The carcinogen 1-methylpyrene forms benzylic DNA adducts in mouse and rat tissues in vivo via a reactive sulphuric acid ester
| Autor: | Bernhard H. Monien, Carolin Bendadani, Walter Meinl, Gisela Dobbernack, Hansruedi Glatt |
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| Rok vydání: | 2013 |
| Předmět: |
Genetically modified mouse
Male Health Toxicology and Mutagenesis Mice Transgenic Toxicology Adduct Hydroxylation chemistry.chemical_compound DNA Adducts Mice Blood serum In vivo Animals Humans Rats Wistar Carcinogen Pyrenes Deoxyadenosines Chemistry Deoxyguanosine General Medicine Sulfuric Acids Arylsulfotransferase In vitro Rats Biochemistry Inactivation Metabolic Carcinogens Female DNA |
| Zdroj: | Archives of toxicology. 88(3) |
| ISSN: | 1432-0738 |
| Popis: | The common polycyclic aromatic hydrocarbon 1-methylpyrene is hepatocarcinogenic in the newborn mouse assay. In vitro studies showed that it is metabolically activated via benzylic hydroxylation and sulphation to a reactive ester, which forms benzylic DNA adducts, N2-(1-methylpyrenyl)-2′-deoxyguanosine (MPdG) and N6-(1-methylpyrenyl)-2′-deoxyadenosine (MPdA). Formation of these adducts was also observed in animals treated with the metabolites, 1-hydroxymethylpyrene and 1-sulphooxymethylpyrene (1-SMP), whereas corresponding data are missing for 1-methylpyrene. In the present study, we treated mice with 1-methylpyrene and subsequently analysed blood serum for the presence of the reactive metabolite 1-SMP and tissue DNA for the presence of MPdG and MPdA adducts. We used wild-type mice and a mouse line transgenic for human sulphotransferases (SULT) 1A1 and 1A2, males and females. All analyses were conducted using ultra-performance liquid chromatography coupled with tandem mass spectrometry, for the adducts with isotope-labelled internal standards. 1-SMP was detected in all treated animals. Its serum level was higher in transgenic mice than in the wild-type (p < 0.001). Likewise, both adducts were detected in liver, kidney and lung DNA of all exposed animals. The transgene significantly enhanced the level of each adduct in each tissue of both sexes (p < 0.01–0.001). Adduct levels were highest in the liver, the target tissue of carcinogenesis, in each animal model used. MPdG and MPdA adducts were also observed in rats treated with 1-methylpyrene. Our findings corroborate the hypothesis that 1-SMP is indeed the ultimate carcinogen of 1-methylpyrene and that human SULT are able to mediate the terminal activation in vivo. |
| Databáze: | OpenAIRE |
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