Enantiospecific effects of ketoconazole on aryl hydrocarbon receptor

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F14%3A33150560" target="_blank" >RIV/61989592:15310/14:33150560 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15110/14:33150560

Výsledek na webu

<a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101832" target="_blank" >http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101832</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1371/journal.pone.0101832" target="_blank" >10.1371/journal.pone.0101832</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Enantiospecific effects of ketoconazole on aryl hydrocarbon receptor

Popis výsledku v původním jazyce

Azole antifungal ketoconazole (KET) was demonstrated to activate aryl hydrocarbon receptor (AhR). Since clinically used KET is a racemic mixture of two cis-enantiomers (2R,4S)-(+)-KET and (2S,4R)-(-)-KET,we examined the effects of KET enantiomers on AhRsignaling pathway. (+)-KET dose-dependently activated AhR in human gene reporter cell line AZ-AHR,and displayed 5-20x higher agonist activity (efficacy),as compared to (-)-KET; both enantiomers were AhR antagonists with equal potency (IC50). Consistently,(+)-KET strongly induced CYP1A1 mRNA and protein in human HepG2 cells,while (-)-KET exerted less than 10% of (+)-KET activity. In primary human hepatocytes,both enantiomers preferentially induced CYP1A2 over CYP1A1 mRNA and protein,and the potency of (+)-KET was slightly higher as compared to (-)-KET. Ligand binding assay with guinea pig liver cytosols revealed that both (+)-KET and (-)-KET are weak ligands of AhR that displaced [H-3]-TCDD with comparable potency. Similarly,both enantio

Název v anglickém jazyce

Enantiospecific effects of ketoconazole on aryl hydrocarbon receptor

Popis výsledku anglicky

Azole antifungal ketoconazole (KET) was demonstrated to activate aryl hydrocarbon receptor (AhR). Since clinically used KET is a racemic mixture of two cis-enantiomers (2R,4S)-(+)-KET and (2S,4R)-(-)-KET,we examined the effects of KET enantiomers on AhRsignaling pathway. (+)-KET dose-dependently activated AhR in human gene reporter cell line AZ-AHR,and displayed 5-20x higher agonist activity (efficacy),as compared to (-)-KET; both enantiomers were AhR antagonists with equal potency (IC50). Consistently,(+)-KET strongly induced CYP1A1 mRNA and protein in human HepG2 cells,while (-)-KET exerted less than 10% of (+)-KET activity. In primary human hepatocytes,both enantiomers preferentially induced CYP1A2 over CYP1A1 mRNA and protein,and the potency of (+)-KET was slightly higher as compared to (-)-KET. Ligand binding assay with guinea pig liver cytosols revealed that both (+)-KET and (-)-KET are weak ligands of AhR that displaced [H-3]-TCDD with comparable potency. Similarly,both enantio

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FR - Farmakologie a lékárnická chemie

OECD FORD obor

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Projekt

<a href="/cs/project/GA13-01809S" target="_blank" >GA13-01809S: Enantiospecifické interakce mezi klinicky užívanými chirálními léčivy a regulačními drahami humánních cytochromů P450.</a><br>

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2014

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

PLoS One

ISSN

1932-6203

e-ISSN

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Svazek periodika

9

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

"e101832"

Kód UT WoS článku

000338637300092

EID výsledku v databázi Scopus

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