Lipopolysaccharide evokes the modulation of brain cytochrome P4501A in the rat.
The cytochrome P450 enzyme system is a multigene family of enzymes that is modulated in the liver during systemic inflammatory responses or during infection Several forms of the enzyme are expressed in discrete areas of the brain and likely play a critical role in the metabolism of drugs and endogenous chemicals in the central nervous system (CNS). Even though the brain responds to inflammation in a manner different from most tissues, we examined the possible modification of a major cytochrome P450 form (CYP1A) in the brain during inflammation confined to that organ. Total brain CYP1A activity, as measured by ethoxyresorufin dealkylase (EROD), was downregulated 24 and 48 h following the administration of a single dose of lipopolysaccharide (LPS). Regionally, a similar effect was determined in the cortex, hippocampus and the mid-brain but the activity in the cerebellum was unaffected. The examination of coronal brain sections using an antibody directed against CYP1A indicated that the enzyme was distributed in discrete cells of the hippocampus, thalamus and cortex and in the tanycytes surrounding the third ventricle. In each of these areas, the immunoreactivity was diminished in animals receiving LPS as compared to saline-treated animals. LPS also evoked the expression of the small molecular weight heat shock protein hsp27 throughout the brain indicating the development of an inflammatory response. These studies indicate that inflammation localized to the CNS causes an alteration in the levels and activity of a major cytochrome P450 form in the brain. This could have implications to the metabolism or activation of drugs and endogenous chemicals in the CNS during a disease state that features an inflammatory component.
Renton
K W
KW
Department of Pharmacology, Dalhousie University Halifax, Sir Charles Tupper Medical Bldg., Halifax, Nova Scotia, Canada. ken.renton@dal.ca
Dibb
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Levatte
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D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D020547:Lateral Ventricles / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004731:Endotoxins; D008070:Lipopolysaccharides; C044101:endotoxin, Escherichia coli; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2