title: Genotoxic activation of the environmental pollutant 3,6-dinitrobenzo[e]pyrene in Salmonella typhimurium umu strains expressing human cytochrome P450 and N-acetyltransferase.
abstract: 3,6-Dinitrobenzo[e]pyrene (DNBeP) is a potent mutagen identified in surface soil in two metropolitan areas of Japan. We investigated whether DNBeP can cause genotoxicity through any metabolic activation pathway in bacteria using the parental strain Salmonella enterica serovar Typhimurium (S. typhimurium) TA1535/pSK1002, nitroreductase (NR)-deficient strain NM1000, the O-acetyltransferase (O-AT)-deficient strain NM2000, bacterial O-AT-overexpressing strain NM2009, and bacterial NR- and O-AT-overexpressing strain NM3009 established in our laboratory. To further clarify the role of human cytochrome P450 (P450 or CYP) and N-acetyltransferase (NAT) enzymes in the bioactivation of DNBeP to genotoxic metabolites, we determined the genotoxicity of DNBeP using a variety of umu tester strains expressing human P450 and NAT enzymes. The dose-dependent induction of umuC by DNBeP was observed at concentrations between 0.01 and 1nM in the O-AT-expression strain, but not in the O-AT-deficient strain. In the CYP3A4-, CYP1A2-, CYP1A1-, and CYP1B1-expressing strains, DNBeP was found to be activated to reactive metabolites that cause the induction of umuC gene expression compared with the parent strain. The induction of DNBeP in the NAT2-expressing strain had a 10-fold lower concentration than that in the NAT1-expressing strain. Collectively, these results suggest that nitroreduction by human CYP1A2, CYP3A4, and CYP1A1 and O-acetylation by human NAT2 contributed to the genotoxic activation of DNBeP to its metabolites.
authors.affiliation: Departments of Applied Chemistry, Faculty of Science, Engineering, Kinki University, 3-4-1 Kowakae, Higashiosaka-shi, Osaka, Japan. oday@apch.kindai.ac.jp
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Oda
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Hirayama
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000123:Acetyltransferases / Q000096:biosynthesis* / Q000235:genetics; D001564:Benzo(a)pyrene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009601:Nitroreductases / Q000096:biosynthesis / Q000235:genetics; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D012989:Soil Pollutants / Q000378:metabolism / Q000633:toxicity*
chemical_list: D009153:Mutagens; D012989:Soil Pollutants; C068923:3,6-dinitrobenzopyrene; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; D009601:Nitroreductases; D000123:Acetyltransferases