Identification of 5-(Deoxyguanosin-N 2-yl)- 1,2-dihydroxy-1,2-dihydro-6-aminochrysene as the Major DNA Lesion in the Mammary Gland of Rats Treated with the Environmental Pollutant 6-Nitrochrysene

• Published in: Chemical research in toxicology 2004-12, Vol.17 (12), p.1591-1599
• Main Authors: El-Bayoumy, Karam, Sharma, Arun K, Lin, Jyh-Ming, Krzeminski, Jacek, Boyiri, Telih, King, Leon C, Lambert, Guy, Padgett, William, Nesnow, Stephen, Amin, Shantu
• Format: Article
• Language: English
• Subjects: Animals; Carcinogens, Environmental - metabolism; Carcinogens, Environmental - toxicity; Chrysenes - chemistry; Chrysenes - metabolism; Chrysenes - toxicity; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - chemistry; DNA Adducts - chemistry; Environmental Pollutants - metabolism; Environmental Pollutants - toxicity; Female; Mammary Glands, Animal - chemistry; Mammary Glands, Animal - drug effects; Rats
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx049849+

The environmental pollutant 6-nitrochrysene (6-NC) is a potent carcinogen in several animal models including the rat mammary gland. 6-NC can be activated to intermediates that can damage DNA by simple nitroreduction, ring oxidation, or a combination of ring oxidation and nitroreduction. Only the first pathway (nitroreduction) has been clearly established, and DNA adducts derived from this pathway have been fully characterized in in vitro systems. We also showed previously that the second pathway, ring oxidation leading to the formation of the bay region diol epoxide of 6-NC, is not responsible for the formation of the major DNA adduct in the mammary gland of rats treated with 6-NC. Therefore, in the present study, we explored the validity of the third pathway that involves the combination of both ring oxidation and nitroreduction of 6-NC to form trans-1,2-dihydroxy-1,2-dihydro-6-hydroxylaminochrysene (1,2-DHD-6-NHOH-C). During the course of this study, we synthesized for the first time 1,2-DHD-6-NHOH-C, N-(deoxyguanosin-8-yl)-6-aminochrysene, and N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene. Incubation of 1,2-DHD-6-NHOH-C with calf thymus DNA resulted in the formation of three adducts. Upon LC/MS combined with 1H NMR analyses, the first eluting adduct was identified as 5-(deoxyguanosin-N 2-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene [5-(dG-N 2-yl)-1,2-DHD-6-AC], the second eluting adduct was identified as N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene, and the last was identified as N-(deoxyinosin-8-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene. We also report here for the first time that among those adducts identified in vitro, only 5-(dG-N 2-yl)-1,2-DHD-6-AC is the major DNA lesion detected in the mammary glands of rats treated with 6-NC.