title: Carcinogenic 3-nitrobenzanthrone but not 2-nitrobenzanthrone is metabolised to an unusual mercapturic acid in rats.
abstract: 3-Nitrobenzanthrone (3-NBA) is an extremely potent mutagen and suspect human carcinogen found in diesel exhaust. Its isomer 2-nitrobenzanthrone (2-NBA) has also been found in ambient air. These isomers differ in mutagenicity in Salmonella by 2-3 orders of magnitude. To identify their urinary metabolites and also to assess the assumed differences in their excretion, rats were dosed orally with 2mg/kg b.w. of either 2-NBA or 3-NBA. Their urine was collected for two consecutive days after dosage. Both LC-ESI-MS and GC-MS confirmed formation of the corresponding aminobenzanthrones (ABA). Excretion of these metabolites within the first day after dosing with 2- and 3-ABA amounted to 0.32±0.06 and 0.83±0.40% of the doses, respectively, while the excretion within the second day was by one order of magnitude lower. A novel mercapturic acid metabolite of 3-NBA was identified in urine by LC-ESI-MS as N-acetyl-S-(3-aminobenzanthron-2-yl)cysteine (3-ABA-MA) by comparison with the authentic standard. Its excretion amounted to 0.49±0.15 and 0.02±0.01% of dose within the first and second day after dosing, respectively. In contrast, no mercapturic acid was detected in the urine of rats dosed with 2-NBA. Observed difference in the mercapturic acid formation between 2- and 3-NBA is a new distinctive feature reflecting differences in the critical step of their metabolism, i.e., benzanthronylnitrenium ion formation that is intrinsically associated with biological activities of these two isomers. Moreover, 3-ABA-MA is a promising candidate biomarker of exposure to the carcinogenic 3-NBA.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Technology, Institute of Chemical Technology, Prague, Technická 1905, CZ-166 28 Prague, Czech Republic. linharti@vscht.cz
authors.forename: Igor
authors.initials: I
authors.lastname: Linhart
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Mráz
authors.forename: Iveta
authors.initials: I
authors.lastname: Hanzlíková
authors.forename: Alexandra
authors.initials: A
authors.lastname: Silhánková
authors.forename: Emil
authors.initials: E
authors.lastname: Frantík
authors.forename: Michal
authors.initials: M
authors.lastname: Himl
mesh_terms: D000111:Acetylcysteine / Q000652:urine*; D000393:Air Pollutants / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine*; D000818:Animals; D001551:Benz(a)Anthracenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine*; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000393:Air Pollutants; D001551:Benz(a)Anthracenes; D002273:Carcinogens; C117220:3-nitrobenzanthrone; D000111:Acetylcysteine