A Metabolic Activation Mechanism of 7H-Dibenzo[c,g]carbazole via O-Quinone. Part 2: Covalent Adducts of 7H-Dibenzo[c,g]carbazole-3,4-dione with Nucleic
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- 作者：Weiling Xue ; Angela Siner ; Mark Rance ; Koka Jayasimhulu ; Glenn Talaska ; and David Warshawsky
- 刊名：Chemical Research in Toxicology
- 出版年：2002
- 出版时间：July 2002
- 年：2002
- 卷：15
- 期：7
- 页码：915 - 921
- 全文大小：148K
- 年卷期：v.15,no.7(July 2002)
- ISSN：1520-5010
文摘
7H-Dibenzo[c,g]carbazole (DBC) is a potent multispecies, multisite carcinogen present inthe environment. The metabolic activation pathways of DBC are not completely known. It ishypothesized that DBC may be metabolically activated by oxidation to the reactive Michaelacceptor o-quinones, which can form stable and depurinating DNA adducts. The synthesis ofDBC-3,4-dione has been previously reported by this research group. In the present article, wedescribe the synthesis and chemical structural elucidation of nine DBC-nucleic acid adductsproduced from reactions of DBC-3,4-dione with Ade, Cyt, 2'-deoxyguanosine (dGuo), 2'-deoxycytidine (dCyd), and Guo. Adducts were isolated from reaction mixtures by HPLC andanalyzed using MS including elemental compositions and collision-activated dissociation (CAD),1H NMR, and two-dimensional chemical shift correlation spectroscopy (COSY) NMR. Theadducts, 7-[3,4-dione-DBC-1-yl]-Ade, N4-[3,4-dione-DBC-1-yl]-Cyt, 5-[3,4-dione-DBC-1-yl]-Cyt,two conformational isomers of N2-[3,4-dihydroxy-DBC-1-yl]-dGuo, and two conformationalisomers of N2-[3,4-dihydroxy-DBC-1-yl]-Guo, were characterized. Two adducts from reactionsof DBC-3,4-dione with dCyd were identified by MS but not fully characterized by NMR due toinstability of the adducts. Under similar conditions, the reactions of DBC-3,4-dione with Guaand 2'-deoxyadenosine (dAdo) did not result in an identifiable adduct. Liver DNA adducts frommice treated topically with DBC-3,4-dione (100 
g) in dimethyl sulfoxide/acetone (15/85, 100L) were identified with 32P-postlabeling. The major adduct chromatographically matched oneof the adducts formed from livers of DBC-treated mouse (adduct 3) using identical conditions.
g) in dimethyl sulfoxide/acetone (15/85, 100L) were identified with 32P-postlabeling. The major adduct chromatographically matched oneof the adducts formed from livers of DBC-treated mouse (adduct 3) using identical conditions.