Hepatic cytochrome P-450 expression in tumor necrosis factor-α receptor (p55/p75) knockout mice after endotoxin administration

Graham W. Warren, Samuel M. Poloyac, Devin S. Gary, Mark P. Mattson, Robert A. Blouin

Research output: Contribution to journalArticle

Abstract

Hepatic cytochromes P-450 (CYP) are well characterized drug and xenobiotic metabolizing enzymes that are extensively regulated by genetic and environmental factors. Inflammatory mediators, including interleukins (ILs), interferons (IFNs), and tumor necrosis factor-α (TNF-α), have been shown to down-regulate several CYP isoforms; however, elucidation of the inflammatory mediators that are responsible for specific CYP down-regulation is difficult. The purpose of this experiment was to evaluate the role endogenous TNF-α plays in the regulation of liver CYP expression after endotoxin administration. Mice deficient in the p55 and p75 TNF receptors and wild- type mice were given Gram-negative bacterial lipopolysaccharide (LPS) and killed 24 h after administration. CYP analysis indicates that LPS decreases CYP1A, CYP2B, CYP3A, and CYP4A independently of TNF-α. CYP2D9 and CYP2E1 activities show differential responses to LPS between wild-type and TNF p55/p75 receptor knockout mice, indicating the down-regulation of CYP2D9 and CYP2E1 is differentially modulated by TNF-α expression. Furthermore, TNF-α appears to affect the constitutive expression of CYP2D9 and CYP2E1. To date, this is the first evidence suggesting that a proinflammatory cytokine is involved in the constitutive regulation of drug-metabolizing enzymes.

Original languageEnglish (US)
Pages (from-to)945-950
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume288
Issue number3
StatePublished - Mar 1999
Externally publishedYes

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Tumor Necrosis Factor Receptors
Knockout Mice
Endotoxins
Cytochrome P-450 Enzyme System
Tumor Necrosis Factor-alpha
Cytochrome P-450 CYP2E1
Liver
Lipopolysaccharides
Down-Regulation
Cytochrome P-450 CYP4A
Cytochrome P-450 CYP3A
Drug and Narcotic Control
Interleukins
Xenobiotics
Enzymes
Interferons
Protein Isoforms
Cytokines
Pharmaceutical Preparations
recombinant human tumor necrosis factor-binding protein-1

ASJC Scopus subject areas

  • Pharmacology

Cite this

Hepatic cytochrome P-450 expression in tumor necrosis factor-α receptor (p55/p75) knockout mice after endotoxin administration. / Warren, Graham W.; Poloyac, Samuel M.; Gary, Devin S.; Mattson, Mark P.; Blouin, Robert A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 288, No. 3, 03.1999, p. 945-950.

Research output: Contribution to journalArticle

Warren, Graham W. ; Poloyac, Samuel M. ; Gary, Devin S. ; Mattson, Mark P. ; Blouin, Robert A. / Hepatic cytochrome P-450 expression in tumor necrosis factor-α receptor (p55/p75) knockout mice after endotoxin administration. In: Journal of Pharmacology and Experimental Therapeutics. 1999 ; Vol. 288, No. 3. pp. 945-950.
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