Carcinogenesis Advance Access originally published online on June 29, 2007
Carcinogenesis 2007 28(11):2391-2397; doi:10.1093/carcin/bgm142
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Comparative mutational profiles of the environmental mammary carcinogen, 6-nitrochrysene and its metabolites in a lacI mammary epithelial cell line
1 Department of Basic Sciences
2 Department of Epidemiology and Health Promotion, College of Dentistry
3 Department of Environmental Medicine, School of Medicine, New York University, New York, NY 10010, USA
4 Department of Pharmacology
5 Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA
* To whom correspondence should be addressed. Tel: +1 717 531 1005; Fax: +1 717 531 7072; Email: kelbayoumy{at}aol.com
The dietary and environmental agent, 6-nitrochrysene (6-NC) is a powerful mammary carcinogen and mutagen in rats. It is known to be metabolized by ring-oxidation, nitro-reduction and a combination of the two pathways. In order to determine the ultimate mutagenic metabolites, we have compared the previously determined mutational profile of 6-NC in rat mammary gland [T. Boyiri, et al. (2004) Carcinogenesis, 25, 637–643] with that of five of its known metabolites in the cII gene of lacI mammary epithelial cells in vitro. In vivo, 6-NC gives rise to three major mutations, AT > GC, AT > TA and GC > TA (in decreasing order) which comprise >70% of the mutations. The metabolite whose mutational profile was most similar to that of 6-NC in vivo was trans-1,2-dihydroxy-1,2-dihydro-N-hydroxy-6-aminochrysene (1,2-DHD-6-NHOH-C) which arises from both ring-oxidation and nitro-reduction. However, metabolites arising from either ring-oxidation or nitro-reduction alone exhibited some similarities to mutational profile of 6-NC. These results, taken in conjunction with previous data showing that the major DNA adducts in mammary tissue of rats treated with 6-NC are products of the reaction of 1,2-DHD-6-NHOH-C with guanine and adenine, make a strong case that 1,2-DHD-6-NHOH-C is the ultimate genotoxic metabolite from 6-NC.
Abbreviations: 6-AC, 6-aminochrysene; 1,2-DHD-6-AC, 1,2-dihydroxy-6-aminochrysene; 1,2-DHD-6-NHOH-C, trans-1,2-dihydroxy-1,2-dihydro-N-hydroxy-6-aminochrysene; 1,2-DHD-6-NC, 1,2-dihydro-1,2-dihydroxy-6-nitrochrysene; MEC, mammary epithelial cell; MS, mutational spectrum; N-OH-6-AC, N-hydroxy-6-aminochrysene; 6-NC, 6-nitrochrysene; PCR, polymerase chain reaction
Received March 8, 2007; revised June 15, 2007; accepted June 16, 2007.