Decrease in brain cytochrome P450 enzyme activities during infection and inflammation of the central nervous system.
The effect of infection and inflammation of the central nervous system (CNS) on cytochrome-P450-dependent activities in brain, spinal cord and liver microsomes was determined. For this, two models were used: (1) the intracerebroventricularly injected lipopolysaccharide (LPS) model and (2) the experimental auto-immune encephalomyelitis (EAE) model. In the LPS model, aminopyrine N-demethylase (AMND) and ethoxycoumarin O-deethylase (ECOD) activities (both P450 dependent) were significantly decreased (35 and 20%, respectively) in brain microsomes. In the EAE model, only ECOD activity was significantly lower (18%). In the liver, a decrease in total P450, AMND and ECOD activities was only observed in the LPS model. In both models, tumour necrosis factor (TNF) was significantly elevated in brain and spinal cord tissues. In serum, TNF was only detectable in the LPS model. It is concluded that an infection or inflammation located in the CNS, which is accompanied by high TNF levels, results in a decrease in P450-dependent metabolism not only in the liver but in the brain as well.
Monshouwer
M
M
Department of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. mario.monshouwer@eu.pnu.com
Agnello
D
D
Ghezzi
P
P
Villa
P
P
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000276:immunology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D016920:Meningitis, Bacterial / Q000201:enzymology* / Q000276:immunology; D008862:Microsomes, Liver / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D015660:7-Alkoxycoumarin O-Dealkylase; D000633:Aminopyrine N-Demethylase