Novel aminoarylcysteine adducts in globin of rats dosed with naphthylamine and nitronaphthalene isomers
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TOXICOKINETICS AND METABOLISM
Novel aminoarylcysteine adducts in globin of rats dosed with naphthylamine and nitronaphthalene isomers Igor Linhart1 · Iveta Hanzlíková2 · Jaroslav Mráz2 · Šárka Dušková2 · Monika Tvrdíková2 · Hana Vachová1 Received: 6 June 2020 / Accepted: 10 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Novel aminonaphthylcysteine (ANC) adducts, formed via naphthylnitrenium ions and/or their metabolic precursors in the biotransformation of naphthylamines (NA) and nitronaphthalenes (NN), were identified and quantified in globin of rats dosed intraperitoneally with 0.16 mmol/kg b.w. of 1-NA, 1-NN, 2-NA and 2-NN. Using HPLC-ESI-MS 2 analysis of the globin hydrolysates, S-(1-amino-2-naphthyl)cysteine (1A2NC) together with S-(4-amino-1-naphthyl)cysteine (4A1NC) were found in rats given 1-NA or 1-NN, and S-(2-amino-1-naphthyl)cysteine (2A1NC) in those given 2-NA or 2-NN. The highest level of ANC was produced by the most mutagenic and carcinogenic isomer 2-NA (35.8 ± 5.4 nmol/g globin). The ratio of ANC adduct levels for 1-NA, 1-NN, 2-NA and 2-NN was 1:2:100:3, respectively. Notably, the ratio of 1A2NC:4A1NC in globin of rats dosed with 1-NA and 1-NN differed significantly (2:98 versus 16:84 respectively), indicating differences in mechanism of the adduct formation. Moreover, aminonaphthylmercapturic acids, formed via conjugation of naphthylnitrenium ions and/ or their metabolic precursors with glutathione, were identified in the rat urine. Their amounts excreted after dosing rats with 1-NA, 1-NN, 2-NA and 2-NN were in the ratio 1:100:40:2, respectively. For all four compounds tested, haemoglobin binding index for ANC was several-fold higher than that for the sulphinamide adducts, generated via nitrosoarene metabolites. Due to involvement of electrophilic intermediates in their formation, ANC adducts in globin may become toxicologically more relevant biomarkers of cumulative exposure to carcinogenic or non-carcinogenic arylamines and nitroarenes than the currently used sulphinamide adducts. Keywords Arylamines · Nitroarenes · Globin adducts · Arylnitrenium ions · Biomarker · Carcinogens
Introduction Aromatic amines (arylamines, A rNH2) have been extensively used as industrial chemicals such as intermediates in manufacturing of azo-dyes, pesticides, and rubber industry products (IARC 2012; Freeman, 2013). In spite of the effective regulation, occupational exposures to some of these products are still of concern. Exposures to arylamines Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02907-y) contains supplementary material, which is available to authorized users. * Igor Linhart [email protected] 1
Department of Organic Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague, Czech Republic
National Institute of Public Health, Prague, Šrobárova 48, 100 42 Prague, Czech Republic
2
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