Abstract
Inflammatory agents such as lipopolysaccharide (LPS) down-regulate the hepatic expression of many cytochrome P450 (P450) mRNAs and proteins. Previous studies suggested that suppression of some P450 mRNAs could involve the regulation or modulation of the nuclear receptors peroxisome proliferator-activated receptor α (PPARα) or pregnane X receptor (PXR). To determine the involvement of these receptors in P450 down-regulation, PPARα knockout (KO), PXR KO, and appropriate wild-type (WT) mice were administered either saline or 1 mg/kg LPS. Hepatic mRNA and protein expression of several P450 isoforms, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF) α, α1-acid glycoprotein (AGP), and fibrinogen (FBG) were examined 16 h later. LPS administration significantly decreased the hepatic expression of CYP1A2, 2A5, 2C29, 2E1, 3A11, 4A10, and 4A14 mRNAs in both groups of PPARα and PXR mice, whereas CYP3A13 mRNA was increased slightly in PPARα WT and KO mice, but not in PXR mice. Effects of LPS administration on mouse hepatic P450 proteins (probed using rat P450 2C, 3A, 4A, and 2E antibodies) were consistent with mRNA results in most cases. LPS treatment significantly increased IL-1β, IL-6, TNFα, AGP, and FBG mRNA in both PPARα and PXR mice, with the greatest effect observed with TNFα. Because decreases in P450 mRNA expression were essentially identical in both WT and KO mice for both nuclear receptors, these data indicate that down-regulation of P450 during inflammation does not require the nuclear receptors PPARα and PXR.
Footnotes
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National Institutes of Health Grant GM-46897 provided funding for this study. Portions of this work were previously presented at the 44th Annual Society of Toxicology meeting, New Orleans, LA.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.085456.
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ABBREVIATIONS: P450, cytochrome P450; LPS, lipopolysaccharide; IL, interleukin; TNF, tumor necrosis factor; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; RXR, retinoid X receptor; KO, knockout; WT, wild type; RT-PCR, reverse transcription-polymerase chain reaction; GAPDH, glyceraldehyde phosphate dehydrogenase; PCR, polymerase chain reaction; PBS, phosphate-buffered saline; AGP, α1-acid glycoprotein; FBG, fibrinogen; TF, transcription factor; LIP, liver-enriched transcriptional inhibitory protein; HNF, hepatocyte nuclear factor.
- Received February 25, 2005.
- Accepted April 26, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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