title: Role of ring oxidation in the metabolic activation of 1-nitropyrene.
abstract: Nitrated polycyclic aromatic hydrocarbons are wide-spread environmental pollutants that have been detected in photocopier toners, airborne particulates, coal fly ash, and diesel engine exhaust emissions. 1-Nitropyrene, a representative nitropolycyclic aromatic hydrocarbon present in diesel particulates, is a mutagen in Salmonella typhimurium and a tumorigen in laboratory animals. The activation of 1-nitropyrene to a bacterial mutagen has been attributed to nitroreduction; however, the metabolic pathways involved in its metabolism to a tumorigen are not known, but may involve nitroreduction, ring oxidation, or a combination of the two. In these experiments, we examined the importance of ring oxidation in the activation of 1-nitropyrene (99.85 to 99.98 percent 1-nitropyrene, 0.15 to 0.02 percent 1,3-, 1,6-, and 1,8-dinitropyrene by mass spectral analyses) to a mammalian-cell mutagen and carcinogen. Chinese hamster ovary cells were used to assess the mutagenicity of ring-oxidized 1-nitropyrene metabolites. In the absence of a rat liver 9,000 x g supernatant, 6-hydroxy-1-nitropyrene, 1-nitropyrene-9,10-oxide, and pyrene-4,5-oxide were the most mutagenic compounds tested. 3-Hydroxy-1-nitropyrene, 8-hydroxy-1-nitropyrene, and 1-nitropyrene-4,5-oxide were weaker mutagens, whereas pyrene and 1-nitropyrene were essentially nonmutagenic. The order of mutagenic potency with S9 was: 1-nitropyrene-4,5-oxide greater than 6-hydroxy-1-nitropyrene approximately 1-nitropyrene-9,10-oxide greater than 1-nitropyrene approximately 3-hydroxy-1-nitropyrene approximately 8-hydroxy-1-nitropyrene greater than pyrene approximately pyrene-4,5-oxide, with the last two compounds being nearly nonmutagenic. The epoxide hydrase inhibitor 1,2-epoxy-3,3,3-trichloropropane increased the mutation frequency fivefold. In addition, guinea pig liver microsomes and Aroclor-induced rat liver microsomes, which increased the formation of 1-nitropyrene-4,5-oxide and 1-nitropyrene-9,10-oxide, increased the mutagenic response. Incubation of 1-nitropyrene-4,5-oxide with calf thymus DNA resulted in the formation of three DNA adducts. A similar adduct pattern was observed when Chinese hamster ovary cells were incubated with the oxide. Inclusion of a nitroreductase, xanthine oxidase, in the in vitro incubations resulted in the formation of an additional adduct identified as N-(deoxyguanosin-8-yl)-1-aminopyrene. This adduct was not observed in Chinese hamster ovary cells treated with 1-nitropyrene-4,5-oxide. 1-Nitropyrene-9,10-oxide reacted with calf thymus DNA to give an adduct pattern similar to that observed with 1-nitropyrene-4,5-oxide. The distribution of adducts was not affected by conducting the reactions in the presence of xanthine oxidase.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock.
authors.forename: F A
authors.initials: FA
authors.lastname: Beland
mesh_terms: D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000187:drug effects; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D010084:Oxidation-Reduction; D011247:Pregnancy; D011721:Pyrenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D011721:Pyrenes; D004247:DNA; C032668:1-nitropyrene