title: Mutagenicity and DNA adduct formation by the urban air pollutant 2-nitrobenzanthrone.
abstract: 2-Nitrobenzanthrone (2-NBA) has recently been detected in ambient air particulate matter. Its isomer 3-nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. The highest mutagenic activity of 2-NBA tested in Salmonella typhimurium was exhibited in strain TA1538-hSULT1A1 expressing human sulfotransferase (SULT) 1A1. 2-NBA also induced mutations in Chinese hamster lung V79 cells expressing human N-acetyltransferase 2 or SULT1A1, but no mutagenicity was observed in the parental cell line. DNA adduct formation in vitro was examined in different human cell lines by thin-layer chromatography (32)P-postlabeling. Whereas 3-NBA formed characteristic DNA adducts in lung A549, liver HepG2, colon HCT116, and breast MCF-7 cells, 2-NBA-derived DNA adducts were only observed in A549 and HepG2 cells, indicating differences in the bioactivation of each isomer. The pattern of 2-NBA-derived DNA adducts in both cell lines consisted of a cluster of up to five adducts. In HepG2 cells DNA binding by 2-NBA was up to 14-fold lower than by 3-NBA. DNA adduct formation of 2-NBA was also investigated in vivo in Wistar rats treated with a single dose of 2, 10, or 100 mg/kg body weight (bw). No DNA adduct formation was detected at doses of up to 10 mg/kg bw 2-NBA, even though 3-NBA induced DNA adducts at a dose of 2 mg/kg bw. Only after administration of one high dose of 100 mg/kg bw 2-NBA was a low level of DNA adduct formation detected, and then only in lung tissue. Density functional theory calculations for both NBAs revealed that the nitrenium ion of the 3-isomer is considerably more stable ( approximately 10 kcal/mol) than that of the 2-isomer, providing a possible explanation for the large differences in DNA adduct formation and mutagenicity between 2- and 3-NBA.
authors.affiliation: Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom. volker.arlt@icr.ac.uk
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Gamboa da Costa
authors.forename: Jóhannes
authors.initials: J
authors.lastname: Reynisson
authors.forename: Takeji
authors.initials: T
authors.lastname: Takamura-Enya
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D015239:Arylsulfotransferase / Q000378:metabolism; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D002460:Cell Line; D002947:Cities; D006224:Cricetinae; D003412:Cricetulus; D018736:DNA Adducts; D005260:Female; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012485:Salmonella typhi / Q000187:drug effects
chemical_list: D000393:Air Pollutants; D001551:Benz(a)Anthracenes; D018736:DNA Adducts; D009153:Mutagens; C511206:N-hydroxy-2-aminobenzanthrone; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C117220:3-nitrobenzanthrone