RT Journal Article
SR Electronic
T1 Hepatic Cytochrome P-450 Expression in Tumor Necrosis Factor-α Receptor (p55/p75) Knockout Mice After Endotoxin Administration
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 945
OP 950
VO 288
IS 3
A1 Graham W. Warren
A1 Samuel M. Poloyac
A1 Devin S. Gary
A1 Mark P. Mattson
A1 Robert A. Blouin
YR 1999
UL http://jpet.aspetjournals.org/content/288/3/945.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics