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Statements

Subject Item
n2:RIV%2F61989592%3A15110%2F14%3A33150566%21RIV15-MSM-15110___
rdf:type
skos:Concept n13:Vysledek
rdfs:seeAlso
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111286&representation=PDF
dcterms:description
Antifungal drug ketoconazole causes severe drug-drug interactions by influencing gene expression and catalytic activity of major drug-metabolizing enzyme cytochrome P450 CYP3A4. Ketoconazole is administered in the form of racemic mixture of two cis-enantiomers, i.e. (+)-ketoconazole and (-)-ketoconazole. Many enantiopure drugs were introduced to human pharmacotherapy in last two decades. In the current paper, we have examined the effects of ketoconazole cis-enantiomers on the expression of CYP3A4 in human hepatocytes and HepG2 cells and on catalytic activity of CYP3A4 in human liver microsomes. We show that both ketoconazole enantiomers induce CYP3A4 mRNA and protein in human hepatocytes and HepG2 cells. Gene reporter assays revealed partial agonist activity of ketoconazole enantiomers towards pregnane X receptor PXR. Catalytic activity of CYP3A4/5 towards two prototypic substrates of CYP3A enzymes, testosterone and midazolam, was determined in presence of both (+)-ketoconazole and (-)-ketoconazole in human liver microsomes. Overall, both ketoconazole cis-enantiomers induced CYP3A4 in human cells and inhibited CYP3A4 in human liver microsomes. While interaction of ketoconazole with PXR and induction of CYP3A4 did not display enantiospecific pattern, inhibition of CYP3A4 catalytic activity by ketoconazole differed for ketoconazole cis-enantiomers ((+)-ketoconazole IC50 1.69 mu M, K-i 0.92 mu M for testosterone, IC50 1.46 mu M, K-i 2.52 mu M for midazolam; (-)-ketoconazole IC50 0.90 mu M, K-i 0.17 mu M for testosterone, IC50 1.04 mu M, K-i 1.51 mu M for midazolam). Antifungal drug ketoconazole causes severe drug-drug interactions by influencing gene expression and catalytic activity of major drug-metabolizing enzyme cytochrome P450 CYP3A4. Ketoconazole is administered in the form of racemic mixture of two cis-enantiomers, i.e. (+)-ketoconazole and (-)-ketoconazole. Many enantiopure drugs were introduced to human pharmacotherapy in last two decades. In the current paper, we have examined the effects of ketoconazole cis-enantiomers on the expression of CYP3A4 in human hepatocytes and HepG2 cells and on catalytic activity of CYP3A4 in human liver microsomes. We show that both ketoconazole enantiomers induce CYP3A4 mRNA and protein in human hepatocytes and HepG2 cells. Gene reporter assays revealed partial agonist activity of ketoconazole enantiomers towards pregnane X receptor PXR. Catalytic activity of CYP3A4/5 towards two prototypic substrates of CYP3A enzymes, testosterone and midazolam, was determined in presence of both (+)-ketoconazole and (-)-ketoconazole in human liver microsomes. Overall, both ketoconazole cis-enantiomers induced CYP3A4 in human cells and inhibited CYP3A4 in human liver microsomes. While interaction of ketoconazole with PXR and induction of CYP3A4 did not display enantiospecific pattern, inhibition of CYP3A4 catalytic activity by ketoconazole differed for ketoconazole cis-enantiomers ((+)-ketoconazole IC50 1.69 mu M, K-i 0.92 mu M for testosterone, IC50 1.46 mu M, K-i 2.52 mu M for midazolam; (-)-ketoconazole IC50 0.90 mu M, K-i 0.17 mu M for testosterone, IC50 1.04 mu M, K-i 1.51 mu M for midazolam).
dcterms:title
Dual Effects of Ketoconazole cis-Enantiomers on CYP3A4 in Human Hepatocytes and HepG2 Cells Dual Effects of Ketoconazole cis-Enantiomers on CYP3A4 in Human Hepatocytes and HepG2 Cells
skos:prefLabel
Dual Effects of Ketoconazole cis-Enantiomers on CYP3A4 in Human Hepatocytes and HepG2 Cells Dual Effects of Ketoconazole cis-Enantiomers on CYP3A4 in Human Hepatocytes and HepG2 Cells
skos:notation
RIV/61989592:15110/14:33150566!RIV15-MSM-15110___
n3:aktivita
n17:S n17:P
n3:aktivity
P(GA13-01809S), S
n3:cisloPeriodika
10
n3:dodaniDat
n6:2015
n3:domaciTvurceVysledku
n5:5961025 n5:2637812 n5:7271859
n3:druhVysledku
n20:J
n3:duvernostUdaju
n15:S
n3:entitaPredkladatele
n19:predkladatel
n3:idSjednocenehoVysledku
12466
n3:idVysledku
RIV/61989592:15110/14:33150566
n3:jazykVysledku
n8:eng
n3:klicovaSlova
lines; activation; metabolism; expression; inhibition; in-vitro; diabetes-mellitus; pregnane-X-receptor
n3:klicoveSlovo
n4:pregnane-X-receptor n4:diabetes-mellitus n4:lines n4:inhibition n4:expression n4:metabolism n4:in-vitro n4:activation
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[4C0369D963A1]
n3:nazevZdroje
PLoS One
n3:obor
n18:FR
n3:pocetDomacichTvurcuVysledku
3
n3:pocetTvurcuVysledku
7
n3:projekt
n14:GA13-01809S
n3:rokUplatneniVysledku
n6:2014
n3:svazekPeriodika
9
n3:tvurceVysledku
Novotná, Aneta Bachleda, Petr Korhoňová, Martina Anzenbacher, Pavel Bartoňková, Iveta Krasulová, Kristýna Dvořák, Zdeněk
n3:wos
000343943500096
s:issn
1932-6203
s:numberOfPages
8
n11:doi
10.1371/journal.pone.0111286
n7:organizacniJednotka
15110