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Research ArticleArticle

Lipopolysaccharide-Mediated Modulation of Cytochromes P450 in Stat1 Null Mice

Jinmei Pan, Qian Xiang, Simon Ball, JoAnn Scatina, John Kao and Jun-Yan Hong
Drug Metabolism and Disposition April 2003, 31 (4) 392-397; DOI: https://doi.org/10.1124/dmd.31.4.392
Jinmei Pan
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Qian Xiang
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Simon Ball
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JoAnn Scatina
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John Kao
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Jun-Yan Hong
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Abstract

Signal transducer and activator of transcription (Stat), a family of transcriptional factors, has been demonstrated to play a critical role in gene regulation in response to inflammatory cytokines, such as interferon and interleukin-6. Inflammatory cytokines and bacterial endotoxin are known to suppress, in most of cases, the constitutive or induced cytochromes P450 (P450) in animals and humans. However, it is not clear if the suppression of P450 by cytokines is through the Stat-signaling pathway. In the present study, we determined whether Stat1 is involved in lipopolysaccharide (LPS)-mediated modulation of P450 in mouse liver. In both Stat1+/+ (wild type) and Stat1−/− (null) mice, a single dose of LPS treatment (1 mg/kg of body weight, i.p.) significantly reduced the expression of CYP3A11, 2C29, and 1A2 mRNA to 8 to 40% of the control levels as determined by real-time quantitative reverse transcription-polymerase chain reaction. The reduction was supported by Western blot analysis. In contrast, LPS significantly induced the level of CYP4A10 mRNA in both Stat1+/+ (338% of control) and Stat1−/− mice (264% of control). Although suppression of mRNA levels of CYP2E1, and 2D9 was not observed in either LPS-treated Stat1 null or wild-type animals, LPS treatment resulted in a reduction of CYP2E1 protein content, which was more significant in Stat1+/+ (23% of control) than in Stat1−/−mice (67% of control). Consistent with this result, the chlorzoxazone 6-hydroxylase and lauric acid 11-hydroxylase activities, as CYP2E1 representative activities, were reduced markedly by LPS in Stat1+/+ but not in Stat1−/− mice. The ethoxyresorufin O-deethylase activity, as a representative CYP1A activity, was also reduced significantly only in LPS-treated Stat1+/+ mice. These data clearly demonstrate that LPS-mediated modulation of CYP3A11, 2B10, 2C29, 1A2, and 4A10 in mouse liver is Stat1-independent. However, the significant difference between the LPS-treated Stat1+/+ and Stat1−/− mice in the levels of CYP2E1 protein and activity as well as in the activity level of CYP1A suggests that Stat1 may be indirectly involved in the post-transcriptional modulation of these two mouse P450 enzymes.

Footnotes

  • ↵1 Current address: Pfizer Global R&D, Ann Arbor, MI 48105.

  • Abbreviations used are::
    P450
    cytochromes P450
    LPS
    lipopolysaccharide
    IL-6
    interleukin 6
    BSA
    bovine serum albumin
    ECL
    enhanced chemiluminescence
    TBS
    Tris-buffered saline
    RT-PCR
    reverse transcription-polymerase chain reaction
    PXR
    pregnane X receptor
    CAR
    constitutive androstane receptor
    iNOS
    inducible nitric oxide synthase
    HPLC
    high performance liquid chromotography
    PROD
    pentoxyresorufin O-dealkylase
    EROD
    ethoxyresorufinO-deethylase
    Stat
    signal transducer and activator of transcription
    • Received July 11, 2002.
    • Accepted December 18, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (4)
Drug Metabolism and Disposition
Vol. 31, Issue 4
1 Apr 2003
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Research ArticleArticle

Lipopolysaccharide-Mediated Modulation of Cytochromes P450 in Stat1 Null Mice

Jinmei Pan, Qian Xiang, Simon Ball, JoAnn Scatina, John Kao and Jun-Yan Hong
Drug Metabolism and Disposition April 1, 2003, 31 (4) 392-397; DOI: https://doi.org/10.1124/dmd.31.4.392

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Research ArticleArticle

Lipopolysaccharide-Mediated Modulation of Cytochromes P450 in Stat1 Null Mice

Jinmei Pan, Qian Xiang, Simon Ball, JoAnn Scatina, John Kao and Jun-Yan Hong
Drug Metabolism and Disposition April 1, 2003, 31 (4) 392-397; DOI: https://doi.org/10.1124/dmd.31.4.392
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