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The carcinogen 1-methylpyrene forms benzylic DNA adducts in mouse and rat tissues in vivo via a reactive sulphuric acid ester

  • Genotoxicity and Carcinogenicity
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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.

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Abbreviations

DMSO:

Dimethylsulphoxide

dN:

2′-Deoxynucleoside(s)

MAK:

Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (Germany)

MPdA:

N 6-(1-methylpyrenyl)-2′-deoxyadenosine

MPdG:

N 2-(1-methylpyrenyl)-2′-deoxyguanosine

MRM:

Multiple reaction monitoring

1-SMP:

1-Sulphooxymethylpyrene

SULT:

Sulphotransferase

tg:

Hemizygous transgenic FVB/N mice carrying the human SULT1A1-SULT1A2 gene cluster in chromosome 9

UPLC–MS/MS:

Ultra-performance liquid chromatography coupled with tandem mass spectrometry

wt:

Wild-type FVB/N mice

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Author notes

  1. Gisela Dobbernack

    Present address: PharmaLex GmbH, Joseph-Meyer-Straße 13-15, 68167, Mannheim, Germany

Authors and Affiliations

  1. Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany

    Carolin Bendadani, Walter Meinl, Bernhard H. Monien, Gisela Dobbernack & Hansruedi Glatt

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  1. Carolin Bendadani
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  2. Walter Meinl
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Correspondence to Hansruedi Glatt.

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Bendadani, C., Meinl, W., Monien, B.H. et al. The carcinogen 1-methylpyrene forms benzylic DNA adducts in mouse and rat tissues in vivo via a reactive sulphuric acid ester. Arch Toxicol 88, 815–821 (2014). https://doi.org/10.1007/s00204-013-1182-6

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