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Received for publication March 4, 2005.
Revised April 25, 2005.
Accepted for publication April 26, 2005.
Inflammatory agents such as lipopolysaccharide (LPS) down-regulate the hepatic expression of many cytochrome P450 (CYP) mRNAs and proteins. Previous studies suggested that suppression of some CYP mRNAs could involve the regulation or modulation of the nuclear receptors peroxisome proliferator activated receptor alpha (PPAR
) or pregnane X receptor (PXR). To determine the involvement of these receptors in CYP down-regulation, PPAR knockout (KO), PXR KO, and appropriate wildtype (WT) mice were administered either saline or 1 mg/kg LPS. Hepatic mRNA and protein expression of several CYP isoforms, interleukin (IL)-1
, IL-6, tumor necrosis factor alpha (TNF), 1-acid glycoprotein (AGP), and fibrinogen (FBG) were examined 16 hours later. LPS administration significantly decreased the hepatic expression of CYP1A2, 2A5, 2C29, 2E1, 3A11, 4A10, and 4A14 mRNAs in both groups of PPAR? and PXR mice, whereas CYP3A13 mRNA was increased slightly in PPAR WT and KO mice, but not in PXR mice. Effects of LPS administration on mouse hepatic CYP proteins (probed using rat P450 2C, 3A, 4A, and 2E antibodies) were consistent with mRNA results in most cases. LPS treatment significantly increased IL-1, IL-6, TNF, AGP, and FBG mRNA in both PPAR and PXR mice, with the greatest effect observed with TNF. Because decreases in CYP mRNA expression were essentially identical in both WT and KO mice for both nuclear receptors, these data indicate that down-regulation of CYP during inflammation does not require the nuclear receptors PPAR and PXR.
Key words:
PPAR, PXR, cytochrome P450, endotoxin, gene regulation, inflammation
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