• MeSH
• farmakologie klinická MeSH
• toxikologie MeSH
• Publikační typ
• biografie MeSH

• O autorovi
• Višňovský, Peter, 1941-2009 Autorita

• MeSH
• farmakokinetika MeSH
• farmakologické účinky MeSH
• farmakologie klinická MeSH
• farmakologie MeSH
• psychofarmakologie MeSH

• Konspekt
• Farmacie. Farmakologie
• Učební osnovy. Vyučovací předměty. Učebnice
• NLK Obory
• farmacie a farmakologie
• farmacie a farmakologie
• NLK Publikační typ
• učebnice vysokých škol

The placental trophoblast at different stages of pregnancy contains some drug transporters and xenobiotic-metabolising enzymes, as well as ligand-activated nuclear receptors, which control their inducible transcriptional regulation. Glucocorticoid receptor alpha (GRalpha) is expressed in both placental syncytiotrophoblast and cytotrophoblast. GRalpha was shown to control inducible expression of several enzymes of the cytochrome P-450 family (CYP) and the drug transporter P-glycoprotein in the liver. However, GRalpha-mediated transcriptional regulation of drug transporters and CYPs has not been studied in the placental trophoblast. In this study, we examined the expression and activity of GRalpha in the transcriptional regulation of P-glycoprotein, CYP3A4, and CYP2C9 in placental trophoblast cell lines. Employing RT-PCR, Western blotting, and luciferase gene reporter assay, we detected the expression and activity of GRalpha in JEG3 and BeWo cell lines. However, we observed that only MDR1 mRNA was up-regulated after treatment of placental cells with dexamethasone. Accordingly, only the promoter of the MDR1 gene was activated by dexamethasone in gene reporter assays in placental cells and the activation was abolished by RU486, an antagonist of GRalpha. CYP3A4 and CYP2C9 promoters were activated in placental cells only after co-transfection with hepatocyte nuclear factor 4alpha (HNF4alpha), which indicates the hepatocyte-specific character of GRalpha-mediated regulation of the genes. On the other hand, coexpression of HNF4alpha had no effect on the activation of the MDR1 gene promoter, suggesting HNF4alpha-independent regulation via GRalpha. We conclude that GRalpha may be involved in the transcriptional regulation of P-glycoprotein in the placental trophoblast. We also indicate that the CYP3A4 and CYP2C9 genes are not inducible through GRalpha in placental cell lines, due to the lack of HNF4alpha expression and possibly some additional hepatocyte-specific transcriptional factors.

• MeSH
• aktivace transkripce fyziologie   MeSH
• aromatické hydroxylasy biosyntéza   MeSH
• buněčné linie MeSH
• cytochrom P-450 CYP3A MeSH
• dexamethason farmakologie   MeSH
• financování organizované MeSH
• hepatocytární jaderný faktor 4 fyziologie   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• nádorové buněčné linie MeSH
• P-glykoprotein biosyntéza   MeSH
• promotorové oblasti (genetika) fyziologie   MeSH
• receptory glukokortikoidů fyziologie   MeSH
• systém (enzymů) cytochromů P-450 biosyntéza   MeSH
• těhotenství MeSH
• trofoblasty metabolismus   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• srovnávací studie MeSH

• Klíčová slova
• farmakodynamika,
• MeSH
• farmakologie metody   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Breast cancer resistance protein (BCRP/ABCG2) is a member of the ATP-binding cassette transporter family that recognizes a variety of chemically unrelated compounds. Its expression has been revealed in many mammal tissues, including placenta. The purpose of this study was to describe its role in transplacental pharmacokinetics using rat placental HRP-1 cell line and dually perfused rat placenta. In HRP-1 cells, expression of Bcrp, but not P-glycoprotein, was revealed at mRNA and protein levels. Cell accumulation studies confirmed Bcrp-dependent uptake of BODIPY FL prazosin. In the placental perfusion studies, a pharmacokinetic model was applied to distinguish between passive and Bcrp-mediated transplacental passage of cimetidine as a model substrate. Bcrp was shown to act in a concentration-dependent manner and to hinder maternal-to-fetal transport of the drug. Fetal-to-maternal clearance of cimetidine was found to be 25 times higher than that in the opposite direction; this asymmetry was partly eliminated by BCRP inhibitors fumitremorgin C (2 microM) or N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918; 2 microM) and abolished at high cimetidine concentrations (1000 microM). When fetal perfusate was recirculated, Bcrp was found to actively remove cimetidine from the fetal compartment to the maternal compartment even against a concentration gradient and to establish a 2-fold maternal-to-fetal concentration ratio. Based on our results, we propose a two-level defensive role of Bcrp in the rat placenta in which the transporter 1) reduces passage of its substrates from mother to fetus but also 2) removes the drug already present in the fetal circulation.

• MeSH
• ABC transportéry analýza   fyziologie   genetika   MeSH
• buněčné linie MeSH
• cimetidin farmakokinetika   MeSH
• financování organizované MeSH
• imunohistochemie MeSH
• krysa rodu rattus MeSH
• messenger RNA analýza   MeSH
• metabolická clearance MeSH
• P-glykoprotein fyziologie   MeSH
• perfuze MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH

PURPOSE: Recent studies have indicated constitutive expression of efflux transporter, breast cancer resistance protein (BCRP, ABCG2), in endothelial cells of the blood-brain barrier (BBB). In epileptogenic brain tumors such as ganglioma, astrocytoma, anaplastic astrocytomas, or glioma multiforme, strong expression of BCRP in the microvasculature of the BBB was observed. Therefore it was hypothesized that this phenomenon could critically influence the bioavailability of drugs in these tumors and potentially contribute to the failure of antiepileptic treatment. The aim of this study was to test whether some commonly used antiepileptic drugs (AEDs) are substrates transported by human BCRP. In particular, we focused on phenobarbital, phenytoin, ethosuximide, primidone, valproate, carbamazepine, clonazepam, and lamotrigine. Furthermore, the inhibitory potency of these AEDs to BCRP was examined. METHODS: To study substrate affinity of tested AEDs to BCRP, transport experiments were performed in epithelial BCRP-expressing MDCKII-BCRP and MDCKII-parent cell lines cultured on microporous membrane. For detection of inhibitory potency of AEDs to BCRP, accumulation assays were carried out in MEF3.8-BCRP cells with known BCRP substrates, BODIPY FL prazosin and mitoxantrone. RESULTS: No obvious interactions of tested AEDs with BCRP transporter were observed. Therefore these drugs in relevant therapeutic concentrations are neither substrates nor inhibitors of BCRP. CONCLUSIONS: Based on our in vitro data we can conclude that resistance to treatment with the tested AEDs probably is not caused by the overexpression of BCRP in the BBB of epileptogenic brain tumors.

• MeSH
• antikonvulziva farmakokinetika   farmakologie   terapeutické užití   MeSH
• biologická dostupnost MeSH
• endoteliální buňky metabolismus   účinky léků   MeSH
• epilepsie farmakoterapie   metabolismus   MeSH
• financování organizované MeSH
• hematoencefalická bariéra metabolismus   účinky léků   MeSH
• kapilární permeabilita účinky léků   MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• myši knockoutované MeSH
• myši MeSH
• nádorové proteiny antagonisté a inhibitory   farmakokinetika   metabolismus   MeSH
• techniky in vitro MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH

Although rat is the most widely used model of glucocorticoid programming of the fetus, the role of rat placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the transplacental pharmacokinetics of the naturally occurring glucocorticoid, corticosterone, has not yet been fully elucidated. In this study, expression of 11beta-HSD2 in the rat placenta on two different gestation days (16 and 22) was examined using quantitative RT-PCR and Western blotting, and dually perfused rat term placenta was employed to evaluate its functional capacity to transfer and metabolize corticosterone. Marked decrease in placental expression of 11beta-HSD2 toward term was observed on both mRNA and protein levels. In perfusion studies, increasing maternal corticosterone concentration from 3 to 200 nM resulted in the fall of 11beta-HSD2 conversion capacity from 64.3 to 16.3%, respectively. Enzyme saturation occurred at about 50 nM substrate concentration. When delivering corticosterone (3 or 100 nM) from the fetal side, a similar decline of 11beta-HSD2 conversion capacity was observed (66.5% and 48.5%, respectively). Addition of carbenoxolone (10 or 100 microM), a non-specific 11beta-HSD inhibitor, to maternal perfusate decreased conversion capacity from 66.7 to 12.6 or 8.1%, respectively. Similarly potent inhibitory effect was observed in feto-maternal studies. Neither saturation nor inhibition of 11beta-HSD2 was associated with transformation of corticosterone in metabolites other than 11-dehydrocorticosterone. These data suggest that 11beta-HSD2 is the principal enzyme controlling transplacental passage of corticosterone in rats and is able to eliminate corticosterone in both maternal and fetal circulations.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• biologický transport MeSH
• financování organizované MeSH
• karbenoxolon farmakologie   MeSH
• kortikosteron metabolismus   MeSH
• krysa rodu rattus MeSH
• perfuze MeSH
• placenta enzymologie   fyziologie   metabolismus   MeSH
• techniky in vitro MeSH
• těhotenství metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• těhotenství metabolismus   MeSH
• ženské pohlaví MeSH
• zvířata MeSH

• Publikační typ
• abstrakt z konference MeSH

• Publikační typ
• abstrakt z konference MeSH

Nukleární receptory PXR a CAR regulují na základě interakce s xenobiotiky expresi enzymů I. a II. fáze biotransformace a některých detoxifikačních lékových transportérů. Ve většině případů se jedná o indukci exprese (up-regulaci) cílových genů, které se přímo podílejí na biotransformaci nebo exkreci xenobiotik. Tímto mechanismem mohou nukleární receptory výrazně modifikovat expozici organismu xenobiotiku, proto jsou často označovány jako xenosenzory. Je-li xenobiotikem léčivo – může být aktivace receptorů PXR nebo CAR příčinou farmakokinetických lékových interakcí, při kterých léčivo zvyšuje aktivitu biotransformačních enzymů nebo transportérů podílejících se na eliminaci jiného spolupodaného léčiva, a mění tak jeho farmakokinetické a případně i farmakodynamické vlastnosti. Je-li xenobiotikem toxická látka, pak nukleárními receptory zprostředkované urychlení eliminace představuje jeden ze základních homeostatických obranných mechanismů. Cílem tohoto přehledového článku je přiblížit nukleární receptory PXR a CAR jako důležité faktory farmakokinetických lékových interakcí.

Based on interaction with xenobiotics, PXR and CAR nuclear receptors regulate expression of phase I and II biotransformation enzymes and some detoxication drug transporters. In most cases, expression (up-regulation) of target genes directly involved in biotransformation or excretion of xenobiotics is induced. By this mechanism, nuclear receptors markedly modify exposure of the organism to the xenobiotic, and that is why they are often called xenosensors. If the xenobiotic is a drug, then activation of PXR and CAR receptors can cause pharmacokinetic drug interactions with the drug enhancing activity of biotransformation enzymes or transporters involved in elimination of another co-administered drug which may lead in turn to changes in pharmacokinetic and possibly also pharmacodynamic properties of the latter. If the xenobiotic is a toxic substance, then the nuclear receptor mediated enhancement of elimination is one of the major homeostatic protective mechanisms. The objective of this review article is to present the PXR and CAR nuclear receptors as important factors in pharmacokinetic drug interactions.

• MeSH
• androstany farmakologie   MeSH
• biotransformace MeSH
• lékové interakce fyziologie   MeSH
• lidé MeSH
• metabolická inaktivace fyziologie   MeSH
• pregnany farmakologie   MeSH
• receptory léků MeSH
• regulace genové exprese MeSH
• transportní proteiny farmakologie   MeSH
• xenobiotika farmakologie   MeSH
• Check Tag
• lidé MeSH