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S-(3-Aminobenzanthron-2-yl)cysteine in the globin of rats as a novel type of adduct and possible biomarker of exposure to 3-nitrobenzanthrone, a potent environmental carcinogen

  • Toxicokinetics and Metabolism
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An Erratum to this article was published on 20 May 2017

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Abstract

3-Nitrobenzanthrone (3-NBA), a potent environmental mutagen and carcinogen, is known to be activated in vivo to 3-benzanthronylnitrenium ion which forms both NH and C2-bound adducts with DNA and also reacts with glutathione giving rise to urinary 3-aminobenzanthron-2-ylmercapturic acid. In this study, acid hydrolysate of globin from rats dosed intraperitoneally with 3-NBA was analysed by HPLC/MS to identify a novel type of cysteine adduct, 3-aminobenzanthron-2-ylcysteine (3-ABA-Cys), confirmed using a synthesised standard. The 3-ABA-Cys levels in globin peaked after single 3-NBA doses of 1 and 2 mg/kg on day 2 to attain 0.25 and 0.49 nmol/g globin, respectively, thereafter declining slowly to 70–80% of their maximum values during 15 days. After dosing rats for three consecutive days with 1 mg 3-NBA/kg a significant cumulation of 3-ABA-Cys in globin was observed. 3-ABA-Cys was also found in the plasma hydrolysate. Herein, after dosing with 1 and 2 mg 3-NBA/kg the adduct levels peaked on day 1 at 0.15 and 0.51 nmol/ml plasma, respectively, thereafter declining rapidly to undetectable levels on day 15. In addition, sulphinamide adducts were also found in the exposed rats, measured indirectly as 3-aminobenzanthrone (3-ABA) split off from globin by mild acid hydrolysis. Levels of both types of adducts in the globin samples parallelled very well with 3-ABA/3-ABA-Cys ratio being around 1:8. In conclusion, 3-ABA-Cys is the first example of arylnitrenium-cysteine adduct in globin representing a new promising class of biomarkers to assess cumulative exposures to aromatic amines, nitroaromatics and heteroaromatic amines.

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  • 20 May 2017

    An erratum to this article has been published.

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Acknowledgements

The study was supported by Ministry of Health of the Czech Republic-DRO (National Institute of Public Health-NIPH, IN 75010330) and University of Chemistry and Technology, Prague, Program of long-term development. Purchase of the principal analytical instrument, Orbitrap Q Exactive mass spectrometer, was supported by European Regional Development Fund (ERDF), Integrated Operational Programme Reg. No. CZ.1.06/3.2.01/11.08435. Skilled technical assistance of M. Tvrdíková, L. Dabrowská, H. Chrástecká, and R. Vajtrová is greatly appreciated.

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Authors and Affiliations

  1. Department of Organic Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, Prague, Technická 5, 166 28, Prague, Czech Republic

    Igor Linhart

  2. National Institute of Public Health, Prague, Šrobárova 48, 10042, Prague, Czech Republic

    Iveta Hanzlíková, Jaroslav Mráz & Šárka Dušková

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  1. Igor Linhart
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  2. Iveta Hanzlíková
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  3. Jaroslav Mráz
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  4. Šárka Dušková
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Correspondence to Igor Linhart.

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An erratum to this article is available at https://doi.org/10.1007/s00204-017-1991-0.

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Linhart, I., Hanzlíková, I., Mráz, J. et al. S-(3-Aminobenzanthron-2-yl)cysteine in the globin of rats as a novel type of adduct and possible biomarker of exposure to 3-nitrobenzanthrone, a potent environmental carcinogen. Arch Toxicol 91, 3317–3325 (2017). https://doi.org/10.1007/s00204-017-1943-8

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