The Formation of Substituted 1,N6-Etheno-2'-deoxyadenosine and 1,N2-Etheno-2'-deoxyguanosine Adducts by cis-2-Butene-1,4-dial, a Reactive Metabolite of Furan
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- 作者：Michael C. Byrns ; Choua C. Vu ; and Lisa A. Peterson
- 刊名：Chemical Research in Toxicology
- 出版年：2004
- 出版时间：December 2004
- 年：2004
- 卷：17
- 期：12
- 页码：1607 - 1613
- 全文大小：129K
- 年卷期：v.17,no.12(December 2004)
- ISSN：1520-5010
文摘
Furan is an environmental chemical that induces liver toxicity and tumor formation inrodents, leading to its classification as a probable human carcinogen. cis-2-Butene-1,4-dial,the metabolite considered responsible for furan's toxicological effects, is mutagenic in the Amesassay and reacts with 2'-deoxycytidine (dCyd), 2'-deoxyadenosine (dAdo), and 2'-deoxyguanosine(dGuo) to form previously characterized diastereomeric adducts. The initially formed dCydadducts are stable to rearrangement, while the dAdo and dGuo adducts are unstable andrearrange to form secondary products. On the basis of UV absorbance, fluorescence, 1H NMR,and mass spectral data, the rearrangement product of the dAdo adduct was identified as thesubstituted etheno-dAdo adduct, 1' '-[3-(2'-deoxy-
-D-erythropentafuranosyl)-3H-imidazo[2,1-i]purin-8-yl]ethane-2' '-al. The NMR characterization of the O-methyloxime derivative of thesecondary dGuo adduct, along with mass spectral and UV data on the underivatized adduct,allowed for its structural assignment as the substituted etheno-dGuo compound, 3-(2'-deoxy--D-erythropentafuranosyl)imidazo-7-(ethane-2' '-al)[1,2-
]purine-9-one. The characterizationof the primary and secondary products formed in the reaction of cis-2-butene-1,4-dial withnucleosides is important for understanding the mechanism of furan-induced carcinogenesis.These secondary adducts retain a reactive aldehyde with the potential to form cross-links andare likely to contribute significantly to furan's toxic and carcinogenic effects.
-D-erythropentafuranosyl)-3H-imidazo[2,1-i]purin-8-yl]ethane-2' '-al. The NMR characterization of the O-methyloxime derivative of thesecondary dGuo adduct, along with mass spectral and UV data on the underivatized adduct,allowed for its structural assignment as the substituted etheno-dGuo compound, 3-(2'-deoxy--D-erythropentafuranosyl)imidazo-7-(ethane-2' '-al)[1,2-]purine-9-one. The characterizationof the primary and secondary products formed in the reaction of cis-2-butene-1,4-dial withnucleosides is important for understanding the mechanism of furan-induced carcinogenesis.These secondary adducts retain a reactive aldehyde with the potential to form cross-links andare likely to contribute significantly to furan's toxic and carcinogenic effects.