Impurities contained in antifungal drug ketoconazole are potent activators of human aryl hydrocarbon receptor

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F15%3A33155391" target="_blank" >RIV/61989592:15310/15:33155391 - isvavai.cz</a>

Výsledek na webu

<a href="http://www.sciencedirect.com/science/article/pii/S0378427415300436" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0378427415300436</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.toxlet.2015.09.004" target="_blank" >10.1016/j.toxlet.2015.09.004</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Impurities contained in antifungal drug ketoconazole are potent activators of human aryl hydrocarbon receptor

Popis výsledku v původním jazyce

Antifungal drug ketoconazole is a mixture of (+)/(-) cis-enantiomers, which also contains several impurities. Ketoconazole was identified as an activator of aryl hydrocarbon receptor AhR by three independent research teams. In the current paper we demonstrate that impurities contained in ketoconazole preparations are strong activators of human AhR and inducers of CYP1A1. Impurity IMP-C had similar potency (EC50), but 10-15 times higher efficacy (magnitude of induction) towards AhR, comparing to (+)-ketoconazole, as revealed by gene reporter assay in AZ-AHR stably transfected cells. Impurities IMP-B and IMP-C, and in lesser extent IMP-E, induced a formation of AhR-DNA complex, as demonstrated by electromobility shift assay EMSA. Impurities IMP-C and IMP-E dose-dependently induced CYP1A1 mRNA after 24 h, and their effects were comparable to those by (+)-ketoconazole. The level of CYP1A1 protein in HepG2 cells was strongly increased by IMP-C after 48 h. In conclusion, our data further elu

Název v anglickém jazyce

Impurities contained in antifungal drug ketoconazole are potent activators of human aryl hydrocarbon receptor

Popis výsledku anglicky

Antifungal drug ketoconazole is a mixture of (+)/(-) cis-enantiomers, which also contains several impurities. Ketoconazole was identified as an activator of aryl hydrocarbon receptor AhR by three independent research teams. In the current paper we demonstrate that impurities contained in ketoconazole preparations are strong activators of human AhR and inducers of CYP1A1. Impurity IMP-C had similar potency (EC50), but 10-15 times higher efficacy (magnitude of induction) towards AhR, comparing to (+)-ketoconazole, as revealed by gene reporter assay in AZ-AHR stably transfected cells. Impurities IMP-B and IMP-C, and in lesser extent IMP-E, induced a formation of AhR-DNA complex, as demonstrated by electromobility shift assay EMSA. Impurities IMP-C and IMP-E dose-dependently induced CYP1A1 mRNA after 24 h, and their effects were comparable to those by (+)-ketoconazole. The level of CYP1A1 protein in HepG2 cells was strongly increased by IMP-C after 48 h. In conclusion, our data further elu

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/GBP303%2F12%2FG163" target="_blank" >GBP303/12/G163: Centrum interakcí potravních doplňků s léčivy a nutrigenetiky</a><br>

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2015

Kód důvěrnosti údajů

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

Název periodika

Toxicology Letters

ISSN

0378-4274

e-ISSN

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Svazek periodika

239

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

IE - Irsko

Počet stran výsledku

6

Strana od-do

67-72

Kód UT WoS článku

000363353600001

EID výsledku v databázi Scopus

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