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Carcinogenesis Advance Access published online on June 29, 2007
Carcinogenesis, doi:10.1093/carcin/bgm142
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Comparative Mutational Profiles of the Environmental Mammary Carcinogen, 6-Nitrochrysene and its Metabolites in a lacI Mammary Epithelial Cell Line

Joseph B. Guttenplan1,2, Zhong-lin Zhao1, Wieslawa Kosinska1, Robert G. Norman3, Jacek Krzeminski4, Yuan-Wan Sun5, Shantu Amin4 and Karam El-Bayoumy5,*

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, NY 10010
4 Department of Pharmacology
5 Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033

* Tel.: 717-531-1005, Fax: 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 metabolite(s), we have compared the previously determined mutational profile of 6-NC in rat mammary gland (T. Boyiri, et al., Carcinogenesis 25, (2004) 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 over 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 nitroreduction 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.

Received March 8, 2007; revised June 15, 2007; accepted June 16, 2007.


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