NAD(P)H:quinone oxidoreductase expression in Cyp1a-knockout and CYP1A-humanized mouse lines and its effect on bioactivation of the carcinogen aristolochic acid I.

2.50
Hdl Handle:
http://hdl.handle.net/10146/269637
Title:
NAD(P)H:quinone oxidoreductase expression in Cyp1a-knockout and CYP1A-humanized mouse lines and its effect on bioactivation of the carcinogen aristolochic acid I.
Authors:
Levova, Katerina; Moserova, Michaela; Nebert, Daniel W.; Phillips, David H.; Frei, Eva; Schmeiser, Heinz H.; Arlt, Volker M.; Stiborova, Marie
Abstract:
Aristolochic acid causes a specific nephropathy (AAN), Balkan endemic nephropathy, and urothelial malignancies. Using Western blotting suitable to determine protein expression, we investigated in several transgenic mouse lines expression of NAD(P)H:quinone oxidoreductase (NQO1)-the most efficient cytosolic enzyme that reductively activates aristolochic acid I (AAI). The mouse tissues used were from previous studies [Arlt et al., Chem. Res. Toxicol. 24 (2011) 1710; Stiborova et al., Toxicol. Sci. 125 (2012) 345], in which the role of microsomal cytochrome P450 (CYP) enzymes in AAI metabolism in vivo had been determined. We found that NQO1 levels in liver, kidney and lung of Cyp1a1⁻/⁻, Cyp1a2⁻/⁻ and Cyp1a1/1a2⁻/⁻ knockout mouse lines, as well as in two CYP1A-humanized mouse lines harboring functional human CYP1A1 and CYP1A2 and lacking the mouse Cyp1a1/1a2 orthologs, differed from NQO1 levels in wild-type mice. NQO1 protein and enzymic activity were induced in hepatic and renal cytosolic fractions isolated from AAI-pretreated mice, compared with those in untreated mice. Furthermore, this increase in hepatic NQO1 enzyme activity was associated with bioactivation of AAI and elevated AAI-DNA adduct levels in ex vivo incubations of cytosolic fractions with DNA and AAI. In conclusion, AAI appears to increase its own metabolic activation by inducing NQO1, thereby enhancing its own genotoxic potential.
Citation:
Toxicol. Appl. Pharmacol. 2012, 265 (3):360-367
Journal:
Toxicology and Applied Pharmacology
Issue Date:
15-Dec-2012
URI:
http://hdl.handle.net/10146/269637
DOI:
10.1016/j.taap.2012.09.004
PubMed ID:
22982977
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0041008X12004000
Type:
Article
Language:
en
ISSN:
1096-0333
Sponsors:
Financial support from GACR (grant 303/09/0472 and 305/09/H008) and Charles University in Prague (UNCE 204025/2012) is highly acknowledged. Work at King's College London is supported by Cancer Research UK. D.H. Phillips and V.M. Arlt are members of the European Union Network of Excellence ECNIS2 (Environmental Cancer Risk, Nutrition and Individual Susceptibility). D.W. Nebert has been supported by R01 ES ES014403 and the P30 ES006096 Center grant.
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorLevova, Katerinaen_GB
dc.contributor.authorMoserova, Michaelaen_GB
dc.contributor.authorNebert, Daniel W.en_GB
dc.contributor.authorPhillips, David H.en_GB
dc.contributor.authorFrei, Evaen_GB
dc.contributor.authorSchmeiser, Heinz H.en_GB
dc.contributor.authorArlt, Volker M.en_GB
dc.contributor.authorStiborova, Marieen_GB
dc.date.accessioned2013-02-15T13:25:50Zen
dc.date.available2013-02-15T13:25:50Zen
dc.date.issued2012-12-15en
dc.identifier.citationToxicol. Appl. Pharmacol. 2012, 265 (3):360-367en_GB
dc.identifier.issn1096-0333en
dc.identifier.pmid22982977en
dc.identifier.doi10.1016/j.taap.2012.09.004en
dc.identifier.urihttp://hdl.handle.net/10146/269637en
dc.description.abstractAristolochic acid causes a specific nephropathy (AAN), Balkan endemic nephropathy, and urothelial malignancies. Using Western blotting suitable to determine protein expression, we investigated in several transgenic mouse lines expression of NAD(P)H:quinone oxidoreductase (NQO1)-the most efficient cytosolic enzyme that reductively activates aristolochic acid I (AAI). The mouse tissues used were from previous studies [Arlt et al., Chem. Res. Toxicol. 24 (2011) 1710; Stiborova et al., Toxicol. Sci. 125 (2012) 345], in which the role of microsomal cytochrome P450 (CYP) enzymes in AAI metabolism in vivo had been determined. We found that NQO1 levels in liver, kidney and lung of Cyp1a1⁻/⁻, Cyp1a2⁻/⁻ and Cyp1a1/1a2⁻/⁻ knockout mouse lines, as well as in two CYP1A-humanized mouse lines harboring functional human CYP1A1 and CYP1A2 and lacking the mouse Cyp1a1/1a2 orthologs, differed from NQO1 levels in wild-type mice. NQO1 protein and enzymic activity were induced in hepatic and renal cytosolic fractions isolated from AAI-pretreated mice, compared with those in untreated mice. Furthermore, this increase in hepatic NQO1 enzyme activity was associated with bioactivation of AAI and elevated AAI-DNA adduct levels in ex vivo incubations of cytosolic fractions with DNA and AAI. In conclusion, AAI appears to increase its own metabolic activation by inducing NQO1, thereby enhancing its own genotoxic potential.en_GB
dc.description.sponsorshipFinancial support from GACR (grant 303/09/0472 and 305/09/H008) and Charles University in Prague (UNCE 204025/2012) is highly acknowledged. Work at King's College London is supported by Cancer Research UK. D.H. Phillips and V.M. Arlt are members of the European Union Network of Excellence ECNIS2 (Environmental Cancer Risk, Nutrition and Individual Susceptibility). D.W. Nebert has been supported by R01 ES ES014403 and the P30 ES006096 Center grant.en_GB
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0041008X12004000en_GB
dc.rightsArchived with thanks to Toxicology and applied pharmacologyen_GB
dc.subjectAristolochic aciden_GB
dc.subjectCarcinogensen_GB
dc.subjectNephropathyen_GB
dc.subjectMouse modelsen_GB
dc.subjectDNA adductsen_GB
dc.subjectProtein expressionen_GB
dc.subjectNAD(P)H:quinone oxidoreductaseen_GB
dc.subjectMetabolic activationen_GB
dc.titleNAD(P)H:quinone oxidoreductase expression in Cyp1a-knockout and CYP1A-humanized mouse lines and its effect on bioactivation of the carcinogen aristolochic acid I.en
dc.typeArticleen
dc.identifier.journalToxicology and Applied Pharmacologyen_GB

Related articles on PubMed

All Items in ECNIS-NIOM are protected by copyright, with all rights reserved, unless otherwise indicated.