Nejvíce citovaný článek - PubMed ID 18548509
Amiodarone modulates pharmacokinetics of low-dose methotrexate in rats
AIM: To investigate the effect of resveratrol on biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats. METHODS: Resveratrol (RSV) or saline were administered to rats by daily oral gavage for 28 d after sham operation or reversible bile duct obstruction (BDO). Bile was collected 24 h after the last gavage during an intravenous bolus dose of the Mdr1/Mrp2 substrate azithromycin. Bile acids, glutathione and azithromycin were measured in bile to quantify their level of biliary secretion. Liver expression of enzymes and transporters relevant for bile production and biliary secretion of major bile constituents and drugs were analyzed at the mRNA and protein levels using qRT-PCR and Western blot analysis, respectively. The TR-FRET PXR Competitive Binding Assay kit was used to determine the agonism of RSV at the pregnane X receptor. RESULTS: RSV increased bile flow in sham-operated rats due to increased biliary secretion of bile acids (BA) and glutathione. This effect was accompanied by the induction of the hepatic rate-limiting transporters for bile acids and glutathione, Bsep and Mrp2, respectively. RSV also induced Cyp7a1, an enzyme that is crucial for bile acid synthesis; Mrp4, a transporter important for BA secretion from hepatocytes to blood; and Mdr1, the major apical transporter for xenobiotics. The findings were supported by increased biliary secretion of azithromycin. The TR-FRET PXR competitive binding assay confirmed RSV as a weak agonist of the human nuclear receptor PXR, which is a transcriptional regulator of Mdr1/Mrp2. RSV demonstrated significant hepatoprotective properties against BDO-induced cirrhosis. RSV also reduced bile flow in BDO rats without any corresponding change in the levels of the transporters and enzymes involved in RSV-mediated hepatoprotection. CONCLUSION: Resveratrol administration for 28 d has a distinct effect on bile flow and biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats.
- Klíčová slova
- Azithromycin, Bile acids, Bile production, Pregnane X receptor, Resveratrol,
- MeSH
- ABC transportéry metabolismus MeSH
- antiflogistika nesteroidní farmakologie terapeutické užití MeSH
- antioxidancia farmakologie terapeutické užití MeSH
- aplikace orální MeSH
- azithromycin farmakokinetika MeSH
- cholestáza farmakoterapie etiologie patofyziologie MeSH
- glutathion metabolismus MeSH
- hepatocyty účinky léků metabolismus MeSH
- játra účinky léků metabolismus patofyziologie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar MeSH
- pregnanový X receptor MeSH
- resveratrol MeSH
- steroidní receptory agonisté MeSH
- stilbeny farmakologie terapeutické užití MeSH
- žlučové kyseliny a soli chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ABC transportéry MeSH
- antiflogistika nesteroidní MeSH
- antioxidancia MeSH
- azithromycin MeSH
- glutathion MeSH
- pregnanový X receptor MeSH
- resveratrol MeSH
- steroidní receptory MeSH
- stilbeny MeSH
- žlučové kyseliny a soli MeSH
Methotrexate (MTX) released from bone cement showed a useful local effect in animal models of bone tumours. However, local toxic reactions such as impaired wound healing were observed in areas surrounding the MTX-loaded implant. Therefore, we hypothesised that MTX released from bone cement would have harmful effects on human mesenchymal stem cells (MSC)-one of the basic components of bone marrow and tissue reparatory processes. Moreover, elution of MTX was calculated from implants prepared either with liquid or powdered MTX. During the 28-day incubation, the cement compounded with liquid MTX showed the highest elution rate of the drug. MTX released from pellets produced a significant decrease in proliferation of MSC as a consequence of a blockade of their cell cycle in the S/G2 phase. These findings indicate impairment of stem cell function in marginal areas surrounding the MTX-loaded cement and may help to explain problems with regeneration of tissues in these locations.
Le Methotrexate (MTX) libéré par le ciment acrylique a un effet certain sur les tumeurs osseuses développées sur un modèle animal. Cependant, des réactions toxiques locales telles que défauts de cicatrisation ont été observées à proximité de l’implantation de ce ciment. Nous faisons donc l’hypothèse que le Methotrexate MTX libéré par le ciment a un effet nocif néfaste sur les cellules mésenchyméteuses humaines MSC qui sont l’un des composants de base de la moelle osseuse et des phénomènes de la réparation tissulaire. De plus, la dynamique de pénétration du méthotrexate a été analysée à partir d’implants préparés avec du liquide ou de la poudre de méthotrexate. Au cours des 28 jours d’incubation, le ciment préparé avec du méthotrexate liquide montre un taux important de pénétration de la drogue. Le méthotrexate libéré des billes de ciment entraîne une diminution significative de la prolifération des cellules mésenchyméteuses avec un bloquage cellulaire à la phase S/G2. Ces travaux montrent que la fonction cellulaire est altérée au voisInage du méthotrexate pouvant expliquer les problèmes de régénétration tissulaire.
- MeSH
- antimetabolity antitumorózní aplikace a dávkování chemie MeSH
- buňky kostní dřeně účinky léků patologie MeSH
- interfáze účinky léků MeSH
- kostní cementy chemie MeSH
- kultivované buňky MeSH
- lidé MeSH
- methotrexát aplikace a dávkování chemie MeSH
- mezenchymální kmenové buňky účinky léků patologie MeSH
- proliferace buněk účinky léků MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antimetabolity antitumorózní MeSH
- kostní cementy MeSH
- methotrexát MeSH