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Statements

Subject Item
n2:RIV%2F00216208%3A11310%2F11%3A10100497%21RIV12-GA0-11310___
rdf:type
n7:Vysledek skos:Concept
rdfs:seeAlso
http://dx.doi.org/10.1093/toxsci/kfr050
dcterms:description
Aristolochic acid (AA) causes aristolochic acid nephropathy, Balkan endemic nephropathy, and their urothelial malignancies. To identify enzymes involved in the metabolism of aristolochic acid I (AAI), the major toxic component of AA we used HRN (hepatic cytochrome P450 [Cyp] reductase null) mice, in which NADPH:Cyp oxidoreductase (Por) is deleted in hepatocytes. AAI was demethylated by hepatic Cyps in vitro to 8-hydroxy-aristolochic acid I (AAIa), indicating that less AAI is distributed to extrahepatic organs in wild-type (WT) mice. Indeed, AAI-DNA-adduct levels were significantly higher in organs of HRN mice, having low hepatic AAI demethylation capacity, than in WT mice. Absence of AAI demethylation in HRN mouse liver was confirmed in vitro; hepatic microsomes from WT, but not from HRN mice, oxidized AAI to AAIa. To define the role of hepatic Cyps in AAI demethylation, modulation of AAIa formation by CYP inducers was investigated. We conclude that AAI demethylation is attributable mainly to Cyp1a1/2. The higher AAI-DNA adduct levels in HRN than WT mice were the result of the lack of hepatic AAI demethylation concomitant with a higher activity of cytosolic NAD(P)H:quinone oxidoreductase (Nqo1), which activates AAI. Mouse hepatic Cyp1a1/2 also activated AAI to DNA adducts under hypoxic conditions in vitro, but in renal microsomes, Por and Cyp3a are more important than Cyp1a for AAI-DNA adduct formation. We propose that AAI activation and detoxication in mice are dictated mainly by AAI binding affinity to Cyp1a1/2 or Nqo1, by their turnover, and by the balance between oxidation and reduction of AAI by Cyp1a. Aristolochic acid (AA) causes aristolochic acid nephropathy, Balkan endemic nephropathy, and their urothelial malignancies. To identify enzymes involved in the metabolism of aristolochic acid I (AAI), the major toxic component of AA we used HRN (hepatic cytochrome P450 [Cyp] reductase null) mice, in which NADPH:Cyp oxidoreductase (Por) is deleted in hepatocytes. AAI was demethylated by hepatic Cyps in vitro to 8-hydroxy-aristolochic acid I (AAIa), indicating that less AAI is distributed to extrahepatic organs in wild-type (WT) mice. Indeed, AAI-DNA-adduct levels were significantly higher in organs of HRN mice, having low hepatic AAI demethylation capacity, than in WT mice. Absence of AAI demethylation in HRN mouse liver was confirmed in vitro; hepatic microsomes from WT, but not from HRN mice, oxidized AAI to AAIa. To define the role of hepatic Cyps in AAI demethylation, modulation of AAIa formation by CYP inducers was investigated. We conclude that AAI demethylation is attributable mainly to Cyp1a1/2. The higher AAI-DNA adduct levels in HRN than WT mice were the result of the lack of hepatic AAI demethylation concomitant with a higher activity of cytosolic NAD(P)H:quinone oxidoreductase (Nqo1), which activates AAI. Mouse hepatic Cyp1a1/2 also activated AAI to DNA adducts under hypoxic conditions in vitro, but in renal microsomes, Por and Cyp3a are more important than Cyp1a for AAI-DNA adduct formation. We propose that AAI activation and detoxication in mice are dictated mainly by AAI binding affinity to Cyp1a1/2 or Nqo1, by their turnover, and by the balance between oxidation and reduction of AAI by Cyp1a.
dcterms:title
Role of Cytochromes P450 1A1/2 in Detoxication and Activation of Carcinogenic Aristolochic Acid I: Studies with the Hepatic NADPH:Cytochrome P450 Reductase Null (HRN) Mouse Model Role of Cytochromes P450 1A1/2 in Detoxication and Activation of Carcinogenic Aristolochic Acid I: Studies with the Hepatic NADPH:Cytochrome P450 Reductase Null (HRN) Mouse Model
skos:prefLabel
Role of Cytochromes P450 1A1/2 in Detoxication and Activation of Carcinogenic Aristolochic Acid I: Studies with the Hepatic NADPH:Cytochrome P450 Reductase Null (HRN) Mouse Model Role of Cytochromes P450 1A1/2 in Detoxication and Activation of Carcinogenic Aristolochic Acid I: Studies with the Hepatic NADPH:Cytochrome P450 Reductase Null (HRN) Mouse Model
skos:notation
RIV/00216208:11310/11:10100497!RIV12-GA0-11310___
n7:predkladatel
n8:orjk%3A11310
n3:aktivita
n13:Z n13:I n13:S n13:P
n3:aktivity
I, P(1M0505), P(GA303/09/0472), P(GD305/09/H008), S, Z(MSM0021620808)
n3:cisloPeriodika
1
n3:dodaniDat
n6:2012
n3:domaciTvurceVysledku
n10:6798055 n10:6282555 n10:1070177 n10:8486573 n10:9501894
n3:druhVysledku
n20:J
n3:duvernostUdaju
n17:S
n3:entitaPredkladatele
n18:predkladatel
n3:idSjednocenehoVysledku
227425
n3:idVysledku
RIV/00216208:11310/11:10100497
n3:jazykVysledku
n11:eng
n3:klicovaSlova
sudan-i; environmental-pollutant; gene-expression; urothelial cancer; metabolic-activation; prostaglandin-h synthase; anticancer drug ellipticine; dna adduct formation; chinese herbs nephropathy; Balkan endemic nephropathy
n3:klicoveSlovo
n4:metabolic-activation n4:urothelial%20cancer n4:environmental-pollutant n4:dna%20adduct%20formation n4:gene-expression n4:chinese%20herbs%20nephropathy n4:Balkan%20endemic%20nephropathy n4:anticancer%20drug%20ellipticine n4:prostaglandin-h%20synthase n4:sudan-i
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[B423C11FD634]
n3:nazevZdroje
Toxicological Sciences
n3:obor
n21:CE
n3:pocetDomacichTvurcuVysledku
5
n3:pocetTvurcuVysledku
12
n3:projekt
n5:GA303%2F09%2F0472 n5:GD305%2F09%2FH008 n5:1M0505
n3:rokUplatneniVysledku
n6:2011
n3:svazekPeriodika
121
n3:tvurceVysledku
Schmeiser, Heinz H. Wolf, C. Roland Mareš, Jaroslav Kotrbová, Věra Moserová, Michaela Frei, Eva Phillips, David H. Arlt,, Volker M. Levová, Kateřina Henderson, Colin J. Šulc, Miroslav Stiborová, Marie
n3:wos
000289807200005
n3:zamer
n16:MSM0021620808
s:issn
1096-6080
s:numberOfPages
14
n22:doi
10.1093/toxsci/kfr050
n12:organizacniJednotka
11310