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ARTICLE INFO Keywords: Schisandrin B Fructus schisandrae CYP3A4 Inhibit Microsome Pharmacokinetic ABSTRACT To investigate the possible drug interaction, this study is designed to evaluate the ability or Schisandrin B (Sch [...]

BACKGROUND: Previous studies have indicated that cytochrome P450s (CYPs) are involved in the metabolism of polybrominated diphenyl ether (PBDE) flame retardants in humans, resulting in the formation of hydroxylated PBDEs [...]

Introduction The aryl hydrocarbon receptor (AHR) mediates both adaptive and toxic effects of halogenated aromatic hydrocarbons (HAHs) such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAHs) such [...], The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands, and mediates adaptive and toxic responses to the environmental pollutant 2, 3, 7, 8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts the expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially nonmetabolized AHR agonist, and [Ahr.sup.-/-] mice as the preferred model to determine the AHR-dependence of biological responses, we now show that 2 mouse hepatic STAT5b target genes, Cyp2d9, and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHR-dependent manner. TCDD also decreased hepatic mRNA levels for GH receptor, Janus kinase 2, and STAT5a/b with AHR-dependence. Without inducing selected hepatic inflammatory markers, TCDD caused AHR-dependent induction of Cyplal and NADPH-cytochrome P450 oxidoreductase (Por) and suppression of Cyp3a11. In vehicle-treated mice, basal mRNA levels for CYP2D9, CYP3A11, POR, serum amyloid protein P, and MUP2 were influenced by Ahr genetic status. We conclude that AHR activation per se leads to dysregulation of hepatic GH signaling components and suppression of some, but not all, STAT5b target genes. Key words: aryl hydrocarbon receptor, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin, cytochrome P450, growth hormone receptor, Janus kinase 2, signal transducer and activator of transcription 5b, cytokine-inducible Src homology 2 domain-containing protein, major urinary protein 2, inflammatory markers, NADPH-cytochrome P450 oxidoreductase. Le recepteur des hydrocarbures d'aryles (AHR) joue un role physiologique en absence d'exposition aux ligands exogenes et sert d'intermediate aux reponses adaptatives et toxiques a un agent polluant environnemental, la 2, 3, 7, 8-tetrachlorodibenzo-p-dioxine (TCDD). Un agoniste du AHR facilement metabolise, le 3-methylcholanthrene, perturbe l'expression des composantes hepatiques de la signalisation de l'hormone de croissance (GH) chez la souris et supprime le cytochrome P450 2D9 (Cyp2d9), un gene specifique au male controle par la GH pulsatile au moyen du facteur de transcription STAT5b (signal transducer and activator of transcription 5b). En utilisant la TCDD comme agoniste essentiellement non metabolisable du AHR et des souris [Ahr.sup.-/-] comme modele privilegie pour determiner la dependance des reponses biologiques au AHR, nous montrons maintenant que deux genes hepatiques de souris cibles par STAT5b, Cyp2d9 et Mup2 (major urinary protein 2) sont supprimes par le TCDD de facon dependante du AHR. La TCDD diminuait aussi les niveaux hepatiques de l'ARNm du recepteur de la GH, de la Janus kinase 2 et de STAT5a/b de facon dependante du AHR. Sans induire des marqueurs hepatiques inflammatoires selectionnes, la TCDD induisait de facon dependante au AHR le Cyp1a1 et la NADPH-cytochrome P450 oxydoreductase (Por) et supprimait Cyp3a11. Chez les souris traitees au vehicule seul, les niveaux de base de CYP2D9, CYP3A11, POR, la proteine amyloi'de serique P et MUP2 etaient influences par le statut genetique en Ahr. Nous concluons que l' activation du AHR en soi conduit a un dereglement des composantes hepatiques signaletiques de la GH et a la suppression de certains genes cibles de STAT5b, mais pas tous. Mots-cles: recepteur d'hydrocarbures d'aryles, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxine, cytochrome P450, recepteur de l'hormone de croissance, Janus kinase 2, STAT5b (signal transducer and activator of transcription 5b), CIS (cytokine-inducible Src homology domain 2 containing protein), MUP2 (major urinary protein 2), marqueurs inflammatoires, NAPDH-cytochrome P450 oxydoreductase. [Traduit par la Redaction]

Oxysterols are oxygenated derivatives of cholesterol synthesized through enzymatic (12) or non-enzymatic (13) processes. Oxysterols exert profound biological effects in cholesterol and fatty-acid metabolism, immune regulation, and possibly neurodegenerative diseases [...], EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein-Barr-virus infection (1). Recent studies indicated that this receptor controls follicular B-cell migration and T-cell-dependent antibody production (2-6). Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism (7-9). The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors (10,11). Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7α,25-dihydroxycholesterol (OHC), with a dissociation constant of 450 pM for EBI2. In vitro, 7α,25-OHC stimulated the migration of EBI2-expressing mouse B and T cells with half-maximum effective concentration values around 500 pM, but had no effect on EBI2-deficient cells. In vivo, EBI2-deficient B cells or normal B cells desensitized by 7α,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7α,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7α,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T-zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice. Our results show an unexpected causal link between EBI2, an orphan G-protein-coupled receptor controlling B-cell migration, and the known immunological effects of certain oxysterols, thus uncovering a previously unknown role for this class of molecules.