The environmental pollutant and carcinogen 3-nitrobenzanthrone induces cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase in rat lung and kidney, thereby enhancing its own genotoxicity.

2.50
Hdl Handle:
http://hdl.handle.net/10146/38100
Title:
The environmental pollutant and carcinogen 3-nitrobenzanthrone induces cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase in rat lung and kidney, thereby enhancing its own genotoxicity.
Authors:
Stiborova, Marie; Dracinska, Helena; Mizerovska, Jana; Frei, Eva; Schmeiser, Heinz H.; Hudecek, Jiri; Hodek, Petr; Phillips, David H.; Arlt, Volker M.
Abstract:
3-Nitrobenzanthrone (3-NBA) is a carcinogen occurring in diesel exhaust and air pollution. Using the (32)P-postlabelling method, we found that 3-NBA and its human metabolite, 3-aminobenzanthrone (3-ABA), are activated to species forming DNA adducts by cytosols and/or microsomes isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney. Each compound generated identical five DNA adducts. We have demonstrated the importance of pulmonary and renal NAD(P)H:quinone oxidoreductase (NQO1) to reduce 3-NBA to species that are further activated by N,O-acetyltransferases and sulfotransferases. Cytochrome P450 (CYP) 1A1 is the essential enzyme for oxidative activation of 3-ABA in microsomes of both organs, while cyclooxygenase plays a minor role. 3-NBA was also investigated for its ability to induce NQO1 and CYP1A1 in lungs and kidneys, and for the influence of such induction on DNA adduct formation by 3-NBA and 3-ABA. When cytosols from rats treated i.p. with 40mg/kg bw of 3-NBA were incubated with 3-NBA, DNA adduct formation was up to 2.1-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. Incubations of 3-ABA with microsomes of 3-NBA-treated rats led to up to a fivefold increase in DNA adduct formation relative to controls. The stimulation of DNA adduct formation correlated with the potential of 3-NBA to induce protein expression and activity of CYP1A1. These results demonstrate that 3-NBA is capable to induce NQO1 and CYP1A1 in lungs and kidney of rats thereby enhancing its own genotoxic and carcinogenic potential.
Citation:
Toxicology 2008, 247 (1):11-22
Journal:
Toxicology
Issue Date:
2-May-2008
URI:
http://hdl.handle.net/10146/38100
DOI:
10.1016/j.tox.2008.01.018
PubMed ID:
18329153
Additional Links:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCN-4RSBYD9-1&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=7c1b12339732dfcf1de6505de2d42026
Type:
Article
Language:
en
ISSN:
0300-483X
Sponsors:
This work was supported in part by Grant Agency of the Czech Republic, grant 303/05/2195, Ministry of Education of the Czech Republic, grant MSM0021620808 and by Cancer Research UK. V.M. Arlt and D.H. Phillips are partners of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943).
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorStiborova, Marie-
dc.contributor.authorDracinska, Helena-
dc.contributor.authorMizerovska, Jana-
dc.contributor.authorFrei, Eva-
dc.contributor.authorSchmeiser, Heinz H.-
dc.contributor.authorHudecek, Jiri-
dc.contributor.authorHodek, Petr-
dc.contributor.authorPhillips, David H.-
dc.contributor.authorArlt, Volker M.-
dc.date.accessioned2008-09-24T10:39:40Z-
dc.date.available2008-09-24T10:39:40Z-
dc.date.issued2008-05-02-
dc.identifier.citationToxicology 2008, 247 (1):11-22en
dc.identifier.issn0300-483X-
dc.identifier.pmid18329153-
dc.identifier.doi10.1016/j.tox.2008.01.018-
dc.identifier.urihttp://hdl.handle.net/10146/38100-
dc.description.abstract3-Nitrobenzanthrone (3-NBA) is a carcinogen occurring in diesel exhaust and air pollution. Using the (32)P-postlabelling method, we found that 3-NBA and its human metabolite, 3-aminobenzanthrone (3-ABA), are activated to species forming DNA adducts by cytosols and/or microsomes isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney. Each compound generated identical five DNA adducts. We have demonstrated the importance of pulmonary and renal NAD(P)H:quinone oxidoreductase (NQO1) to reduce 3-NBA to species that are further activated by N,O-acetyltransferases and sulfotransferases. Cytochrome P450 (CYP) 1A1 is the essential enzyme for oxidative activation of 3-ABA in microsomes of both organs, while cyclooxygenase plays a minor role. 3-NBA was also investigated for its ability to induce NQO1 and CYP1A1 in lungs and kidneys, and for the influence of such induction on DNA adduct formation by 3-NBA and 3-ABA. When cytosols from rats treated i.p. with 40mg/kg bw of 3-NBA were incubated with 3-NBA, DNA adduct formation was up to 2.1-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. Incubations of 3-ABA with microsomes of 3-NBA-treated rats led to up to a fivefold increase in DNA adduct formation relative to controls. The stimulation of DNA adduct formation correlated with the potential of 3-NBA to induce protein expression and activity of CYP1A1. These results demonstrate that 3-NBA is capable to induce NQO1 and CYP1A1 in lungs and kidney of rats thereby enhancing its own genotoxic and carcinogenic potential.en
dc.description.sponsorshipThis work was supported in part by Grant Agency of the Czech Republic, grant 303/05/2195, Ministry of Education of the Czech Republic, grant MSM0021620808 and by Cancer Research UK. V.M. Arlt and D.H. Phillips are partners of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943).en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCN-4RSBYD9-1&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=7c1b12339732dfcf1de6505de2d42026en
dc.subject3-nitrobenzanthroneen
dc.subject3-Aminobenzanthroneen
dc.subjectDNA adductsen
dc.subjectNAD(P)H:quinone oxidoreductaseen
dc.subjectCytochrome P450 1A1en
dc.subjectInductionen
dc.subject.meshAnimals-
dc.subject.meshBenz(a)Anthracenes-
dc.subject.meshCarcinogens-
dc.subject.meshCytochrome P-450 CYP1A1-
dc.subject.meshCytosol-
dc.subject.meshDNA Adducts-
dc.subject.meshEnvironmental Pollutants-
dc.subject.meshEnzyme Induction-
dc.subject.meshKidney-
dc.subject.meshLung-
dc.subject.meshMale-
dc.subject.meshMicrosomes, Liver-
dc.subject.meshMutagenicity Tests-
dc.subject.meshMutagens-
dc.subject.meshNAD(P)H Dehydrogenase (Quinone)-
dc.subject.meshPhosphorus Radioisotopes-
dc.subject.meshRats-
dc.subject.meshRats, Wistar-
dc.titleThe environmental pollutant and carcinogen 3-nitrobenzanthrone induces cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase in rat lung and kidney, thereby enhancing its own genotoxicity.en
dc.typeArticleen
dc.identifier.journalToxicologyen

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