CYP1A1 and CYP1B1 in blood-brain interfaces: CYP1A1-dependent bioactivation of 7,12-dimethylbenz(a)anthracene in endothelial cells.
2003 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 31, no 3, 259-265 p.Article in journal (Refereed) Published
Immunohistochemistry and autoradiography were used to identify sites of the cytochrome P450 enzymes (P450) 1A1 and 1B1 expression and activation of 7,12-dimethylbenz(a)anthracene (DMBA), in the brain of rodents pretreated with the aryl hydrocarbon receptor (AhR) agonists beta-naphthoflavone (BNF), 3,3',4,4',5-pentachlorobiphenyl or vehicle. Immunohistochemistry revealed that CYP1A1 was preferentially induced in endothelial cells (EC) in the choroid plexus, in veins in the leptomeninges, and in cerebral veins of AhR agonist-pretreated mice. No induction occurred in cerebral capillary EC. In vehicle-treated mice no localization of CYP1A1 in EC was observed. CYP1B1 was expressed in smooth muscle cells of arteries in the leptomeninges, in cerebral arteries/arterioles and to a low extent in ependymal cells of AhR agonist- and vehicle-treated mice. No CYP1B1 was detected in capillary loops of the choroid plexus or in cerebral capillaries. Following administration of [(3)H]DMBA to BNF-pretreated mice, a marked irreversible binding in EC of the choroid plexus and of veins in the leptomeninges was observed but not in cerebral capillaries. In vehicle-treated mice, there was no [(3)H]DMBA-binding at these sites. Furthermore, a high level of irreversibly bound [(3)H]DMBA occurred in EC at these sites in precision-cut mouse/rat brain slices and in excised blood-brain interfaces incubated with [(3)H]DMBA. Since [(3)H]DMBA binding sites corresponded with the sites of CYP1A1 induction, we conclude that rodents express a constitutively low but highly inducible and functional CYP1A1 in EC of some of the blood-brain interfaces. The role of CYP1A1/1B1 and environmental pollutants in the etiology of cerebrovascular disease needs further consideration.
Place, publisher, year, edition, pages
2003. Vol. 31, no 3, 259-265 p.
9;10-Dimethyl-1;2-benzanthracene/analysis/*pharmacokinetics, Animals, Aryl Hydrocarbon Hydroxylases/analysis/*metabolism, Biotransformation, Blood-Brain Barrier/*physiology, Brain/metabolism, Cytochrome P-450 CYP1A1/analysis/*metabolism, Endothelium; Vascular/*cytology/*enzymology/metabolism, Female, In Vitro, Mice, Rats, Rats; Sprague-Dawley
Pharmacology and Toxicology
Research subject Toxicology
IdentifiersURN: urn:nbn:se:uu:diva-67100DOI: 10.1124/dmd.31.3.259PubMedID: 12584151OAI: oai:DiVA.org:uu-67100DiVA: diva2:95011