DISTRIBUTION AND INDUCTION OF CYTOCHROME-P450 1A1 AND 1A2 IN RAT-BRAIN

Cytochromes P450 1A1 and 1A2 are involved in the oxidation of a wide s pectrum of endogenous compounds and xenobiotics. Although their presen ce has been repeatedly confirmed in brain tissue, reports regarding th eir distribution in the brain are often contradictory. In the present study the possibility was examined that CYP1A1 and CYP1A2 are localize d and inducible in the brain-CSF barrier and regions with a leaky bloo d brain barrier, where they may serve as a protective metabolic barrie r. CYP1A1 and CYP1A2 levels were determined in subcellular fractions o f multiple brain regions, as well as tissue homogenates of circumventr icular organs, and the meninges by Western blotting and catalytic acti vity in control male rats and rats treated with the inducer P-naphthof lavone (BNF). In control animals CYP1A1 immunoreactive protein was und etectable in regional brain microsomes or whole tissue homogenates of the arachnoid, dura mater, choroid plexus, pineal gland, median eminen ce, and pituitary. However, low levels of ethoxyresorufin O-deethylase (EROD) activity were observed in homogenates of the arachnoid, dura m ater, choroid plexus, pineal gland, and pituitary. Western blotting re vealed only low levels of CYP1A2 immunoreactive protein in brain micro somes from the cortex, cerebellum, brainstem, thalamus, hippocampus, a nd striatum from control animals. Following BNF treatment, EROD activi ty was induced 12-42-fold in the arachnoid, choroid plexus, dura mater , pineal gland, pituitary, and median eminence. Western blot analysis revealed CYP1A1 to be induced in the arachnoid, dura mater, choroid pl exus, pineal gland, and pituitary, while CYP1A2 was undetectable. No i nduction of CYP1A1 or CYP1A2 protein was observed in brain microsomes from the olfactory bulb, cortex, striatum, hippocampus, cerebellum, or brainstem following BNF treatment, providing that the arachnoid membr anes and choroid plexus had been carefully removed prior to brain diss ection. Neither CYP1A1, 1A2 protein, nor EROD activity were detected i n purified brain mitochondria, regardless of treatment or region. In c onclusion, catalytically active CYP1A1 is located in the meninges as w ell as certain circumventricular organs, is inducible by BNF, and appe ars to be absent or expressed constitutively at very low levels in the majority of the brain parenchyma. The localization of CYP1A1 in the b lood-CSF barrier and circumventricular tissues likely plays a role in protecting the brain from xenobiotics. (C) 1998 Academic Press.