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Received for publication March 1, 2005.
Revised July 5, 2005.
Accepted for publication July 6, 2005.
It is well known that inflammatory and infectious conditions of the central nervous system (CNS) differentially regulate hepatic drug metabolism through changes in cytochrome P450 (CYP), however the pathways leading to this regulation remain unknown. We provide evidence delineating a signal transduction pathway for hepatic CYP gene expression downregulation in an established rat model of CNS inflammation using lipopolysaccharide (LPS) injected directly into the lateral cerebral ventricle (i.c.v.). Brain cytokine levels were elevated and the expression of TNF
and I
B
were increased in the liver following the i.c.v. administration of LPS, indicating the presence of an inflammatory response in the brain and liver. The expression of CYP2D1/5, CYP2B1/2, and CYP1A1 was downregulated following CNS inflammation. The binding of several transcription factors (NF-B, AP-1, CREB, C/EBP) to responsive elements on CYP promoter regions was examined using electromobility shift assays. Binding of both NF-B and C/EBP to the promoter regions of CYP2D5 and CYP2B1, respectively, was increased, indicating that they play an important role in the regulation of these two isoforms during inflammatory responses. Evidence is also provided suggesting that the rapid transfer of LPS from the CNS into the periphery likely accounts for the downregulation of CYPs in the liver.
Key words:
CYP expression, CYP gene regulation, cytochrome P450
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