Lipopolysaccharide evokes the modulation of brain cytochrome P4501A in therat

The cytochrome P450 enzyme system is a multigene family of enzymes that is modulated in the liver during systemic inflammatory responses or during inf ection Several forms of the enzyme are expressed in discrete areas of the b rain and likely play a critical role in the metabolism of drugs and endogen ous chemicals in the central nervous system (CNS). Even though the brain re sponds to inflammation in a manner different from most tissues, we examined the possible modification of a major cytochrome P450 form (CYP1A) in the b rain during inflammation confined to that organ. Total brain CYP1A activity , as measured by ethoxyresorufin dealkylase (EROD), was downregulated 24 an d 48 h following the administration of a single dose of Lipopolysaccharide (LPS). Regionally, a similar effect was determined in the cortex, hippocamp us and the mid-brain but the activity in the cerebellum was unaffected. The examination of coronal brain sections using an antibody directed against C YP1A indicated that the enzyme was distributed in discrete cells of the hip pocampus, thalamus and cortex and in the tanycytes surrounding the third ve ntricle. in each of these areas, the immunoreactivity was diminished in ani mals receiving LPS as compared to saline-treated animals. LPS also evoked t he expression of the small molecular weight heat shock protein hsp27 throug hout the brain indicating the development of an inflammatory response. Thes e studies indicate that inflammation localized to the CNS causes an alterat ion 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 in flammatory component. (C) 1999 Elsevier Science B.V. All rights reserved.