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

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 pro-vide evidence delineating a signal transduction pathway for he-patic P450 gene expression down-regulation in an established rat model of CNS inflammation using lipopolysaccharide (LPS) in-jected (i.c.v.) directly into the lateral cerebral ventricle. Brain cyto-kine levels were elevated, and the expression of tumor necrosis factor and inhibitor of B alpha (IB) 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 follow-ing CNS inflammation. The binding of several transcription factors [nuclear factor of the enhancer in B cells (NF-B), activato