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 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 kappaB alpha (IkappaBalpha) 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-kappaB), 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-kappaB 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.
Abdulla
Dalya
D
Department of Pharmacology, Sir Charles Tupper Medical Bldg., Dalhousie University, Halifax, N.S., B3H 4H7, Canada.
Goralski
Kerry B
KB
Del Busto Cano
Elena Garcia
EG
Renton
Kenneth W
KW
D000818:Animals; D001921:Brain / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D002490:Central Nervous System / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D050882:CREB-Binding Protein; C494363:CREBBP protein, human