LOCALIZATION OF DRUG-METABOLIZING ENZYME-ACTIVITIES TO BLOOD-BRAIN INTERFACES AND CIRCUMVENTRICULAR ORGANS

The brain, with the exception of the choroid plexuses and circumventri cular organs, is partially protected from the invasion of blood-borne chemicals by the specific morphological properties of the cerebral mic rovessels, namely, the tight junctions of the blood-brain barrier. Rec ently, several enzymes that are primarily involved in hepatic drug met abolism have been shown to exist in the brain, albeit at relatively lo w specific activities. In the present study, the hypothesis that these enzymes are located primarily at blood-brain interfaces, where they f orm an ''enzymatic barrier,'' is tested. By using microdissection tech niques or a gradient-centrifugation isolation procedure, the activitie s of seven drug-metabolizing enzymes in isolated microvessels, choroid plexuses, meningeal membranes, and tissue from three circumventricula r organs (the neural lobe of the hypophysis, pineal gland, and median eminence) were assayed. With two exceptions, the activities of these e nzymes were higher in the three circumventricular organs and cerebral microvessel than in the cortex. Very high membrane-bound epoxide hydro lase and UDP-glucuronosyltransferase activities (approaching those in liver) and somewhat high 7-benzoxyresorufin-O-dealkylase and NADPH-cyt ochrome P-450 reductase activities were determined in the choroid plex uses. The pia-arachnoid membranes, but not the dura matter, displayed drug-metabolizing enzyme activities, notably that of epoxide hydrolase . The drug-metabolizing enzymes located at these nonparenchymal sites may function to protect brain tissue from harmful compounds.