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.
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.
Stiborová
Marie
M
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic. stiborov@natur.cuni.cz
Dracínská
Helena
H
Mizerovská
Jana
J
Frei
Eva
E
Schmeiser
Heinz H
HH
Hudecek
Jirí
J
Hodek
Petr
P
Phillips
David H
DH
Arlt
Volker M
VM
D000818:Animals; D001551:Benz(a)Anthracenes / Q000494:pharmacology* / Q000633:toxicity; D002273:Carcinogens / Q000494:pharmacology* / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects* / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004785:Environmental Pollutants / Q000494:pharmacology / Q000633:toxicity; D004790:Enzyme Induction; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology* / Q000633:toxicity; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects* / Q000378:metabolism; D010761:Phosphorus Radioisotopes; D051381:Rats; D017208:Rats, Wistar
C475568:3-aminobenzanthrone; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D018736:DNA Adducts; D004785:Environmental Pollutants; D009153:Mutagens; D010761:Phosphorus Radioisotopes; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C117220:3-nitrobenzanthrone