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Research ArticleArticle

Constitutive Androgen Receptor-Null Mice Are Sensitive to the Toxic Effects of Parathion: Association with Reduced Cytochrome P450-Mediated Parathion Metabolism

Linda C. Mota, Juan P. Hernandez and William S. Baldwin
Drug Metabolism and Disposition September 2010, 38 (9) 1582-1588; DOI: https://doi.org/10.1124/dmd.110.032961
Linda C. Mota
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Juan P. Hernandez
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William S. Baldwin
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This article has a correction. Please see:

  • Correction to: “Constitutive Androgen Receptor-Null Mice Are Sensitive to the Toxic Effects of Parathion: Association with Reduced Cytochrome P450-Mediated Parathion Metabolism” - August 01, 2015

Abstract

Constitutive androgen receptor (CAR) is activated by several chemicals and in turn regulates multiple detoxification genes. Our research demonstrates that parathion is one of the most potent, environmentally relevant CAR activators with an EC50 of 1.43 μM. Therefore, animal studies were conducted to determine whether CAR was activated by parathion in vivo. Surprisingly, CAR-null mice, but not wild-type (WT) mice, showed significant parathion-induced toxicity. However, parathion did not induce Cyp2b expression, suggesting that parathion is not a CAR activator in vivo, presumably because of its short half-life. CAR expression is also associated with the expression of several drug-metabolizing cytochromes P450 (P450). CAR-null mice demonstrate lower expression of Cyp2b9, Cyp2b10, Cyp2c29, and Cyp3a11 primarily, but not exclusively in males. Therefore, we incubated microsomes from untreated WT and CAR-null mice with parathion in the presence of esterase inhibitors to determine whether CAR-null mice show perturbed P450-mediated parathion metabolism compared with that in WT mice. The metabolism of parathion to paraoxon and p-nitrophenol (PNP) was reduced in CAR-null mice with male CAR-null mice showing reduced production of both paraoxon and PNP, and female CAR-null mice showing reduced production of only PNP. Overall, the data indicate that CAR-null mice metabolize parathion slower than WT mice. These results provide a potential mechanism for increased sensitivity of individuals with lower CAR activity such as newborns to parathion and potentially other chemicals due to decreased metabolic capacity.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant R15-ES017321]; the National Institutes of Health National Institute of General Medical Sciences [S06-GM008012]; and Clemson University.

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

    doi:10.1124/dmd.110.032961.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    PNP
    p-nitrophenyl
    CAR
    constitutive androstane receptor
    PXR
    pregnane X receptor
    WT
    wild-type
    DHA
    dihydroandrosterone
    iso-OMPA
    tetraisopropyl pyrophosphoramide
    TCPOBOP
    1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene
    mCAR
    mouse CAR
    Q
    quantitative
    PCR
    polymerase chain reaction
    HPLC
    high-performance liquid chromatography
    Ct
    threshold cycle.

  • Received April 20, 2010.
  • Accepted June 23, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (9)
Drug Metabolism and Disposition
Vol. 38, Issue 9
1 Sep 2010
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Research ArticleArticle

Constitutive Androgen Receptor-Null Mice Are Sensitive to the Toxic Effects of Parathion: Association with Reduced Cytochrome P450-Mediated Parathion Metabolism

Linda C. Mota, Juan P. Hernandez and William S. Baldwin
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1582-1588; DOI: https://doi.org/10.1124/dmd.110.032961

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Research ArticleArticle

Constitutive Androgen Receptor-Null Mice Are Sensitive to the Toxic Effects of Parathion: Association with Reduced Cytochrome P450-Mediated Parathion Metabolism

Linda C. Mota, Juan P. Hernandez and William S. Baldwin
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1582-1588; DOI: https://doi.org/10.1124/dmd.110.032961
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