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Molecular Pharmacology

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Research ArticleArticle

A Comparison of the Roles of Peroxisome Proliferator-Activated Receptor and Retinoic Acid Receptor on CYP26 Regulation

Suzanne Tay, Leslie Dickmann, Vaishali Dixit and Nina Isoherranen
Molecular Pharmacology February 2010, 77 (2) 218-227; DOI: https://doi.org/10.1124/mol.109.059071
Suzanne Tay
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Leslie Dickmann
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Vaishali Dixit
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Nina Isoherranen
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Abstract

The cytochrome P450 26 family is believed to be responsible for all-trans-retinoic acid (atRA) metabolism and elimination in the human fetus and adults. CYP26A1 and CYP26B1 mRNA is expressed in a tissue-specific manner, and mice in which the CPY26 isoform has been knocked out show distinct malformations and lethality. The aim of this study was to determine differences in CYP26A1 and CYP26B1 regulation and expression. Analysis of CYP26A1 and CYP26B1 expression in a panel of 57 human livers showed CYP26A1 to be the major CYP26 isoform present in the liver, and its expression to be subject to large interindividual variability between donors. CYP26A1 and retinoic acid receptor (RAR) β were found to be greatly inducible by atRA in HepG2 cells, whereas CYP26B1, RARα, and RARγ were induced to a much lesser extent. Based on treatments with RAR isoform-selective ligands, RARα is the major isoform responsible for CYP26A1 and RARβ induction in HepG2 cells. Classic cytochrome P450 inducers did not affect CYP26 transcription, whereas the peroxisome proliferator-activated receptor (PPAR) γ agonists pioglitazone and rosiglitazone up-regulated CYP26B1 transcription by as much as 209- ± 80-fold and CYP26A1 by 10-fold. RARβ was also up-regulated by pioglitazone and rosiglitazone. CYP26B1 induction by PPARγ agonists was abolished by the irreversible PPARγ antagonist 2-chloro-5-nitrobenzanilide (GW9662), whereas RARβ and CYP26A1 induction was unaffected by GW9662. Overall, the results of this study suggest that CYP26B1 and CYP26A1 are regulated by different nuclear receptors, resulting in tissue-specific expression patterns. The fact that drugs can alter the expression of CYP26 enzymes may have toxicological and therapeutic importance.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM081596, P01-GM32165].

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

    doi:10.1124/mol.109.059071.

  • ABBREVIATIONS:

    atRA
    all-trans-retinoic acid
    RAR
    retinoic acid receptor
    RXR
    retinoid X receptor
    P450
    cytochrome P450
    AM580
    4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid
    DRB
    5,6-dichlorobenzimidazole 1-β-d-ribofuranoside
    GW9662
    2-chloro-5-nitrobenzanilide
    L-165,041
    [4-]3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid
    TTNPB
    4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid
    AC55649
    4′-octyl-[1,1′-biphenyl]-4-carboxylic acid
    DMSO
    dimethyl sulfoxide
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase
    PPAR
    peroxisome proliferator-activated receptor
    DM
    differentiation medium
    PCR
    polymerase chain reaction
    PBS
    phosphate-buffered saline
    RARE
    retinoic acid response element.

  • Received July 2, 2009.
  • Accepted October 30, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (2)
Molecular Pharmacology
Vol. 77, Issue 2
1 Feb 2010
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Research ArticleArticle

A Comparison of the Roles of Peroxisome Proliferator-Activated Receptor and Retinoic Acid Receptor on CYP26 Regulation

Suzanne Tay, Leslie Dickmann, Vaishali Dixit and Nina Isoherranen
Molecular Pharmacology February 1, 2010, 77 (2) 218-227; DOI: https://doi.org/10.1124/mol.109.059071

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Research ArticleArticle

A Comparison of the Roles of Peroxisome Proliferator-Activated Receptor and Retinoic Acid Receptor on CYP26 Regulation

Suzanne Tay, Leslie Dickmann, Vaishali Dixit and Nina Isoherranen
Molecular Pharmacology February 1, 2010, 77 (2) 218-227; DOI: https://doi.org/10.1124/mol.109.059071
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