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Research ArticleArticle

THE SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN HEPATIC CYTOCHROME P450 REGULATION IN THE RAT DURING A LIPOPOLYSACCHARIDE-INDUCED MODEL OF CENTRAL NERVOUS SYSTEM INFLAMMATION

Dalya Abdulla, Kerry B. Goralski, Elena Garcia Del Busto Cano and Kenneth W. Renton
Drug Metabolism and Disposition October 2005, 33 (10) 1521-1531; DOI: https://doi.org/10.1124/dmd.105.004564
Dalya Abdulla
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Kerry B. Goralski
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Elena Garcia Del Busto Cano
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Kenneth W. Renton
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Abstract

It is well known that inflammatory and infectious conditions of the central nervous system (CNS) differentially regulate hepatic drug metabolism through changes in cytochrome P450 (P450); however, the pathways leading to this regulation remain unknown. We provide evidence delineating a signal transduction pathway for hepatic P450 gene expression down-regulation in an established rat model of CNS inflammation using lipopolysaccharide (LPS) injected (i.c.v.) directly into the lateral cerebral ventricle. Brain cytokine levels were elevated, and the expression of tumor necrosis factor α and inhibitor of κB alpha (IκBα) were increased in the liver following the i.c.v. administration of LPS, indicating the presence of an inflammatory response in the brain and liver. The expression of CYP2D1/5, CYP2B1/2, and CYP1A1 was down-regulated following CNS inflammation. The binding of several transcription factors [nuclear factor of the κ enhancer in B cells (NF-κB), activator protein-1, cAMP response element binding protein, CCAAT-enhancer binding protein (C/EBP)] to responsive elements on P450 promoter regions was examined using electromobility shift assays. Binding of both NF-κB and C/EBP to the promoter regions of CYP2D5 and CYP2B1, respectively, was increased, indicating that they play an important role in the regulation of these two isoforms during inflammatory responses. Evidence is also provided suggesting that the rapid transfer of LPS from the CNS into the periphery likely accounts for the down-regulation of P450s in the liver.

Footnotes

  • This work was supported by a grant from the Canadian Institute for Health Research (CIHR). D.A. was funded by an Eliza Ritchie doctoral research award. K.B.G. was funded by fellowships from CIHR, IWK Health Centre, and the Nova Scotia Health Research Foundation.

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

  • doi:10.1124/dmd.105.004564.

  • ABBREVIATIONS: P450, cytochrome P450; LPS, lipopolysaccharide; CNS, central nervous system; NO, nitric oxide; TNFα, tumor necrosis factor α; IκBα, inhibitor of κB alpha; IL-1β, interleukin-1β; IL-6, interleukin-6; IFNγ; interferon γ; NF-κB, nuclear factor of the κ enhancer in B cells; AP-1, activator protein-1; CREB, cAMP response element binding protein; C/EBP, CAAT enhancer binding protein; EROD, 7-ethoxyresorufin O-dealkylase; PROD, pentoxyresorufin O-dealkylase; ICE-1, IL-1 converting enzyme; PCR, polymerase chain reaction; DTT, dithiothreitol; MAPKK, mitogen-activated protein kinase kinase; EMSA, electromobility shift assay.

    • Received March 1, 2005.
    • Accepted July 6, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (10)
Drug Metabolism and Disposition
Vol. 33, Issue 10
1 Oct 2005
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Research ArticleArticle

THE SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN HEPATIC CYTOCHROME P450 REGULATION IN THE RAT DURING A LIPOPOLYSACCHARIDE-INDUCED MODEL OF CENTRAL NERVOUS SYSTEM INFLAMMATION

Dalya Abdulla, Kerry B. Goralski, Elena Garcia Del Busto Cano and Kenneth W. Renton
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1521-1531; DOI: https://doi.org/10.1124/dmd.105.004564

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Research ArticleArticle

THE SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN HEPATIC CYTOCHROME P450 REGULATION IN THE RAT DURING A LIPOPOLYSACCHARIDE-INDUCED MODEL OF CENTRAL NERVOUS SYSTEM INFLAMMATION

Dalya Abdulla, Kerry B. Goralski, Elena Garcia Del Busto Cano and Kenneth W. Renton
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1521-1531; DOI: https://doi.org/10.1124/dmd.105.004564
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