Identification of 5-(Deoxyguanosin-N2-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-N
详细信息 查看全文
- 作者：Karam El-Bayoumy ; Arun K. Sharma ; Jyh-Ming Lin ; Jacek Krzeminski ; Telih Boyiri ; Leon C. King ; Guy Lambert ; William Padgett ; Stephen Nesnow ; and Shantu Amin
- 刊名：Chemical Research in Toxicology
- 出版年：2004
- 出版时间：December 2004
- 年：2004
- 卷：17
- 期：12
- 页码：1591 - 1599
- 全文大小：198K
- 年卷期：v.17,no.12(December 2004)
- ISSN：1520-5010
文摘
The environmental pollutant 6-nitrochrysene (6-NC) is a potent carcinogen in several animalmodels including the rat mammary gland. 6-NC can be activated to intermediates that candamage DNA by simple nitroreduction, ring oxidation, or a combination of ring oxidation andnitroreduction. Only the first pathway (nitroreduction) has been clearly established, and DNAadducts derived from this pathway have been fully characterized in in vitro systems. We alsoshowed previously that the second pathway, ring oxidation leading to the formation of the bayregion diol epoxide of 6-NC, is not responsible for the formation of the major DNA adduct inthe mammary gland of rats treated with 6-NC. Therefore, in the present study, we exploredthe validity of the third pathway that involves the combination of both ring oxidation andnitroreduction 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 DNAresulted in the formation of three adducts. Upon LC/MS combined with 1H NMR analyses,the first eluting adduct was identified as 5-(deoxyguanosin-N2-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene [5-(dG-N2-yl)-1,2-DHD-6-AC], the second eluting adduct was identified asN-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene, and the last was identifiedas N-(deoxyinosin-8-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene. We also report here forthe first time that among those adducts identified in vitro, only 5-(dG-N2-yl)-1,2-DHD-6-AC isthe major DNA lesion detected in the mammary glands of rats treated with 6-NC.