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Drug Metabolism and Disposition Fast Forward
First published on July 8, 2005; DOI: 10.1124/dmd.105.004564

0090-9556/05/3310-1521-1531$20.00
DMD 33:1521-1531, 2005

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THE SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN HEPATIC CYTOCHROME P450 REGULATION IN THE RAT DURING A LIPOPOLYSACCHARIDE-INDUCED MODEL OF CENTRAL NERVOUS SYSTEM INFLAMMATION

Dalya Abdulla, Kerry B. Goralski, Elena Garcia Del Busto Cano, and Kenneth W. Renton

Department of Pharmacology (D.A., K.B.G., E.G.D.B.C., K.W.R.) and Department of Pediatrics, Isaak Walton Killam Health Center (K.B.G.), Dalhousie University, Halifax, Nova Scotia, Canada

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 (P450); however, the pathways leading to this regulation remain unknown. We provide evidence delineating a signal transduction pathway for hepatic P450 gene expression down-regulation in an established rat model of CNS inflammation using lipopolysaccharide (LPS) injected (i.c.v.) directly into the lateral cerebral ventricle. Brain cytokine levels were elevated, and the expression of tumor necrosis factor {alpha} and inhibitor of {kappa}B alpha (I{kappa}B{alpha}) 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 down-regulated following CNS inflammation. The binding of several transcription factors [nuclear factor of the {kappa} enhancer in B cells (NF-{kappa}B), activator protein-1, cAMP response element binding protein, CCAAT-enhancer binding protein (C/EBP)] to responsive elements on P450 promoter regions was examined using electromobility shift assays. Binding of both NF-{kappa}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 down-regulation of P450s in the liver.

Address correspondence to: Kenneth W. Renton, Dept. of Pharmacology, Sir Charles Tupper Medical Bldg., Dalhousie University, Halifax, N.S., B3H 4H7, Canada. E-mail: Ken.Renton{at}dal.ca




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