Aryl hydrocarbon receptor-dependent upregulation of Cyp1b1 by TCDD and diesel exhaust particles in rat brain microvessels

<p>Abstract</p> <p>Background</p> <p>AhR activates the transcription of several target genes including CYP1B1. Recently, we showed <it>CYP1B1 </it>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.</p> <p>Methods</p> <p>Expression 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 <it>ex vivo </it>and/or <it>in vivo </it>exposure to TCDD, heavy hydrocarbons containing diesel exhaust particles (DEP) or Δ⁹-tetrahydrocannabinol (Δ⁹-THC).</p> <p>Results</p> <p>After <it>ex vivo </it>exposure to TCDD (a highly potent AhR ligand) for 3 h, <it>Cyp1b1 </it>expression was significantly increased by 2.3-fold in brain microvessels. A single i.p. dose of TCDD also increased <it>Cyp1b1 </it>transcripts (22-fold) and Cyp1b1 protein (2-fold) in rat brain microvessels at 72 h after TCDD. Likewise, DEP treatment (<it>in vivo </it>and <it>ex vivo</it>) 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 <it>in vivo </it>treatment with Δ⁹-THC once daily for 7 seven days had no effect on <it>Cyp1b1 </it>expression</p> <p>Conclusions</p> <p>Our results show that TCDD and DEP strongly induced Cyp1b1 in rat brain microvessels, likely through AhR activation.</p

CNS Delivery Via Adsorptive Transcytosis

Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The transcytotic pathways present at the BBB and its morphological and enzymatic properties provide the means for movement of the molecules through the endothelial cytoplasm. AMT-based drug delivery to the brain was performed using cationic proteins and cell-penetrating peptides (CPPs). Protein cationization using either synthetic or natural polyamines is discussed and some examples of diamine/polyamine modified proteins that cross BBB are described. Two main families of CPPs belonging to the Tat-derived peptides and Syn-B vectors have been extensively used in CPP vector-mediated strategies allowing delivery of a large variety of small molecules as well as proteins across cell membranes in vitro and the BBB in vivo. CPP strategy suffers from several limitations such as toxicity and immunogenicity—like the cationization strategy—as well as the instability of peptide vectors in biological media. The review concludes by stressing the need to improve the understanding of AMT mechanisms at BBB and the effectiveness of cationized proteins and CPP-vectorized proteins as neurotherapeutics

LE TETRAPEPTIDE ACETYL-SERYL-ASPARTYL-LYSYL-PROLINE, UN MARQUEUR DE L'INHIBITION DE L'ENZYME DE CONVERSION DE L'ANGIOTENSINE I (ASPECTS PHARMACOCINETIQUES ET PHARMACOLOGIQUES)

PARIS-BIUSJ-Physique recherche (751052113) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Hydroxychloroquine and Azithromycin to Treat Patients With COVID‐19: Both Friends and Foes?

International audienc

L'alosétron, traitement dans le syndrome de l'intestin irritable (étude de sa pharmacocinétique chez les sujets insuffisants rénaux)

PARIS-BIUP (751062107) / SudocSudocFranceF

Régulation de l'expression du cytochrome P450 1B1 par le récepteur aryl hydrocarbon au niveau de la barrière hémato-encéphalique

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Expression, localisation et régulation des transporteurs ABC et des cytochromes P450 au niveau de la barrière hémato-encéphalique humaine

Le passage cérébral d un composé peut être freiné par les transporteurs ABC et les enzymes exprimés au niveau des cellules endothéliales des capillaires cérébraux. L expression relative des transporteurs ABC au niveau de la barrière hémato-encéphalique(BHE) humaine est inconnue tout comme celle des cytochromes P450(CYP). Nous avons établi un profil d expression des gènes codant pour des transporteurs ABC, des CYPs et certains facteurs de transcription au niveau de microvaisseaux cérébraux humains issus de neurochirurgie. Les gènes codant pour la BCRP, le CYP1B1 et AhR sont majoritairement exprimés. Nous avons aussi participé à la caractérisation de la lignée hCMEC/D3. Nous avons mis en évidence l existence d une voie de régulation faisant intervenir AhR et impliquée dans la régulation de l expression des gènes CYP1A1 et CYP1B1. Enfin nous avons établit une cartographie de l expression des gènes codant pour les transporteurs ABC dans différentes régions cérébrales humaines.The brain uptake of a drug can be reduced by ABC transporters and enzymes expressed in endothelial cells of brain microvessels. Relative expression of ABC transporters and cytochromes P450 (CYP) has never been investigated at the adult human BBB. We have established the expression patterns of the gene encoding some ABC transporters, CYPs and transcription factors using isolated human brain microvessels from neurosurgery. The genes encoding BCRP, CYP1B1 and the transcription factor AhR are mainly expressed. We investigated the expression of the same genes in the hCMEC/D3 cell line, an in vitro model of the human BBB. We shown that the AhR-mediated regulatory pathway is involved in the induction of CYP1A1 and CYP1B1 genes expression in this cell line. Finally, in a third study, we investigated the transcript expression profile of several ABC transporters in different areas of the adult normal brainPARIS-BIUP (751062107) / SudocSudocFranceF

Bioéquivalence d'une forme orale (revue des requis réglementaires européens et Nord-Américains)

PARIS-BIUP (751062107) / SudocSudocFranceF

Pharmacologie et toxicologie de la 3,4-méthylènedioxymétamphétamine (MDMA, ecstasy)

PARIS-BIUP (751062107) / SudocSudocFranceF

L'iode stable et la prévention des expositions à l'iode radioactif

PARIS-BIUP (751062107) / SudocSudocFranceF