title: The carcinogen 1-methylpyrene forms benzylic DNA adducts in mouse and rat tissues in vivo via a reactive sulphuric acid ester.
abstract: 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, N(2)-(1-methylpyrenyl)-2'-deoxyguanosine (MPdG) and N(6)-(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.
authors: Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
authors: Carolin
authors: C
authors: Bendadani
authors: Walter
authors: W
authors: Meinl
authors: Bernhard H
authors: BH
authors: Monien
authors: Gisela
authors: G
authors: Dobbernack
authors: Hansruedi
authors: H
authors: Glatt
mesh_terms: D000818:Animals; D015239:Arylsulfotransferase / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000737:chemistry / Q000494:pharmacology*; D018736:DNA Adducts / Q000737:chemistry*; D003839:Deoxyadenosines / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011721:Pyrenes / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013464:Sulfuric Acids / Q000737:chemistry
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D003839:Deoxyadenosines; C000597463:N(2)-(1-methylpyrenyl)-2'-deoxyguanosine; C000597464:N(6)-(1-methylpyrenyl)-2'-deoxyadenosine; D011721:Pyrenes; D013464:Sulfuric Acids; C102088:1-sulfooxymethylpyrene; C053035:1-methylpyrene; C065833:1-hydroxymethylpyrene; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C513290:SULT1A2 protein, human; D003849:Deoxyguanosine; C033158:sulfuric acid