Abstract
BackgroundAhR activates the transcription of several target genes including CYP1B1. Recently, we showed CYP1B1 as the major cytochrome P450 (CYP) enzyme expressed in human brain microvessels. Here, we studied the effect of AhR activation by environmental pollutants on the expression of Cyp1b1 in rat brain microvessels.MethodsExpression of AhR and Cyp1b1 was detected in isolated rat brain microvessels. AhR was immunovisualised in brain microvessel endothelial cells. The effect of AhR ligands on Cyp1b1 expression was studied using isolated brain microvessels after ex vivo and/or in vivo exposure to TCDD, heavy hydrocarbons containing diesel exhaust particles (DEP) or Δ9-tetrahydrocannabinol (Δ9-THC).ResultsAfter ex vivo exposure to TCDD (a highly potent AhR ligand) for 3 h, Cyp1b1 expression was significantly increased by 2.3-fold in brain microvessels. A single i.p. dose of TCDD also increased Cyp1b1 transcripts (22-fold) and Cyp1b1 protein (2-fold) in rat brain microvessels at 72 h after TCDD. Likewise, DEP treatment (in vivo and ex vivo) strongly induced Cyp1b1 protein in brain microvessels. DEP-mediated Cyp1b1 induction was inhibited by actinomycin D, cycloheximide, or by an AhR antagonist. In contrast, a sub-chronic in vivo treatment with Δ9-THC once daily for 7 seven days had no effect on Cyp1b1 expressionConclusionsOur results show that TCDD and DEP strongly induced Cyp1b1 in rat brain microvessels, likely through AhR activation.
Highlights
aryl hydrocarbon receptor (AhR) activates the transcription of several target genes including CYP1B1
Upon ligand binding in the cytosol, AhR translocates into the nucleus where it heterodimerizes with its partner aryl hydrocarbon nuclear translocator (ARNT)
AhR protein was detected after immunoprecipitation and western blotting in brain microvessels, which showed a strong signal for AhR (Figure 1B)
Summary
AhR activates the transcription of several target genes including CYP1B1. We showed CYP1B1 as the major cytochrome P450 (CYP) enzyme expressed in human brain microvessels. We studied the effect of AhR activation by environmental pollutants on the expression of Cyp1b1 in rat brain microvessels. Expression of genes encoding CYP enzymes is regulated in several peripheral tissues by transcription factors such as the pregnane-X-receptor (PXR), the constitutive androstane receptor (CAR), and the aryl hydrocarbon receptor (AhR) [2]. TCDD, the most potent AhR activator, highly induced the expression of CYP1B1 and CYP1A1 in hCMEC/D3 cells [11]. Cyp1b1 selectively bioactivates various PAHs (benzo[a]pyrene, DMBA, anthracenes) into intermediates that are DNA-reactive [16] All these studies suggest that AhR control the expression of CYP1B1 at the BBB
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