic Phase I and II Drug-Metabolizing Genes and Transporters using AhR-, CAR-, PXR-, PPARα-, and Nrf2-Null Mice

Lauren M. Aleksunes and Curtis D. Klaassen
Drug Metabolism and Disposition July 2012, 40 (7) 1366-1379; DOI: https://doi.org/10.1124/dmd.112.045112
Lauren M. Aleksunes
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Curtis D. Klaassen
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Abstract

The transcription factors aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor α (PPARα), and nuclear factor erythroid 2-related factor 2 (Nrf2) regulate genes encoding drug-metabolizing enzymes and transporters in livers of mice after chemical activation. However, the specificity of their transcriptional regulation has not been determined systematically in vivo. The purpose of this study was to identify genes encoding drug-metabolizing enzymes and transporters altered by chemical activators in a transcription factor-dependent manner using wild-type and transcription factor-null mice. Chemical activators were administered intraperitoneally to mice once daily for 4 days. Livers were collected 24 h after the final dose, and total RNA was isolated for mRNA quantification of cytochromes P450, NAD(P)H quinone oxidoreductase 1 (Nqo1), aldehyde dehydrogenases (Aldhs), glutathione transferases (Gsts), sulfotransferases (Sults), UDP-glucuronosyltransferases (Ugts), organic anion-transporting polypeptides (Oatps), and multidrug resistance-associated proteins (Mrps). Pharmacological activation of each transcription factor leads to mRNA induction of drug metabolic and transport genes in livers of male and female wild-type mice, but no change in null mice: AhR (Cyp1a2, Nqo1, Aldh7a1, Ugt1a1, Ugt1a6, Ugt1a9, Ugt2b35, Sult5a1, Gstm3, and Mrp4), CAR (Cyp2b10, Aldh1a1, Aldh1a7, Ugt1a1, Ugt2b34, Sult1e1, Sult3a1, Sult5a1, Papps2, Gstt1, Gsta1, Gsta4, Gstm1–4, and Mrp2–4), PXR (Cyp3a11, Ugt1a1, Ugt1a5, Ugt1a9, Gsta1, Gstm1–m3, Oatp1a4, and Mrp3), PPARα (Cyp4a14, Aldh1a1, mGst3, Gstm4, and Mrp4), and Nrf2 (Nqo1, Aldh1a1, Gsta1, Gsta4, Gstm1–m4, mGst3, and Mrp3–4). Taken together, these data reveal transcription factor specificity and overlap in regulating hepatic drug disposition genes by chemical activators. Coordinated regulation of phase I, phase II, and transport genes by activators of transcription factors can have implications in development of pharmaceuticals as well as risk assessment of environmental contaminants.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK080774, DK081461]; National Institutes of Health National Institute of Environmental Health Sciences [Grants ES019487, ES020522, ES009649, ES007079]; National Institutes of Health National Center for Research Resources [Grant RR021940]; and in part by National Institutes of Health National Institute of Environmental Health Sciences-sponsored University of Medicine and Dentistry of New Jersey Center for Environmental Exposures and Disease [Grant P30-ES005022].

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

    http://dx.doi.org/10.1124/dmd.112.045112.

  • ABBREVIATIONS:

    AhR
    aryl hydrocarbon receptor
    CAR
    aryl hydrocarbon receptor
    PXR
    pregnane X receptor
    PPARα
    peroxisome proliferator-activated receptor α
    Nrf2
    nuclear factor erythroid 2-related factor 2
    P450
    cytochrome P450
    TCDD
    2′,3′,7′,8′-tetrachlorodibenzo-p-dioxin
    PCN
    pregnenolone-16-α-carbonitrile
    CBF
    clofibrate
    OPZ
    oltipraz
    Nqo1
    NAD(P)H:quinone oxidoreductase 1
    Aldh
    aldehyde dehydrogenase
    Sult
    sulfotransferase
    Gst
    glutathione transferase
    Ugt
    UDP-glucuronosyltransferase
    Abc
    ATP-binding cassette
    Slc
    solute carrier
    TCPOBOP
    3,3′,5,5′-tetrachloro-1,4-bis(pyridyloxy)benzene
    P450
    cytochrome P450
    Papss2
    3′-phosphoadenosine 5′-phosphosulfate synthase 2
    Oatp
    organic anion-transporting polypeptide
    Mate
    multidrug and toxin extrusion
    Mrp
    multidrug resistance-associated protein.

  • Received February 16, 2012.
  • Accepted April 11, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (7)
Drug Metabolism and Disposition
Vol. 40, Issue 7
1 Jul 2012
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Research ArticleArticle

TRANSCRIPTION FACTOR-GENE INTERACTIONS

Lauren M. Aleksunes and Curtis D. Klaassen
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1366-1379; DOI: https://doi.org/10.1124/dmd.112.045112

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Research ArticleArticle

TRANSCRIPTION FACTOR-GENE INTERACTIONS

Lauren M. Aleksunes and Curtis D. Klaassen
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1366-1379; DOI: https://doi.org/10.1124/dmd.112.045112
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