Analysis of the Major RNA Adduct Derived from Aminophenylnorharman, a Novel Endogenous Mutagen and Carcinogen
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概要
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9-(4'-Aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), a novel endogenous mutagenic/ carcinogenic heterocyclic amine, is known to be a reaction product of 9H-pyrido[3,4-fo]indole (norharman) and aniline. The major APNH-DNA adduct has been reported to be 2'-deoxyguanosin-8-yl-aminophenylnorharman (dGuo-C8-APIMH). However, RIMA adducts may also be important. We here demonstrated formation of APIMH-RIMA adducts and conducted a structural analysis using various spectrometric approaches. When a reaction mixture of an ultimate mutagenic form of APIMH, N-acetoxy-APIMH, and guanosine (Guo) was subjected to LC-ESI/MS analysis, one peak, with a similar UV spectrum to dGuo-C8-APIMH, exhibited a molecular ion peak at m/z 541 along with a fragment peak at m/z 409, consistent with loss of a ribose moiety. From 1H-NMR analysis, its chemical structure was concluded to be N^4-(guanosin-8-yl)-9-(4'-aminophenyl)-9H-pyrido[3,4-Jb]indole (Guo-C8-APIMH). The same adduct was yielded in yeast tRNA incubated with N-acetoxy-APNH. Digestion of tRNA treated with N-acetoxy-APNH resulted in the appearance of one adduct spot visualized by the 32P-postlabeling method, corresponding to Guo-C8-APNHH. No spot was seen with tRIMA alone. Additional analysis of in vivo adduct formation in the livers of rats administered APNH at a concentration of 100 mg/kg revealed that several adduct spots, including one corresponded to Guo-C8-APIMH, were observed. The total adduct levels of APNH-RNA were 28 ± 13.3 (mean±SD) adducts per 10^6 nucleotides. Comparisons demonstrated six times higher levels of total APNH-RNA than total APNH-DNA adducts in the same rat liver samples. These results indicate that APNH-RNA might be a useful biomarker for exposure to APNH.
- 日本環境変異原学会の論文
- 2007-05-28
著者
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KAWAHARA Nobuo
Division of Pharmacognosy, Phytochemistry and Narcotics, National Institute of Health Sciences
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TOTSUKA Yukari
Cancer Prevention Division, National Cancer Center Research Institute
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SUGIMURA Takashi
Cancer Prevention Basic Research Project, National Cancer Center Research Institute
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Takamura-enya Takeji
Department Of Applied Chemistry Kanagawa Institute Of Technology
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Totsuka Yukari
Cancer Prevention Basic Research Project National Cancer Center Research Institute
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Nishigaki Rena
Cancer Prevention Basic Research Project, National Cancer Center Research Institute
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Wakabayash Keiji
Cancer Prevention Basic Research Project, National Cancer Center Research Institute
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Sugimura Takashi
Cancer Prevention Basic Res. Project National Cancer Center Res. Inst.
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Nishigaki Rena
Cancer Prevention Basic Research Project National Cancer Center Research Institute
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Wakabayash Keiji
Cancer Prevention Basic Research Project National Cancer Center Research Institute
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Sugimura Takashi
Cancer Prevention Basic Research Project National Cancer Center Research Institute
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Kawahara Nobuo
Division Of Pharmacognosy And Phytochemistry National Institute Of Health Sciences
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Totsuka Yukari
Cancer Prevention Basic Research Project, National Cancer Center Research Institute
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