3-aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone, induces biotransformation enzymes in rat kidney and lung.
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Schmeiser, Heinz H.
Phillips, David H.
Arlt, Volker M.
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Abstract3-aminobenzanthrone (3-ABA) is the metabolite of the carcinogenic air pollutant 3-nitrobenzanthrone (3-NBA). 3-ABA was investigated for its ability to induce cytochrome P450 1A1 (CYP1A1) and NAD(P)H:quinone oxidoreductase (NQO1) in kidney and lung of rats, and for the influence of such induction on DNA adduct formation by 3-ABA and 3-NBA. NQO1 is the enzyme that reduces 3-NBA to N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) and CYP1A enzymes oxidize 3-ABA to the same intermediate. When activated by cytosolic and and/or microsomal fractions isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney, both compounds generated the same DNA-adduct pattern, consisting of five adducts. When pulmonary cytosols isolated from rats that had been treated i.p. with 40 mg/kg bw of 3-ABA were incubated with 3-NBA, DNA adduct formation was up to 1.7-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. In contrast, no induction of NQO1 expression by 3-ABA treatment was found in the kidney. Incubations of 3-ABA with renal and pulmonary microsomes of 3-ABA-treated rats led to an increase of up to a 4.5-fold in DNA-adduct formation relative to controls. The stimulation of DNA-adduct formation correlated with a higher protein expression and activity of CYP1A1 induced by 3-ABA. These results show that by inducing lung and kidney CYP1A1 and NQO1, 3-ABA increases its own enzymatic activation as well as that of the environmental pollutant, 3-NBA, thereby enhancing the genotoxic and carcinogenic potential of both compounds.
CitationMutat. Res. 2009, 676 (1-2):93-101
SponsorsThis work was supported in part by the Grant Agency of the Czech Republic, grant 203/06/0329, the Ministry of Education of the Czech Republic, grants MSM0021620808 and 1M0505, the German Cancer Research Center 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
- 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: Stiborová M, Dracínská H, Mizerovská J, Frei E, Schmeiser HH, Hudecek J, Hodek P, Phillips DH, Arlt VM
- Issue date: 2008 May 2
- 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
- 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
- Identification of three major DNA adducts formed by the carcinogenic air pollutant 3-nitrobenzanthrone in rat lung at the C8 and N2 position of guanine and at the N6 position of adenine.
- Authors: Arlt VM, Schmeiser HH, Osborne MR, Kawanishi M, Kanno T, Yagi T, Phillips DH, Takamura-Enya T
- Issue date: 2006 May 1