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 1 1999

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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