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Statements

Subject Item
n2:RIV%2F00216208%3A11310%2F12%3A10128677%21RIV13-GA0-11310___
rdf:type
skos:Concept n15:Vysledek
dcterms:description
he herbal drug aristolochic acid (AA) derived from Aristolochia species has been shown to be the cause of aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and their urothelial malignancies. One of the common features of AAN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumor development. One cause for these different responses may be individual differences in the activities of the enzymes catalyzing the biotransformation of AA. Thus, the identification of enzymes principally involved in the metabolism of AAI, the major toxic component of AA, and detailed knowledge of their catalytic specificities is of major importance. Human cytochrome P450 (CYP) 1A1 and 1A2 enzymes were found to be responsible for the AAI reductive activation to form AAI-DNA adducts, while its structurally related analogue, CYP1B1 is almost without such activity. However, knowledge of the differences in mechanistic details of CYP1A1-, 1A2-, and 1B1- mediated reduction is still lacking. Therefore, this feature is the aim of the present study. The experimental observations indicate that CYP1B1 is more than 10x less efficient in reductive activation of AAI than CYP1A2. The docking simulation however predicts the binding pose and binding energy of AAI in the CYP1B1 pocket to be analogous to that found in CYP1A1/2. We believe that the hydroxyl group of S122/T124 residue, with its polar hydrogen placed close to the nitro group of the substrate (AAI), is mechanistically important, for example it could provide a proton required for the stepwise reduction process. The absence of a suitable proton donor in the AAI-CYP1B1 binary complex could be the key difference, as the nitro group is in this complex surrounded only by the hydrophobic residues with potential hydrogen donors not closer than 5 Å. he herbal drug aristolochic acid (AA) derived from Aristolochia species has been shown to be the cause of aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and their urothelial malignancies. One of the common features of AAN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumor development. One cause for these different responses may be individual differences in the activities of the enzymes catalyzing the biotransformation of AA. Thus, the identification of enzymes principally involved in the metabolism of AAI, the major toxic component of AA, and detailed knowledge of their catalytic specificities is of major importance. Human cytochrome P450 (CYP) 1A1 and 1A2 enzymes were found to be responsible for the AAI reductive activation to form AAI-DNA adducts, while its structurally related analogue, CYP1B1 is almost without such activity. However, knowledge of the differences in mechanistic details of CYP1A1-, 1A2-, and 1B1- mediated reduction is still lacking. Therefore, this feature is the aim of the present study. The experimental observations indicate that CYP1B1 is more than 10x less efficient in reductive activation of AAI than CYP1A2. The docking simulation however predicts the binding pose and binding energy of AAI in the CYP1B1 pocket to be analogous to that found in CYP1A1/2. We believe that the hydroxyl group of S122/T124 residue, with its polar hydrogen placed close to the nitro group of the substrate (AAI), is mechanistically important, for example it could provide a proton required for the stepwise reduction process. The absence of a suitable proton donor in the AAI-CYP1B1 binary complex could be the key difference, as the nitro group is in this complex surrounded only by the hydrophobic residues with potential hydrogen donors not closer than 5 Å.
dcterms:title
Theoretical investigation of differences in nitroreduction of aristolochic acid I by cytochromes P450 1A1, 1A2 and 1B1 Theoretical investigation of differences in nitroreduction of aristolochic acid I by cytochromes P450 1A1, 1A2 and 1B1
skos:prefLabel
Theoretical investigation of differences in nitroreduction of aristolochic acid I by cytochromes P450 1A1, 1A2 and 1B1 Theoretical investigation of differences in nitroreduction of aristolochic acid I by cytochromes P450 1A1, 1A2 and 1B1
skos:notation
RIV/00216208:11310/12:10128677!RIV13-GA0-11310___
n15:predkladatel
n16:orjk%3A11310
n3:aktivita
n18:I n18:S n18:P
n3:aktivity
I, P(GA303/09/0472), P(GD305/09/H008), S
n3:cisloPeriodika
Suppl 3
n3:dodaniDat
n11:2013
n3:domaciTvurceVysledku
n12:3062465 n12:8486573 n12:5771943
n3:druhVysledku
n19:J
n3:duvernostUdaju
n7:S
n3:entitaPredkladatele
n10:predkladatel
n3:idSjednocenehoVysledku
174198
n3:idVysledku
RIV/00216208:11310/12:10128677
n3:jazykVysledku
n14:eng
n3:klicovaSlova
molecular modeling; cytochromes P450 1A1, 1A2 and 1B1, metabolic activation; Balkan endemic nephropathy; aristolochic acid nephropathy; aristolochic acid
n3:klicoveSlovo
n9:metabolic%20activation n9:Balkan%20endemic%20nephropathy n9:aristolochic%20acid n9:1A2%20and%201B1 n9:cytochromes%20P450%201A1 n9:molecular%20modeling n9:aristolochic%20acid%20nephropathy
n3:kodStatuVydavatele
SE - Švédské království
n3:kontrolniKodProRIV
[75CDB0ADBFCA]
n3:nazevZdroje
Neuroendocrinology Letters
n3:obor
n6:CE
n3:pocetDomacichTvurcuVysledku
3
n3:pocetTvurcuVysledku
3
n3:projekt
n5:GA303%2F09%2F0472 n5:GD305%2F09%2FH008
n3:rokUplatneniVysledku
n11:2012
n3:svazekPeriodika
33
n3:tvurceVysledku
Jeřábek, Petr Stiborová, Marie Martínek, Václav
s:issn
0172-780X
s:numberOfPages
8
n17:organizacniJednotka
11310