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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Enhanced Induction of Cytochrome P450 Enzymes and CAR Binding in TNF (p55−/−/p75−/−) Double Receptor Knockout Mice Following Phenobarbital Treatment

Peter J. Van Ess, Mark P. Mattson and Robert A. Blouin
Journal of Pharmacology and Experimental Therapeutics March 2002, 300 (3) 824-830; DOI: https://doi.org/10.1124/jpet.300.3.824
Peter J. Van Ess
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Mark P. Mattson
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Robert A. Blouin
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Abstract

Phenobarbital (PB) is a well characterized inducer of cytochrome P450 (P450) 2B and 3A subfamilies. Several proinflammatory cytokines have been shown to negatively modulate the induction of P450 by PB. In addition, PB is known to elicit an inflammatory mitogenic effect on the liver. To date, no studies have evaluated the PB induction profile of hepatic P450 in the absence of an intact tumor necrosis factor-alpha (TNFα) response. To test the hypothesis that endogenous TNFα signaling modulates hepatic P450 induction by PB in vivo, PB induction was examined in TNF (p55−/−/p75−/−) double receptor knockout mice (ko-TNF) and wild-type mice (wt-TNF). CYP2B- and CYP3A-associated activities and protein content were induced to a significantly greater extent (p < 0.05) in ko-TNF mice compared with wt-TNF mice. In parallel with enhanced CYP2B induction, an apparent elevation in the nuclear accumulation of the principal regulatory protein for transcription of CYP2B genes, the constitutively activated receptor (CAR), was detected in ko-TNF nuclear extracts following PB treatment. Additionally, nuclear factor κ-B binding was induced by PB in wt-TNF mice, but not in ko-TNF mice, indicating that the hepatic inflammatory response following PB treatment differed between wt-TNF and ko-TNF mice. These data demonstrate that endogenous TNFα signaling modulates PB induction of hepatic CYP2B and CYP3A isoforms in vivo. Further, the data presented herein suggest that endogenous TNFα signaling influences PB induction of CYP2B through inhibition of CAR nuclear accumulation.

Footnotes

  • This work was supported by grants to R. A. B. from the Kentucky Spinal Cord Head Injury Research Trust (BB-9502-K) and to M. P. M. from the National Institutes of Health (NS29001, AG14554, and NS35253). P. V. E. was supported by the University of Kentucky Research Challenge Trust Fund and a Research Service Award from the American Foundation for Pharmaceutical Education.

  • Abbreviations:
    P450
    cytochrome P450
    APR
    acute phase response
    LPS
    lipopolysaccharide
    TNFα
    tumor necrosis factor-alpha
    IL
    interleukin
    PB
    phenobarbital
    RXR
    retinoid X receptor
    PBREM
    PB-responsive enhancer module
    NF-κB
    nuclear factor kappa-B
    16β-OHT
    16β-hydroxytestosterone
    PROD
    7-pentoxyresorufinO-dealkylase
    ELISA
    enzyme-linked immunosorbent assay
    PBS
    phosphate-buffered saline
    CAR
    constitutively activated receptor
    ko
    knockout
    wt
    wild-type
    EMSA
    electrophoretic mobility shift assay
    PXR
    pregnane X receptor
    • Received August 28, 2001.
    • Accepted November 11, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 3
1 Mar 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Enhanced Induction of Cytochrome P450 Enzymes and CAR Binding in TNF (p55−/−/p75−/−) Double Receptor Knockout Mice Following Phenobarbital Treatment

Peter J. Van Ess, Mark P. Mattson and Robert A. Blouin
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 824-830; DOI: https://doi.org/10.1124/jpet.300.3.824

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Enhanced Induction of Cytochrome P450 Enzymes and CAR Binding in TNF (p55−/−/p75−/−) Double Receptor Knockout Mice Following Phenobarbital Treatment

Peter J. Van Ess, Mark P. Mattson and Robert A. Blouin
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 824-830; DOI: https://doi.org/10.1124/jpet.300.3.824
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