title: Reductive metabolism of 1-nitropyrene accompanies deamination of cytosine.
abstract: 1-Nitropyrene (1-NP), a common environmental pollutant, is a mutagen and tumorigen. Nitroreduction is a major pathway by which 1-NP is metabolized. In order to study the mutational specificity of reductively activated 1-NP, single-stranded M13mp18 DNA was treated with tritium-labeled 1-nitrosopyrene in the presence of ascorbic acid to generate N-hydroxy-1-aminopyrene in situ. HPLC analysis of the treated DNA, following enzymatic digestion, showed that > 95% of tritium was located in one major adduct, N-(deoxyguanosin-8-yl)-1-aminopyrene. Transfection of these adducted M13 DNA in Escherichia coli indicated a dose-dependent reduction in viability with concomitant enhancement in mutagenesis in the lacZ gene fragment. Without SOS functions, the major type of mutation was C-->T transition (48%). Further studies have shown that cytosine deamination occurred during ascorbic acid-induced nitroreduction, which was likely responsible for the C-->T transitions. Deamination of cytosine alco occurred at a significant frequency when nitroreduction of either 1-NP or 1-nitrosopyrene was catalyzed by xanthine oxidase, a mammalian nitroreductase.
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs 06269.
authors.forename: S A
authors.initials: SA
authors.lastname: Malia
authors.forename: A K
authors.initials: AK
authors.lastname: Basu
mesh_terms: D001483:Base Sequence; D003596:Cytosine / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D003641:Deamination; D004926:Escherichia coli; D007763:Lac Operon / Q000187:drug effects; D008969:Molecular Sequence Data; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity; D010084:Oxidation-Reduction; D011721:Pyrenes / Q000378:metabolism* / Q000633:toxicity; D014969:Xanthine Oxidase / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D009153:Mutagens; D011721:Pyrenes; D003596:Cytosine; D004247:DNA; D014969:Xanthine Oxidase; D001616:beta-Galactosidase; C032668:1-nitropyrene