Pleiotropic effects of gold(I) mixed-ligand complexes of 9- deazahypoxanthine on transcriptional activity of receptors for steroid hormones, nuclear receptors and xenoreceptors in human hepatocytes and cell lines
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F16%3A33159495" target="_blank" >RIV/61989592:15310/16:33159495 - isvavai.cz</a>
Výsledek na webu
<a href="http://www.sciencedirect.com/science/article/pii/S022352341630472X" target="_blank" >http://www.sciencedirect.com/science/article/pii/S022352341630472X</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2016.05.064" target="_blank" >10.1016/j.ejmech.2016.05.064</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Pleiotropic effects of gold(I) mixed-ligand complexes of 9- deazahypoxanthine on transcriptional activity of receptors for steroid hormones, nuclear receptors and xenoreceptors in human hepatocytes and cell lines
Popis výsledku v původním jazyce
Development of metal-based compounds is an important research avenue in anti-cancer and anti-inflammatory drug discovery. Here we examined the effects of three gold (I) mixed-ligand complexes with the general formula [Au(L-n)(PPh3)] (1, 2, 3) involving triphenylphosphine (PPh3) and a deprotonated form of O-substituted derivatives of 9-deazahypoxanthine (L-n) on the transcriptional activity of aryl hydrocarbon receptor (AhR), androgen receptor (AR), glucocorticoid receptor (GR), thyroid receptor (TR), pregnane X receptor (PXR) and vitamin D receptor (VDR), employing gene reporter assays. In addition, we measured mRNA (RT-PCR) and protein (western blot) expression of target genes for those receptors, including drug-metabolizing P450s, in primary human hepatocytes and cancer cell lines LS180 and HepG2. The tested compounds displayed anti-glucocorticoid effects, as revealed by inhibition of dexamethasone-inducible transcriptional activity of GR and down-regulation of tyrosine aminotransferase. All the compounds slightly and dose-dependently activated PXR and AhR, and moderately induced CYP3A4 and CYP1A1/2 genes in human hepatocytes and LS180 cells. The complexes antagonized basal and ligand-activated AR and VDR, indicating inverse agonist behaviour. Both basal and thyroid hormone-inducible transcriptional activity of TR was dose-dependently increased by all tested compounds. In contrast, the expression of SPOT14 mRNA was decreased by tested compounds in human hepatocytes and HepG2 cells. In conclusion, if intended for human pharmacotherapy, the potential of the complexes 1-3 to influence studied receptors should be taken in account. (C) 2016 Elsevier Masson SAS.
Název v anglickém jazyce
Pleiotropic effects of gold(I) mixed-ligand complexes of 9- deazahypoxanthine on transcriptional activity of receptors for steroid hormones, nuclear receptors and xenoreceptors in human hepatocytes and cell lines
Popis výsledku anglicky
Development of metal-based compounds is an important research avenue in anti-cancer and anti-inflammatory drug discovery. Here we examined the effects of three gold (I) mixed-ligand complexes with the general formula [Au(L-n)(PPh3)] (1, 2, 3) involving triphenylphosphine (PPh3) and a deprotonated form of O-substituted derivatives of 9-deazahypoxanthine (L-n) on the transcriptional activity of aryl hydrocarbon receptor (AhR), androgen receptor (AR), glucocorticoid receptor (GR), thyroid receptor (TR), pregnane X receptor (PXR) and vitamin D receptor (VDR), employing gene reporter assays. In addition, we measured mRNA (RT-PCR) and protein (western blot) expression of target genes for those receptors, including drug-metabolizing P450s, in primary human hepatocytes and cancer cell lines LS180 and HepG2. The tested compounds displayed anti-glucocorticoid effects, as revealed by inhibition of dexamethasone-inducible transcriptional activity of GR and down-regulation of tyrosine aminotransferase. All the compounds slightly and dose-dependently activated PXR and AhR, and moderately induced CYP3A4 and CYP1A1/2 genes in human hepatocytes and LS180 cells. The complexes antagonized basal and ligand-activated AR and VDR, indicating inverse agonist behaviour. Both basal and thyroid hormone-inducible transcriptional activity of TR was dose-dependently increased by all tested compounds. In contrast, the expression of SPOT14 mRNA was decreased by tested compounds in human hepatocytes and HepG2 cells. In conclusion, if intended for human pharmacotherapy, the potential of the complexes 1-3 to influence studied receptors should be taken in account. (C) 2016 Elsevier Masson SAS.
Klasifikace
Druh
J<sub>x</sub> - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)
CEP obor
FR - Farmakologie a lékárnická chemie
OECD FORD obor
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Návaznosti výsledku
Projekt
Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2016
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
European Journal of Medicinal Chemistry
ISSN
0223-5234
e-ISSN
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Svazek periodika
121
Číslo periodika v rámci svazku
OCT
Stát vydavatele periodika
FR - Francouzská republika
Počet stran výsledku
11
Strana od-do
530-540
Kód UT WoS článku
000382269700045
EID výsledku v databázi Scopus
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