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CYP1A1 and CYP1B1 in blood-brain interfaces:: CYP1A1-dependent bioactivation of 7,12-dimethylbenz[a]anthracene in endothelial cells
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
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
Abstract [en]

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.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-93507DOI: 10.1124/dmd.31.3.259ISI: 000180959300003PubMedID: 12584151OAI: oai:DiVA.org:uu-93507DiVA: diva2:167001
Available from: 2005-09-23 Created: 2005-09-23 Last updated: 2011-03-09Bibliographically approved
In thesis
1. Selective Retention of β-Carbolines and 7,12-Dimethylbenz[a]anthracene in the Brain: Role of Neuromelanin and Cytochrome P450 for Toxicity
Open this publication in new window or tab >>Selective Retention of β-Carbolines and 7,12-Dimethylbenz[a]anthracene in the Brain: Role of Neuromelanin and Cytochrome P450 for Toxicity
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The ß-carbolines norharman and harman structurally resemble the synthetic compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that is known for its ability to damage neuromelanin-containing dopaminergic neurons of the substantia nigra and thereby induce parkinsonism. MPTP is, however, not normally present in the environment whereas the ß-carbolines are present in cooked food and tobacco smoke.

In this thesis it was demonstrated that norharman and harman had affinity to melanin and were retained in neuromelanin-containing neurons of frogs up to 30 days post-injection (the longest survival time examined). It was also demonstrated that norharman induced neurodegeneration, activation of glia cells and motor impairment in mice. Furthermore, this compound induced ER stress and cell death in PC12 cells. An in vitro model of dopamine melanin-loaded PC12 cells was developed in order to study the effect of melanin on norharman-induced toxicity. In this model, melanin seemed to attenuate toxicity induced by low concentrations of norharman. After exposure to the highest concentration of norharman, melanin clusters were disaggregated and there was an increased expression of stress proteins and caspases-3, known to be involved in apoptosis.

The polycyclic aromatic hydrocarbon, 7,12-dimethylbenz[a]anthracene was demonstrated to have a CYP1A1-dependent localization in endothelial cells in the choroid plexus, in the veins in the leptomeninges and in the cerebral veins of mice pre-treated with CYP1-inducers.

These results demonstrate that the distribution of environmental compounds could be influenced by the presence of neuromelanin and expression of CYP enzymes in the brain and that norharman may induce neurotoxic effects in vivo and in vitro.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 17
Toxicology, β-carboline, neuromelanin, norharman, harman, parkinsonism, Parkinson's disease, motoric impairment, behaviour, glia cells, substantia nigra, dopamine melanin, PC12 cells, ER stress, grp78, hsp90, cytochrome P450, CYP1A1, CYP1B1, blood-brain interfaces, 7,12-dimethylbenz[a]anthracene, polycyclic aromatic hydrocarbon, endothelial cell, smooth muscle cell, bioactivation, Toxikologi
National Category
Pharmacology and Toxicology
Research subject
urn:nbn:se:uu:diva-5941 (URN)91-554-6347-9 (ISBN)
Public defence
2005-10-14, C4:301, BMC, Husargatan 3, Uppsala, 09:30
Available from: 2005-09-23 Created: 2005-09-23Bibliographically approved

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