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Research ArticleArticle

Role of Nitric Oxide in Down-Regulation of CYP2B1 Protein, but Not RNA, in Primary Cultures of Rat Hepatocytes

Luc Ferrari, Ning Peng, James R. Halpert and Edward T. Morgan
Molecular Pharmacology July 2001, 60 (1) 209-216; DOI: https://doi.org/10.1124/mol.60.1.209
Luc Ferrari
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Ning Peng
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James R. Halpert
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Edward T. Morgan
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Abstract

There are conflicting reports about the role of nitric oxide in the down-regulation of cytochrome P450 that occurs when animals or cultured hepatocytes are exposed to inflammatory stimuli. Here, we investigated the participation of NO in the down-regulation of CYP2B1 by bacterial endotoxin (LPS) in rat hepatocytes cultured on Matrigel. LPS caused the down-regulation of CYP2B1 mRNA to 20% of control values within 12 h of treatment, and this was not reversed by concentrations of NO synthase inhibitors that completely blocked NO production. LPS was several orders of magnitude more potent in the down-regulation of CYP2B1 mRNA than in induction of NO production. In contrast, concentrations of LPS in the 1 to 100 ng/ml range induced NO production and produced a rapid down-regulation of CYP2B1 protein to 30% and <5% of control at 6 and 24 h, respectively, that could be completely prevented both by inhibitors of NO synthase and by LY83583, which prevents NO synthase-2 induction. The blockade of CYP2B1 down-regulation by NO synthase inhibitors was reversed by arginine, and the NO donors S-nitrosoglutathione andS-nitroso-N-acetylpenicillamine mimicked CYP2B1 protein suppression. Taken together, these experiments demonstrate two independent mechanisms of CYP2B1 down-regulation by LPS: a rapid, NO-dependent suppression of the protein occurring at high concentrations of LPS and a slower, NO-independent pretranslational suppression occurring at low concentrations of LPS.

  • Abbreviations

    P450
    cytochrome P450
    NOS
    nitric-oxide synthase
    LPS
    bacterial lipopolysaccharide
    IL
    interleukin
    PB
    phenobarbital
    TNF
    tumor necrosis factor
    NMA
    Nω-monomethyl-l-arginine
    AG
    aminoguanidine
    GSNO
    S-nitrosoglutathione
    SNAP
    S-nitroso-N-acetylpenicillamine
    SSC
    standard saline citrate
    PROD
    pentoxyresorufinO-dealkylase
    NOx
    nitrate + nitrite
    • Received October 12, 2000.
    • Accepted April 9, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Molecular Pharmacology: 60 (1)
    Molecular Pharmacology
    Vol. 60, Issue 1
    1 Jul 2001
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    Research ArticleArticle

    Role of Nitric Oxide in Down-Regulation of CYP2B1 Protein, but Not RNA, in Primary Cultures of Rat Hepatocytes

    Luc Ferrari, Ning Peng, James R. Halpert and Edward T. Morgan
    Molecular Pharmacology July 1, 2001, 60 (1) 209-216; DOI: https://doi.org/10.1124/mol.60.1.209

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    Research ArticleArticle

    Role of Nitric Oxide in Down-Regulation of CYP2B1 Protein, but Not RNA, in Primary Cultures of Rat Hepatocytes

    Luc Ferrari, Ning Peng, James R. Halpert and Edward T. Morgan
    Molecular Pharmacology July 1, 2001, 60 (1) 209-216; DOI: https://doi.org/10.1124/mol.60.1.209
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