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Statements

Subject Item
n2:RIV%2F00216208%3A11310%2F14%3A10288886%21RIV15-MSM-11310___
rdf:type
n16:Vysledek skos:Concept
rdfs:seeAlso
http://www.nel.edu/archive_issues/o/35_s2/35_s2_Stiborova_123-132.pdf
dcterms:description
OBJECTIVES: Dicoumarol is known to act as an inhibitor of NAD(P)H:quinone oxidoreductase (NQO1). This cytosolic reductase significantly contributes to the genotoxicity of the nephrotoxic and carcinogenic alkaloid aristolochic acid I (AAI). Aristolochic acid causes aristolochic acid nephropathy (AAN), and Balkan endemic nephropathy (BEN), as well as associated urothelial malignancies. NQO1 is the most efficient enzyme responsible for the reductive bioactivation of AAI to species forming covalent AAI-DNA adducts. However, it is still not known how dicoumarol influences the NQO1-mediated reductive bioactivation of AAI. METHODS: AAI-DNA adduct formation was determined by 32P-postlabeling. Expression of NQO1 mRNA and NQO1 protein was determined by real-time polymerase chain reaction and Western blotting, respectively. RESULTS: In this study, dicoumarol inhibited AAI bioactivation to form AAI-DNA adducts mediated by rat and human NQO1 in vitro as expected. We however, demonstrated that dicoumarol acts as an inducer of NQO1 in kidney and lung of rats treated with this NQO1 inhibitor in vivo, both at protein and activity levels. This NQO1 induction increased the potency of kidney cytosol to bioactivate AAI and elevated AAI-DNA adduct levels were found in ex-vivo incubations of AAI with renal cytosols and DNA. NQO1 mRNA levels were induced in liver only by dicoumarol. CONCLUSION: Our results indicate a dual role of dicoumarol in NQO1-mediated genotoxicty of AAI. It acts both as an NQO1 inhibitor mainly in vitro and as an NQO1 inducer if administered to rats. OBJECTIVES: Dicoumarol is known to act as an inhibitor of NAD(P)H:quinone oxidoreductase (NQO1). This cytosolic reductase significantly contributes to the genotoxicity of the nephrotoxic and carcinogenic alkaloid aristolochic acid I (AAI). Aristolochic acid causes aristolochic acid nephropathy (AAN), and Balkan endemic nephropathy (BEN), as well as associated urothelial malignancies. NQO1 is the most efficient enzyme responsible for the reductive bioactivation of AAI to species forming covalent AAI-DNA adducts. However, it is still not known how dicoumarol influences the NQO1-mediated reductive bioactivation of AAI. METHODS: AAI-DNA adduct formation was determined by 32P-postlabeling. Expression of NQO1 mRNA and NQO1 protein was determined by real-time polymerase chain reaction and Western blotting, respectively. RESULTS: In this study, dicoumarol inhibited AAI bioactivation to form AAI-DNA adducts mediated by rat and human NQO1 in vitro as expected. We however, demonstrated that dicoumarol acts as an inducer of NQO1 in kidney and lung of rats treated with this NQO1 inhibitor in vivo, both at protein and activity levels. This NQO1 induction increased the potency of kidney cytosol to bioactivate AAI and elevated AAI-DNA adduct levels were found in ex-vivo incubations of AAI with renal cytosols and DNA. NQO1 mRNA levels were induced in liver only by dicoumarol. CONCLUSION: Our results indicate a dual role of dicoumarol in NQO1-mediated genotoxicty of AAI. It acts both as an NQO1 inhibitor mainly in vitro and as an NQO1 inducer if administered to rats.
dcterms:title
Dicoumarol inhibits rat NAD(P)H:quinone oxidoreductase in vitro and induces its expression in vivo Dicoumarol inhibits rat NAD(P)H:quinone oxidoreductase in vitro and induces its expression in vivo
skos:prefLabel
Dicoumarol inhibits rat NAD(P)H:quinone oxidoreductase in vitro and induces its expression in vivo Dicoumarol inhibits rat NAD(P)H:quinone oxidoreductase in vitro and induces its expression in vivo
skos:notation
RIV/00216208:11310/14:10288886!RIV15-MSM-11310___
n4:aktivita
n14:I n14:S n14:P
n4:aktivity
I, P(GA14-18344S), S
n4:cisloPeriodika
Suppl. 2
n4:dodaniDat
n5:2015
n4:domaciTvurceVysledku
n7:3699323 n7:6491758 n7:2035952 n7:9501894 n7:8486573 n7:6282555
n4:druhVysledku
n13:J
n4:duvernostUdaju
n11:S
n4:entitaPredkladatele
n12:predkladatel
n4:idSjednocenehoVysledku
11245
n4:idVysledku
RIV/00216208:11310/14:10288886
n4:jazykVysledku
n17:eng
n4:klicovaSlova
rat model; DNA adducts; metabolic activation; Western blotting; protein expression; dicoumarol; NAD(P)H:quinone oxidoreductase; Balkan endemic nephropathy; aristolochic acid nephropathy; aristolochic acid
n4:klicoveSlovo
n6:Balkan%20endemic%20nephropathy n6:protein%20expression n6:rat%20model n6:DNA%20adducts n6:dicoumarol n6:Western%20blotting n6:NAD%28P%29H%3Aquinone%20oxidoreductase n6:metabolic%20activation n6:aristolochic%20acid%20nephropathy n6:aristolochic%20acid
n4:kodStatuVydavatele
SE - Švédské království
n4:kontrolniKodProRIV
[2057BEC32377]
n4:nazevZdroje
Neuroendocrinology Letters
n4:obor
n8:CE
n4:pocetDomacichTvurcuVysledku
6
n4:pocetTvurcuVysledku
9
n4:projekt
n10:GA14-18344S
n4:rokUplatneniVysledku
n5:2014
n4:svazekPeriodika
35
n4:tvurceVysledku
Stiborová, Marie Šulc, Miroslav Schmeiser, Heinz H. Hodek, Petr Dračínská, Helena Levová, Kateřina Bárta, František Arlt, Volker M. Frei, Eva
s:issn
0172-780X
s:numberOfPages
10
n9:organizacniJednotka
11310