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.
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Schmeiser, Heinz H.
Phillips, David H.
Arlt, Volker M.
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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.
CitationToxicology 2008, 247 (1):11-22
SponsorsThis 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).
- Induction of biotransformation enzymes by the carcinogenic air-pollutant 3-nitrobenzanthrone in liver, kidney and lung, after intra-tracheal instillation in rats.
- Authors: Mizerovská J, Dračínská H, Frei E, Schmeiser HH, Arlt VM, Stiborová M
- Issue date: 2011 Feb 28
- 3-aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone, induces biotransformation enzymes in rat kidney and lung.
- Authors: Stiborová M, Dracínská H, Martínková M, Mizerovská J, Hudecek J, Hodek P, Liberda J, Frei E, Schmeiser HH, Phillips DH, Arlt VM
- Issue date: 2009 May 31
- The environmental pollutant and carcinogen 3-nitrobenzanthrone and its human metabolite 3-aminobenzanthrone are potent inducers of rat hepatic cytochromes P450 1A1 and -1A2 and NAD(P)H:quinone oxidoreductase.
- Authors: Stiborová M, Dracínská H, Hájková J, Kaderábková P, Frei E, Schmeiser HH, Soucek P, Phillips DH, Arlt VM
- Issue date: 2006 Aug
- Environmental pollutant and potent mutagen 3-nitrobenzanthrone forms DNA adducts after reduction by NAD(P)H:quinone oxidoreductase and conjugation by acetyltransferases and sulfotransferases in human hepatic cytosols.
- Authors: Arlt VM, Stiborova M, Henderson CJ, Osborne MR, Bieler CA, Frei E, Martinek V, Sopko B, Wolf CR, Schmeiser HH, Phillips DH
- Issue date: 2005 Apr 1
- 3-aminobenzanthrone, a human metabolite of the environmental pollutant 3-nitrobenzanthrone, forms DNA adducts after metabolic activation by human and rat liver microsomes: evidence for activation by cytochrome P450 1A1 and P450 1A2.
- Authors: Arlt VM, Hewer A, Sorg BL, Schmeiser HH, Phillips DH, Stiborova M
- Issue date: 2004 Aug