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Research ArticleArticle

CYP1A1 and CYP1B1 in Blood-Brain Interfaces: CYP1A1-Dependent Bioactivation of 7,12-Dimethylbenz(a)anthracene in Endothelial Cells

Lizette Granberg, Anna Östergren, Ingvar Brandt and Eva B. Brittebo
Drug Metabolism and Disposition March 2003, 31 (3) 259-265; DOI: https://doi.org/10.1124/dmd.31.3.259
Lizette Granberg
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Anna Östergren
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Ingvar Brandt
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Eva B. Brittebo
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Abstract

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 β-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 [3H]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 [3H]DMBA-binding at these sites. Furthermore, a high level of irreversibly bound [3H]DMBA occurred in EC at these sites in precision-cut mouse/rat brain slices and in excised blood-brain interfaces incubated with [3H]DMBA. Since [3H]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.

Footnotes

  • ↵1 Present address: Distribution Imaging, Safety Assessment, AstraZeneca R&D Södertälje, S-151 85 Södertalje, Sweden.

  • This study was supported financially by the Swedish Environmental Protection Agency, the Swedish Research Council and FORMAS and presented in part at the 37th European Congress of Toxicology (Eurotox'99), Oslo, Norway, June 27–30, 1999.

  • Abbreviations used are::
    P450
    cytochrome P450 enzymes
    AhR
    aryl hydrocarbon receptor
    EROD
    7-ethoxyresorufinO-deethylase
    BNF
    β-naphthoflavone
    PAHs
    polycyclic aromatic hydrocarbons
    DMBA
    7,12-dimethylbenz(a)anthracene
    B(a)P
    benzo(a)pyrene
    PCB 126
    3,3′,4,4′,5-pentachlorobiphenyl
    EC
    endothelial cells
    SMC
    smooth muscle cells
    DMSO
    dimethyl sulfoxide
    FDMEM
    fully supplemented Dulbeccos Modified Eagle's Medium
    BSA
    bovine serum albumin
    PBS
    phosphate-buffered saline
    PBS-T
    PBS with 0.3% Triton X-100
    Trp-P-1
    3-amino-1,4-dimethyl-5H-pyrido-[4,3-b]indole
    CSF
    blood-cerebrospinal fluid
    P-gp
    P-glycoprotein
    HUVEC
    human umbilical vein EC
    • Received March 25, 2002.
    • Accepted November 22, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (3)
Drug Metabolism and Disposition
Vol. 31, Issue 3
1 Mar 2003
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Research ArticleArticle

CYP1A1 and CYP1B1 in Blood-Brain Interfaces: CYP1A1-Dependent Bioactivation of 7,12-Dimethylbenz(a)anthracene in Endothelial Cells

Lizette Granberg, Anna Östergren, Ingvar Brandt and Eva B. Brittebo
Drug Metabolism and Disposition March 1, 2003, 31 (3) 259-265; DOI: https://doi.org/10.1124/dmd.31.3.259

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Research ArticleArticle

CYP1A1 and CYP1B1 in Blood-Brain Interfaces: CYP1A1-Dependent Bioactivation of 7,12-Dimethylbenz(a)anthracene in Endothelial Cells

Lizette Granberg, Anna Östergren, Ingvar Brandt and Eva B. Brittebo
Drug Metabolism and Disposition March 1, 2003, 31 (3) 259-265; DOI: https://doi.org/10.1124/dmd.31.3.259
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