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
Language English Country Ireland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
18329153
DOI
10.1016/j.tox.2008.01.018
PII: S0300-483X(08)00037-1
Knihovny.cz E-resources
- MeSH
- DNA Adducts metabolism MeSH
- Benz(a)Anthracenes pharmacology toxicity MeSH
- Cytochrome P-450 CYP1A1 drug effects metabolism MeSH
- Cytosol drug effects metabolism MeSH
- Enzyme Induction MeSH
- Microsomes, Liver drug effects metabolism MeSH
- Carcinogens pharmacology toxicity MeSH
- Rats MeSH
- Environmental Pollutants pharmacology toxicity MeSH
- Kidney drug effects metabolism MeSH
- Mutagens pharmacology toxicity MeSH
- NAD(P)H Dehydrogenase (Quinone) drug effects metabolism MeSH
- Lung drug effects metabolism MeSH
- Rats, Wistar MeSH
- Phosphorus Radioisotopes MeSH
- Mutagenicity Tests MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 3-aminobenzanthrone MeSH Browser
- 3-nitrobenzanthrone MeSH Browser
- DNA Adducts MeSH
- Benz(a)Anthracenes MeSH
- Cytochrome P-450 CYP1A1 MeSH
- Carcinogens MeSH
- Environmental Pollutants MeSH
- Mutagens MeSH
- NAD(P)H Dehydrogenase (Quinone) MeSH
- Phosphorus Radioisotopes MeSH
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.
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