Novel aminoarylcysteine adducts in globin of rats dosed with naphthylamine and nitronaphthalene isomers.
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-MS2 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.
['Linhart|Igor|I|0000-0003-2682-4326', 'Hanzlíková|Iveta|I|', 'Mráz|Jaroslav|J|0000-0002-9984-5593', 'Dušková|Šárka|Š|', 'Tvrdíková|Monika|M|', 'Vachová|Hana|H|']
D015057:1-Naphthylamine D015081:2-Naphthylamine D000111:Acetylcysteine D000818:Animals D015415:Biomarkers D003545:Cysteine D005914:Globins D007274:Injections, Intraperitoneal D008297:Male D009281:Naphthalenes D011485:Protein Binding D017208:Rats, Wistar
Carcinogens Biomarker Arylamines Nitroarenes Arylnitrenium ions Globin adducts