ToxSci Advance Access originally published online on May 4, 2007
Toxicological Sciences 2007 98(2):445-457; doi:10.1093/toxsci/kfm103
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Mutagenicity and DNA Adduct Formation by the Urban Air Pollutant 2-Nitrobenzanthrone
* Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
Department of Toxicology, German Institute of Human Nutrition, D-14558 Potsdam-Rehbruecke, Nuthetal, Germany
Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
Department of Applied Chemistry, Kanagawa Institute of Technology, 1030 Shimo-ogino, Atsugi-shi 243-0292, Kanagawa, Japan
1 To whom all correspondence should be addressed at Institute of Cancer Research, Section of Molecular Carcinogenesis, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. Fax: +44 20-8722-4052. E-mail: volker.arlt{at}icr.ac.uk.
Received February 15, 2007; accepted April 26, 2007
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Abstract |
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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 32P-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 (
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.
Key Words: 2-nitrobenzanthrone; 3-nitrobenzanthrone; air pollution; mutagenicity; DNA adducts; 32P-postlabeling.
2 Present address: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR.
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