title: 3-aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone, induces biotransformation enzymes in rat kidney and lung.
abstract: 3-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.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic. stiborov@natur.cuni.cz
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
authors.forename: Helena
authors.initials: H
authors.lastname: Dracínská
authors.forename: Markéta
authors.initials: M
authors.lastname: Martínková
authors.forename: Jana
authors.initials: J
authors.lastname: Mizerovská
authors.forename: Jirí
authors.initials: J
authors.lastname: Hudecek
authors.forename: Petr
authors.initials: P
authors.lastname: Hodek
authors.forename: Jirí
authors.initials: J
authors.lastname: Liberda
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
mesh_terms: D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism* / Q000494:pharmacology*; D001711:Biotransformation; D002274:Carcinogens, Environmental / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D018736:DNA Adducts; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C475568:3-aminobenzanthrone; D001551:Benz(a)Anthracenes; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C117220:3-nitrobenzanthrone