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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Hepatic Cytochrome P450 Gene Regulation during Endotoxin-Induced Inflammation in Nuclear Receptor Knockout Mice

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia

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 (PPAR) or pregnane X receptor (PXR). To determine the involvement of these receptors in P450 down-regulation, PPAR 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)-1, IL-6, tumor necrosis factor (TNF) , 1-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 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 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-1, IL-6, TNF, AGP, and FBG mRNA in both PPAR and PXR mice, with the greatest effect observed with TNF. 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 PPAR and PXR.

Address correspondence to: Dr. Edward T. Morgan, Department of Pharmacology, Emory University School of Medicine, 5119 O. Wayne Rollins Research Center, 1510 Clifton Rd. NE, Atlanta, GA 30322. E-mail: edward.morgan{at}emory.edu

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