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Research ArticleArticle

A Novel Defensive Mechanism against Acetaminophen Toxicity in the Mouse Lateral Nasal Gland: Role of CYP2A5-Mediated Regulation of Testosterone Homeostasis and Salivary Androgen-Binding Protein Expression

Xin Zhou, Yuan Wei, Fang Xie, Christina M. Laukaitis, Robert C. Karn, Kerri Kluetzman, Jun Gu, Qing-Yu Zhang, Dean W. Roberts and Xinxin Ding
Molecular Pharmacology April 2011, 79 (4) 710-723; DOI: https://doi.org/10.1124/mol.110.070045
Xin Zhou
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Yuan Wei
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Fang Xie
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Christina M. Laukaitis
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Robert C. Karn
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Kerri Kluetzman
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Jun Gu
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Qing-Yu Zhang
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Dean W. Roberts
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Xinxin Ding
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Abstract

To identify novel factors or mechanisms that are important for the resistance of tissues to chemical toxicity, we have determined the mechanisms underlying the previously observed increases in resistance to acetaminophen (APAP) toxicity in the lateral nasal gland (LNG) of the male Cyp2g1-null/Cyp2a5-low mouse. Initial studies established that Cyp2a5-null mice, but not a newly generated strain of Cyp2g1-null mice, were resistant to APAP toxicity in the LNG; therefore, subsequent studies were focused on the Cyp2a5-null mice. Compared with the wild-type (WT) male mouse, the Cyp2a5-null male mouse had intact capability to metabolize APAP to reactive intermediates in the LNG, as well as unaltered circulating levels of APAP, APAP-GSH, APAP-glucuronide, and APAP-sulfate. However, it displayed reduced tissue levels of APAP and APAP-GSH and increased tissue levels of testosterone and salivary androgen-binding protein (ABP) in the LNG. Furthermore, we found that ABP was able to compete with GSH and cellular proteins for adduction with reactive metabolites of APAP in vitro. The amounts of APAP-ABP adducts formed in vivo were greater, whereas the amounts of APAP adducts formed with other cellular proteins were substantially lower, in the LNG of APAP-treated male Cyp2a5-null mice compared with the LNG of APAP-treated male WT mice. We propose that through its critical role in testosterone metabolism, CYP2A5 regulates 1) the bioavailability of APAP and APAP-GSH (presumably through modulation of the rates of xenobiotic excretion from the LNG) and 2) the expression of ABP, which can quench reactive APAP metabolites and thereby spare critical cellular proteins from inactivation.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES007462] (to X.D.); the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK081406] (to D.W.R.); the Arkansas Children's Hospital Research Institute and the Arkansas Biosciences Institute, the major research component of the Tobacco Settlement Proceeds Act of 2000 (to D.W.R.); the National Institutes of Health National Cancer Institute/University of Arizona SPORE in GI Cancer [Grants CA95060, CA023074] (to C.M.L.); and the National Institutes of Health National Institute of Child Health and Human Development [Grant 5F33-HD055016-02] (to R.C.K.).

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

    doi:10.1124/mol.110.070045.

  • ABBREVIATIONS:

    APAP
    acetaminophen
    P450
    cytochrome P450
    PCR
    polymerase chain reaction
    HPLC
    high-performance liquid chromatography
    LC-MS
    liquid chromatography-mass spectrometry
    LNG
    lateral nasal gland
    APAP-G
    acetaminophen-glucuronide
    APAP-S
    acetaminophen-sulfate
    ABP
    salivary androgen-binding protein
    WT
    wild type
    B6
    C57BL/6
    kbp
    kilobase pair(s)
    ES
    embryonic stem
    E2-Glu
    17β-estradiol-3-(β-d-glucuronide)
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase.

  • Received November 16, 2010.
  • Accepted January 19, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticleArticle

A Novel Defensive Mechanism against Acetaminophen Toxicity in the Mouse Lateral Nasal Gland: Role of CYP2A5-Mediated Regulation of Testosterone Homeostasis and Salivary Androgen-Binding Protein Expression

Xin Zhou, Yuan Wei, Fang Xie, Christina M. Laukaitis, Robert C. Karn, Kerri Kluetzman, Jun Gu, Qing-Yu Zhang, Dean W. Roberts and Xinxin Ding
Molecular Pharmacology April 1, 2011, 79 (4) 710-723; DOI: https://doi.org/10.1124/mol.110.070045

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Research ArticleArticle

A Novel Defensive Mechanism against Acetaminophen Toxicity in the Mouse Lateral Nasal Gland: Role of CYP2A5-Mediated Regulation of Testosterone Homeostasis and Salivary Androgen-Binding Protein Expression

Xin Zhou, Yuan Wei, Fang Xie, Christina M. Laukaitis, Robert C. Karn, Kerri Kluetzman, Jun Gu, Qing-Yu Zhang, Dean W. Roberts and Xinxin Ding
Molecular Pharmacology April 1, 2011, 79 (4) 710-723; DOI: https://doi.org/10.1124/mol.110.070045
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