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 spectrum of endogenous compounds and xenobiotics. Although their presence has been repeatedly confirmed in brain tissue, reports regarding their distribution in the brain are often contradictory. In the present study the possibility was examined that CYP1A1 and CYP1A2 are localized and inducible in the brain-CSF barrier and regions with a leaky blood brain barrier, where they may serve as a protective metabolic barrier. CYP1A1 and CYP1A2 levels were determined in subcellular fractions of multiple brain regions, as well as tissue homogenates of circumventricular organs, and the meninges by Western blotting and catalytic activity in control male rats and rats treated with the inducer beta-naphthoflavone (BNF). In control animals CYP1A1 immunoreactive protein was undetectable in regional brain microsomes or whole tissue homogenates of the arachnoid, dura mater, choroid plexus, pineal gland, median eminence, and pituitary. However, low levels of ethoxyresorufin O-deethylase (EROD) activity were observed in homogenates of the arachnoid, dura mater, choroid plexus, pineal gland, and pituitary. Western blotting revealed only low levels of CYP1A2 immunoreactive protein in brain microsomes from the cortex, cerebellum, brainstem, thalamus, hippocampus, and striatum from control animals. Following BNF treatment, EROD activity 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 plexus, pineal gland, and pituitary, while CYP1A2 was undetectable. No induction 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 membranes and choroid plexus had been carefully removed prior to brain dissection. Neither CYP1A1, 1A2 protein, nor EROD activity were detected in purified brain mitochondria, regardless of treatment or region. In conclusion, catalytically active CYP1A1 is located in the meninges as well as certain circumventricular organs, is inducible by BNF, and appears to be absent or expressed constitutively at very low levels in the majority of the brain parenchyma. The localization of CYP1A1 in the blood-CSF barrier and circumventricular tissues likely plays a role in protecting the brain from xenobiotics.
Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
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Morse
A P
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Stein
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PE
Thomas
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Lowndes
D000818:Animals; D001099:Arachnoid / Q000187:drug effects / Q000201:enzymology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D004388:Dura Mater / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019324:beta-Naphthoflavone / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019324:beta-Naphthoflavone; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2